Developing new therapies for Neuronal Ceroid Lipofuscinoses (NCL) commonly known as Batten disease BATCure Project Report

Project achievements For the best chance of success, in any rare disease, and Progress has been made in the areas of drug Batten disease is no exception, the basis for any future discovery and the development of gene therapy treatment must be based on science driven research of approaches for CLN3, CLN6 & CLN7 disease. The the highest quality. BATCure was designed to work in group have utilised new technologies in science and this way - to bring together a talented, diverse group diagnosis to great effect. These results are already with the necessary skills and expertise to offer a novel emerging in scientific publications and will continue strategic and integrated approach to a set of very to do so over the next few years. complex diseases. “As a charity, being part of BATCure has allowed us to “I truly enjoy working with the top researchers from bring the family voice to a major research project. It Batten disease all around Europe who are devoted to developing has provided vital resources for us to strengthen our treatments for Batten disease. My role within the project links with other Patient Organisations in Europe and The Neuronal Ceroid Lipofuscinoses (NCL), commonly Professor Sara Mole, UCL, followed a clear path with a is to provide financial, contractual and administrative worldwide, patients, their families and the professionals known as Batten disease, are a group of devastating multifaceted integrated approach to the problem. support and to ensure the timely delivery of all the who care for them.” life-limiting neurodegenerative diseases affecting “I put together the BATCure project consortium and results. Significant progress has been achieved. Heather Band, Scientific Officer, BDFA children and young people for which, at present, there acted as the overall Coordinator. In this role I ensured Evghenia Scripnic, European Project Manager is no cure. that the project proceeded as planned to achieve “At BATCure we believe that we have taken science This disease encompasses a progressive loss of its aims. We have exceeded expectations with some Young scientists have participated contributing to driven research forward for the benefit of all those physical and mental abilities that includes visual exciting new science discovered along the way. All their continued involvement in rare disease research. affected by Batten disease. Our work on CLN3, CLN6 and impairment and blindness, severe epileptic seizures partners met regularly to share and discuss progress. One of the highlights was hosting NCL2018, the CLN7 disease has improved our understanding of all that are difficult to control, involuntary muscle spasms, Over the 3 years we have developed excellent working biennial international scientific meeting. aspects of the disease from basic research to improved speech loss and the deterioration of motor skills. relationships and I know that collaborations will diagnosis & clinical outcomes. We have worked continue beyond the end of this award. It has been a lot “Cooperation, discussions and exchange of ideas, efficiently together and have long-term ambitions for of hard work but something that we will be drawing on during the regular meetings and at international NCL research.” Changing the outcomes for those in our research for many years to come.” conferences between partners were inspiring.” Professor Sara Mole, Project Coordinator, UCL affected by Batten disease Dr. Stephan Storch, UKE, Hamburg Professor Sara E. Mole, BATCure Coordinator and Batten disease is a rare neurological disease with Professor in Molecular Cell Biology at UCL “My laboratory was new to Batten disease research. only 1-2 thousand new cases being diagnosed Joining BATCure was challenging and at the same worldwide each year. This presents a particular set of Patient involvement time encouraging, as metabolism was never previously For any BATCure enquiries, please challenges when working towards finding successful associated with Batten disease. The opportunity to contact Sara Mole, Project Leader treatments and ultimately a cure. As with many A ground-breaking addition to this project was collaborate with widely reputed Batten disease experts +44 (0) 20 7679 7257 rare diseases the disease is not well known from a including the patient voice as central to all the work within the UK and the rest of Europe brought to our [email protected] general clinical or public perspective. It is a complex of the consortium, and the UK Batten Disease Family group the new dimension of translational research. disease and in order to develop treatments requires a Association (BDFA) was invited to participate to Thanks to this experience, we have now secured further www.batcure.eu BATCure BAT_Cure multidisciplinary approach to maximise the chances represent all those affected by this devastating disease. funding to investigate other metabolic aspects of Batten of success. disease. This has now become a new research line BATCure has received funding from the European Union’s We are pleased to present the achievements of Horizon 2020 research and innovation programme under BATCure focused on developing therapeutic BATCure, featuring the diverse and different 14 within my laboratory.” grant agreement No 666918 Dr. Juan Bolanos, USAL options for three types of the disease CLN3, CLN6 partners, from 7 countries, involved in the project over and CLN7 disease. The BATCure consortium led by the past 3 years. One of the aims for the work of my Laboratory was to use yeast as the BATCure is the largest research project that the BDFA has been involved simplest cell model of a human disease. We made new yeast strains that with and we were delighted to take a leading role in the project, ensuring carry mutations in their ‘CLN3’ gene (called btn1) and used these to look that the voice of patients and affected families is central a major research at whether removing any of the other 5000 yeast genes makes the yeast initiative. grow better or worse. This gave us an insight into what is happening at a cellular level in the disease, which pathways are most important and In the first 2 years, Laura Codd, the BATCure Project Administrator whether they can be used to offset the effects of disease, as many of these worked to establish links between the consortium, patients and their genes work the same way in us. families and over 20 Patient Organisations and Foundations worldwide. The BDFA’s work including managing communication of the project We have begun to test whether manipulating these has the same effect news, organising laboratory open days, developing resources, raising in mammalian cells or in zebrafish, with Dr Claire Russell at the Royal Heather Band and Laura Codd at the BDFA awareness and disseminating the project results. Veterinary College (RVC). In collaboration with our partners at UCL we designed and delivered We screened drug libraries in our Batten disease yeast model to see our online patient survey, in 10 languages over 15 countries within the which drugs make the yeast grow better. The most promising compounds, European Union. The survey focused on four main areas identified as the along with many new compounds synthesised at the Latvian Institute for most important to families. Issues around diagnosis, access to quality Professor Sara E. Mole, Professor in Organic Synthesis, were tested further in the yeast strains and human information on research, participation in the International disease Molecular Cell Biology at The Mole cells that model Batten disease. The most promising of these compounds registry and to gain families’ thoughts on potential barriers to taking part Laboratory, UCL MRC Laboratory for are now being tested in zebrafish. in clinical trials. Molecular Cell Biology We looked at changes in the metabolism of yeast and patient cells with The response exceeded our expectations and the results are available AcureOmics. We now have a better understanding of what CLN3 is doing on www.batcure.eu (family area). Thank you to all those who took part, within cells and have begun trying to understand what the different parts our fellow Patient Organisations for their help in promoting our work and of CLN3 are doing in yeast and in mammalian cells, with Dr Lloyd-Evans consortium members for their invaluable support. at Cardiff University. It was an opportunity for us to bring the impact of living day-to day with a diagnosis of Batten disease directly to researchers. It is wonderful to read Hands-on activities at the laboratory open in this report how family stories are an inspiration and on behalf of all day Kings College London. those affected we thank our BATCure partners for all their hard work over the past 3 years.

The project has exceed expectations, new and lasting collaborations Conclusions

Overall, the BATCure Family Survey was well received by the target audience and uptake was higher than expected. Communication, cooperation and support were excellent from all the consortium members and POs across the EU. The feedback from families affected by this devastating disease and have been made. The work of BATCure will continue beyond the end of those that represent them has been that BATCure is being very successful in providing a method for One of the first steps for our work as part of the BATCure project wasdirect engagement the by affected families in a major research project. The research has highlighted several key areas of focus for action going forward: the project, in June 2019. 1) Survey results on diagnosis were consistent with established data and, even noting the small base Developing new therapies for Neuronal Ceroid Lipofuscinoses (NCL) generation of zebrafish which exhibit the hallmarks of Batten disease. We sizes, showed some substantial differences and highlighted areas for improvement. The BDFA will commonly known as Batten disease continue to work with POs to monitor and promote best practice in diagnosis across the EU. It is currently exploring working with a leading UK centre on improving the diagnostic journey for CLN3 wanted the disease to be present in the embryo because we can quickly disease. BATCure Family Survey 2) Families’ understanding of research, preferred information formats and platforms and their Executive Summary preference for lay information from reliable professional sources will be incorporated into the final dissemination plans for the project. Areas of focus will include: Heather Band, BDFA • Update and improvement of the Family Area of the BATCure website. and easily test the most promising compounds, identified by our partners, • Discussions with partners to ensure the provision of lay information in all 10 languages. • Developing tailored dissemination events across the consortium.

3) A key action point emerging from the survey results will be for the BDFA and other POs to work with BATCure consortium members to develop a proposal on a way forward to address the from their work with cellular models of the disease. issues highlighted relating to the DEM-CHILD registry. Any initiative to increase awareness and participation has to be of benefit given the importance of participation to disease registries in a rare disease, such as Batten disease.

4) Feedback on clinical trials has emphasised the importance of quality of life and how important early consultation with affected families is for success, to ensure their voice is heard. The BATCure consortium is ideally placed to do this as it moves forward, taking the promising We generated zebrafish with mutations in CLN3, CLN6a and CLN7 research developmentsgenes from the project to clinical applications. What is NCL (Batten disease)? Neuronal Ceroid Lipofuscinoses (NCL) or Batten The BATCure Family Survey was an online survey There are several options to consider should families wish Authors and contributors disease is a life-limiting neurodegenerative disease for patients affected by Batten disease and their to explore ways of maximising the limited time available for which there is no cure. It causes a progressive families, providing them with an opportunity to There are grants and funds available to ensure that the work to share with their children. Contacting a charitable wish- CLN6 Disease, Variant Late-Infantile involved is affordable. An occupational therapist will consult granting organisation may lead to them being able to create loss of physical and mental abilities that includes inform and contribute to the EU-funded BATCure Heather Band - Scientific Officer, Batten Disease Family Association (BDFA) on all aspects of any adaptations and assist the family in some valuable and significant memories. have now been identified in late-infantile variant patients, DEM-CHILD Internationalresearch project Registry (www.batcure.eu). 49% of the sample are aware of the DEM-CHILD in collaboration with UCL. Research does not always go to plan Lauraand Codd - BATCure Administrator, BDFA blindness and seizures. The disease usually begins undertaking this process. all resulting in abnormal storage of proteins and lipids (fats) in childhood, and can occur as early as 6 months, or registry but this varies substantially by country, in neurons (nerve cells) and other cells. The cells cannot Professor Sara E Mole - BATCure Project Coordinator, University College London (UCL) Where can I get additional information and Are there any alternative names? as late as the teenage years or even adulthood.The DEM-CHILD InternationalThe survey Registry was set and up anddatabase securely hostedranging by from 74% in the UK to 17% in the support? function properly and this leads to the development of the Dr Angela Schulz - Department of Pediatrics, Universitätsklinikum Hamburg-Eppendorf (UKE) Will there be an impact on the child's education? symptoms associated with CLN6 disease. aims to collect and analyseUniversity data College from patients London with (UCL) and wasNetherlands. open Significant factors in driving awareness Dr Sander Smith - Principal Research Associate, Institute of Ophthalmology, UCL CLN6 disease, variant late-infantile was one of the first Demographics and diagnosis The gender split in the sample is 54% Male and 46% an NCL diagnosis. It is an important mechanism for Education will continue to be important for the child and family The BDFA offers support to any family member, friend, What is BATCure and the BATCure online from July to October 2017. It initiallywould went seem live to be the presence of POs and clinicians variant types of Neuronal Ceroid Lipofuscinosis (NCLs) to Evghenia Scripnic - European Project Manager, ERIO, UCL and there will be many aspects that require consideration professional or organisation involved in caring for a child with How are NCLs inherited? Female and the vast majorityFamily have Survey?CLN3 disease patients to participatein English in, and contributeand was subsequently to, research launched who in promote nine the registry and the presence of be identified and was originally termed early Juvenile Batten surprisingly these zebrafish models either had a very mild form of the and significant assistance from those around them. CLN6 disease or any other form of NCL throughout the UK. In total, 142 surveys were completed. These disease. (63%). This correlates with available incidence in the field. additional languages. Survey data was anonymised.clinical trial sites. Awareness is highest among those We provide informed guidance and assistance as well as Thanks also to all the patients and family providedmembers information who took the about time 162 to complete affected individualsthe BATCure survey and to Most forms of NCL are inherited as “autosomal recessive” data for the most commonBATCure NCLs. 6% is a of 3-year the sample research project which began affected by CLN2 - this may be linked to the CLN2 The Children and Families Act 2014 came into force in seeking to actively increase awareness of the disease and disorders. This is one of several ways that a trait, disorder, our partner Patient Organisations across the EU who helped achieve an excellent response rate by sharing the TM Enzyme Replacement Therapy trial since from 15 different European countries. As would be reported that the type ofin Batten January disease 2016 andis ‘unknown’ is funded under a EuropeanRegistries assist inWhat understanding were the disease, survey recruiting objectives? Brineura September 2014. The introduction of the 0-25 Education, facilitate future research to identify potential therapies and What are Neuronal Ceroid Lipofuscinoses (NCLs)? or disease can be passed down through families. An survey in their own countries. Health and Care Plan should help children, young people ultimately a cure. expected, levels of survey participation were highest – this figure is higher thanUnion expected, (EU) call: perhaps New Therapies for Rare Diseases.patients for clinical trials, tracking disease course, participating families may have had more active autosomal recessive disorder means that both copies of and families affected by NCL. Education, Health and Care the gene are abnormal (one inherited from each parent) with in countries with established Patient Organisations indicating challenges in diagnosis and provision safety monitoringThe and key supporting objectives research. of the surveyThe were to gain These refer to several different genetic life-limiting disease or no detectable disease. Therefore, they did not prove a good It involves ten research groups, three companies contact with clinicians and POs who have shared (EHC) Plans will gradually replace Statements of Special We organise conferences, workshops and are able to neither working properly. The disease does not depend on To find out more about the BATCure project or to request an electronic copy of the full survey report, please neurodegenerative diseases that share similar features. and well developed NCL disease communities. of diagnostic information to affected families. The collection of NCL patient data also assists in achieving Educational Needs. arrange connections with other affected families. The BDFA and a Patient Organisation (PO) across seven EU information from patients and their familiesinformation of their about the registry. Although the different forms of NCL are sometimes the sex of an individual. contact: Heather Band of residence also coordinate a Small Grants Scheme that can provide by country majority of the samplecountries. (86%) reported The goal only of onethe project is to advanceearlier the diagnosis understanding and proactive interventionsof current research for those and clinical trial described according to the age of the child at the onset , BDFA Scientific participation Officer Children who do not yet have a Statement will have a assistance for a range of needs. Survey Survey participation by country of residence child affected by Batten disease. affected, increasing quality of life and supportive care. of the disease, they are now better classified according to ([email protected]) development of new therapeutic options for patients development and to ascertain their readinessAmong to those aware of the registry, over half have statutory Education, Health and Care Needs assessment. What are the chances of inheriting CLN6 disease? Registry the gene identified as the cause e.g. CLN6 (gene) disease, -CHILD Internationalparticipate in studies and in future clinical trials,taken and part (59%). This figure is lower than would be An EHC Plan will be drawn up that is personalised to meet The BDFA has a Support and Advocacy Partner who is and their families living with CLN3, CLN6 or CLN7 of DEM fected CLN6 disease is inherited awareness variant late-infantile (age of onset), CLN3 (gene) disease, Unaf The median age of CLN3 disease diagnosis showsPrompted Prompted awarenesshighlight of any DEM-CHILD obstacles that would prevent themhoped from and mechanisms for converting awareness the education, health and care needs of the child. able to assist with many of the issues highlighted in this Unaffected Carrier as an autosomal model to test new drugs. A different approach was needed and so we 25 disease. juvenile (age of onset). Carrier Mother www.batcure.eu @BAT_Cure BATCure document and can discuss each of them in greater detail Father substantial variation by country. The median for Internationaldoing Registry so. into participation need to be explored. A real point recessive disorder, 20 19 It remains probable that many parents will continue to and on a more personal basis. which means that both 20 all CLN3 disease is 7.9yrs but the country medians The Batten Disease Family Association (BDFA)100 of concern is that around one fifth of those aware of need guidance, understanding and support when trying What causes NCL? chromosomes carry range from 6.5yrs in Finland to 10.3yrs in France. The results will be used to inform the work of thethe registry do not actually know whether or not they to navigate the process of statutory assessment and the The BDFA family folder can also provide further specific This project has received funding from the European Union’s Horizon 2020 research13 and innovation13 programme under grant agreement No 666918. are the representative PO in the project and are90 mutations in the CLN6 15 drawing up of the EHC Plan. information on CLN6 disease. The folder is free for all families Although base sizesresponsible are low, this for does ensuring suggest that clear the voice of patients BATCure consortium, key stakeholders and feedhave participated (21%). Since the first genes causing NCL were identified in 1995, gene. Therefore both 9 80 and available to professionals at a cost of £25. biological parents of a used our joint expertise to test the compounds in zebrafish where the % differences in the anddiagnostic affected journey families of ispatients heard in the project. A key directly into current59% and future exploitation plans over 400 mutations in 14 different genes have been described 10 6 6 70 The BDFA has expertise in this field and can be approached 5 4 4 that cause the various forms of NCL disease. Our cells contain child with this diagnosis depending on theirmechanism location. for this was through the design and for the project. Whilst BATCure focuses on CLN3,Over half of those who are aware of the registry by any parties seeking information or help. Please contact the BDFA Family Support and Advocacy will be carriers of the 1 60 49% % thousands of genes that are lined up along chromosomes. [VALUE]49% % [VALUE]42% Partner via our Freephone Helpline: 0800 046 9832 or 5 delivery of a family survey. CLN6 and CLN7 disease, the survey was widenedbut to have not participated or do not know if they Human cells contain 23 pairs of chromosomes (46 in total). disease but physically 50 The BDFA Educational Advisor may be able to provide email: [email protected] for further information unaffected by it. A child Looking at genetic diagnosis, the survey data include those affected by all forms of NCL. have participated, are not sure how to do so (54%). specific support and can be contacted via and to order a copy of the family folder. Most genes control the manufacture of at least one protein. 40 [email protected] born to parents who 0 suggests that the majority of those with Batten This suggests that there is scope for medical 0800 046 9832 email: These proteins have different functions and include enzymes 30 that act to speed up molecular chemical reactions. The both carry the autosomal amount of CLN3 was depleted in a transient way. disease have received a genetic diagnosis (82%). There are a number of local and national organisations that Affected professionals and POs to work together to improve Unaffected recessive mutation in Unaffected CLN6 20 NCLs are caused by abnormal genes, which are unable Non- Carrier Dr Clinton Monfries, the BATCure Researcher are also able to offer various forms of support and information Carrier Disease However, given that around one fifth of affected the CLN6 gene has a communication around registry access and the In what other ways can families be supported? to produce the required proteins. As a result, the cells do Affected 10 that will be relevant to families. The BDFA can provide details 25% (1 in 4) chance of individuals still either do not have one or do not participation process. not work properly and this leads to the development of 25% Country of residence Other NCLs and information about them. 50% 1 0 CLN2 only 25% inheriting the abnormal know if they have one, there still remains scope for CLN3 only The realities of caring for a child who has CLN6 disease symptoms associated with these diseases. All NCLs 3 improvement. can place enormous strain on a family, both physical and It may also be appropriate for a referral to be made to a local malfunctioning genes from both parents and developing in the aquaria at the RVC, which houses many Q1: Where do you live? emotional. It will impact upon all members in numerous children’s hospice service, as this can offer an additional Q1: Where do you live? (Base size: 142) Q11: Are you aware of this registry? What specifically causes CLN6 disease? CLN6 disease. ways and so being made aware that support is available to experienced and skilled source of holistic support. Base size: 142 Q11: Are you aware of this registry? Base size: All NCLs: 140, CLN3: 87, CLN2: 22, Other NCLs: 31 (Base size: All NCLs: 140, CLN3: 87, CLN2: 22, Other NCLs: 31) groups and individuals to help with the challenges that will They will have a 50% (1 in 2) chance of inheriting one be faced is important. This support extends to wider family The gene called CLN6 was identified as the cause of disease in 1997, and lies on chromosome 15. It encodes a protein abnormal gene, which would make them a carrier who is It was crucial to collaborate with partners such as UCL, TIGEM and members and step-relatives. unaffected by the disease. There is a 25% (1 in 4) chance zebrafish. whose function is not well understood. The protein is found in (prompted) Batten disease the cell in a structure called the Endoplasmic Reticulum (ER). of the child being born with two normal genes and therefore research into being non-affected (not a carrier). about current The information in this document is provided on the understanding that it is intended for general information purposes only, therefore This is a network of flattened tubular membranes similar to source of information Clinical trials the Batten Disease Family Association (BDFA) accepts no responsibility or liability for any other form of use, nor for circumstances arising the cell membrane, but inside the cell. One of the functions Main from any unintended or unsanctioned use. The BDFA have made every effort to ensure that the information provided is appropriate and of the ER is to assemble and package proteins that are then When it is known that both parents are carriers of the Current research Main source of information about current accurate at the time of publication. All decisions pertaining to care and treatment of an individual child should be managed, in conjunction abnormal gene, we refer to there being a 2 in 3 chance of with parents or legal guardians, by qualified professionals working for the appropriate health, educational and social services. transported to other parts of the cell or released outside Cardiff University to narrow down the numbers of candidate compounds, research into Batten disease (prompted) Patients/affected families were first asked which three of nine different factors would be most important to them of the cell. Another function makes the lipids (fats) that are a child being a carrier, once it is established that they are Some of the information contained in this leaflet is based upon chapters in "The Neuronal Ceroid Lipofuscinoses (Batten Disease) Just half of patients/affected families feel that they when making a decision about whether or not to take part in a clinical trial. These included both emotional and 2nd Edition” by Mole, Williams & Goebel (Eds), Oxford University Press 2011 and is used with permission. found in all membranes within the cell. unaffected by the disease. have the information they need about research practical considerations. A child’s quality of life (84%), treatment safety (71%) and potential side effects (67%) Contributors: BDFA Harriet Lunnemann QSW, Heather Band MSc, Barbara Cole QTVI, Matt Hobbs RN. Advisors: Professor Paul Gissen, Scientific and Medical Advisor, Professor Sara Mole, Scientific Advisor, The supervisory team consisted of Prof Ahad into NCL (50%). This figure varies substantially by Websites were found to be the top three factors in clinical trial consideration. These three factors stood out from others by Clare Beesley PhD, Scientific Advisor. With support from Bluepepper Designs. Many different mutations (mistakes) in the CLN6 gene www.bdfa-uk.org.uk country with the proportion who feel that they have (not social media) some distance. Nineteen qualitative © Batten Disease Family Association, 2017(r) Registered Charity in England and Wales Website:No. 1084908 www.bdfa-uk.org.uk - Scotland SCO47408 15% as they have the facilities to screen thousands of compounds. Of the the information they need highest in UK (63%) and Patient BDFA, The Old Library, Email: 4 Boundary [email protected] Road, Farnborough, Hants. GU14 6SF 0800 046 9832 Freephone Helpline: 0800 046 9832 lowest in the Netherlands (17%). Organisations In order to provide an opportunity for survey participants to describe their perceived barriers to trial in their own Freephone Helpline: Rahim, Prof Robert Harvey and Dr Jason Rihel (eg. BDFA) words, the survey also asked ‘What would definitely prevent you participating in a clinical trial?’ Freephone Helpline: 0800 046 9832

Among those patients and affected families who Doctor/Medical 43% responses were recorded. The main barriers emerged as a significant negative impact on quality of patient’s life Professionals www.bdfa-uk.org.uk do not feel that they have the information they 21% and negative side effects. These support the findings from the prompted question and reinforce the importance from UCL, Dr Claire Russell from RVC. first three compounds, two look promising as potential treatments, and need, there is a thirst for an even greater volume of that families place on quality of life issues when considering taking part in a clinical trial. information about research and in a format that is Other “Whether it is negative easier to understand. 21% for quality of life” “Side effects to Family member, POs were found to be the main source of information Norway we expect to test a further three or four compounds, continuing our be weighed up” about current research into Batten disease (43%) with 2 Family member, doctors/medical professionals the main source for a Germany further fifth of the sample (21%). This suggests that, Q8: Which of the following is your main source of if POs and doctors/medical professionalsQ8: Which are of able the following is your maininformation source of information about about the the current research taking place current research taking place into Batten disease? (Base size: 142) collaborations beyond BATCure. to work closely together to share relevant research into Batten disease? Base size: 142 information with families, then around two thirds of the patient population can be served this way. Having tested all of them on zebrafish lacking CLN3, we can then compare the results and test them in combination before selecting the most promising compound(s) to go forward for testing in Batten disease mouse models. I now have tried and trusted collaborators for future projects.

One of the first steps for our work as part of the BATCure project was the generation of zebrafish which exhibit the hallmarks of Batten disease. We wanted the disease to be present in the embryo becauseDr Claire we Russell, The Royal Veterinary College can quickly and easily test the most promising compounds, identified by our partners, from their work with cellular models of the disease.

We generated zebrafish with mutations in CLN3, CLN6a and CLN7 genes in collaboration with UCL. Research does not always go to plan and suprisingly these zebrafish models either had a very mild form of the disease or no detectable disease. Therefore, they did not prove a good model to test new drugs.

A different approach was needed and so we used our joint expertise to test the compounds in zebrafish where the amount of CLN3 was depleted in a transient way.

It was crucial to collaborate with partners such as UCL, TIGEM and Cardiff University to narrow down the numbers of candidate compounds, as they have the facilities to screen thousands of compounds. Of the Dr Clinton Monfries, the Researcher first three compounds, two look promising as potential treatments, and we expect to test a further three employed to complete the lab work in the or four compounds, continuing our collaborations beyond BATCure. aquaria at the RVC, which houses many zebrafish. Having tested all of them on zebrafish lacking CLN3, we can then compare the results and test them in combination before selecting the most promising compound(s) to go forward for testing in Batten The supervisory team consisted of Prof Ahad disease mouse models. Rahim, Prof Robert Harvey and Dr Jason Rihel from UCL, Dr Claire Russell from RVC. I now have tried and trusted collaborators for future projects.

Dr Claire Russell, The Royal Veterinary College

The aim of the gene therapy work was to develop new treatments for the The McKay lab were tasked with generating stem cells from Batten brain and for the eye in all three forms of Batten disease investigated disease patient cells, which had been previously taken with consent. From by BATCure. Building on our previous work on CLN6 gene therapy, we this we can “reprogramme” the cells to produce induced pluripotent managed to develop effective vectors and methods to restore CLN6 to the stem cells (iPSC) which have two unique properties that make them ideal brain and to the eye of CLN6-deficient mice, to normalise their lifespan to study Batten disease. and improve their mobility and their vision. 1) they can grow and divide indefinitely, meaning they are an As the mouse model of CLN3 disease does not have brain disease, we inexhaustible research resource only targeted their eyes in this project. We treated the retina (the layer of nerve cells lining the back wall inside the eye that senses light and 2) in the lab they have the capacity to mature into any functional cell sends signals to the brain) preventing the loss of nerve cells and the type in the human body. concomitant blindness. The combined evidence that CLN3 gene therapy can preserve nerve cells in the eye and that CLN6 gene delivery is Consequently, iPSC from a patient with Batten disease, can be made in effective, in the brains of CLN6 mice, makes us confident that CLN3 gene the lab to become brain neurons, glial cells (cells that protect neurons in The aim of the gene therapy work was to develop new treatments for the brain and for the therapy for the brain is also a realistic prospect. the brain) or even heart cells. eye in all three forms of Batten disease investigated by BATCure. Building on our previous work on CLN6 gene therapy, we managed to develop effective vectors and methods to Working on the CLN7 mouse model, we showed that gene therapy can The BATCure team at Professor We have now generated the largest repository of Batten disease restore CLN6 to the brain and to the eyeDr of SanderCLN6-deficient Smith andmice, to normalise their lifespan Tristan McKay’s Lab at MMU Dr Sophia-Martha kleine Holthaus preserve vision and mobility and prolong the animals’ survival. However, iPSC lines in the world and these cells are available to all academic and improve their mobility and their vision. (Professor in Stem Cell Biology) at UCL these results were less dramatic and less consistent than for CLN3 and researchers worldwide working to find a cure for Batten disease. As the mouse model of CLN3 disease does not have brain disease, we only targeted their CLN6 and there is an indication that there may be a risk of toxicity eyes in this project. We treated the retina (the layer of nerve cells lining the back wall associated with CLN7 gene therapy. It is important that the underlying In our laboratory we have been studying neural cells specified from iPSC inside the eye that senses light and sends signals to the brain) preventing the loss of nerve cause of this toxicity is identified before the treatment is tested in lines generated from CLN7 patients. We have embarked on an exciting cells and the concomitant blindness. The combined evidence that CLN3 gene therapy can the clinic, and we will continue to work with other members of the new study to map all the proteins expressed in CLN7 neural cells and preserve nerve cells in the eye and that CLN6 gene delivery is effective, in the brains of CLN6 mice, makes us confident that CLN3 gene therapy for the brain is also a realistic consortiumDr Sander to discover Smith and what Dr is Sophia happening-Martha in kleine this model. Holthaus at UCL compare them to unaffected neural cells, which will help us isolate prospect. groups of proteins that are either over or under-represented in CLN7 disease. Working on the CLN7 mouse model, we showed that gene therapy can preserve vision and mobility and prolong the animals’ survival. However, these results were less dramatic and We have created conditions that mimic the stresses that CLN7 neural cells less consistent than for CLN3 and CLN6 and there is an indication that there may be a risk of toxicity associated with CLN7 gene therapy. It is important that the underlying cause of are known to be under as the disease progresses. This approach, called this toxicity is identified before the treatment is tested in the clinic, and we will continue to “proteomics”, is capable of identifying and detecting changes in the work with other members of the consortium to discover what is happening in this model. quantities of proteins known to be involved in maintaining the health of cells in stressful conditions. BATCure has allowed us to create a hub for Batten disease gene therapy expertise across four institutes at University College London, drawing in additional funding from other sources to develop therapies for two (hopefully soon, three) further forms of Batten Some proteins function in the cell by sending signals to one another Disease. under certain conditions such as stress. Often these “signalling pathways” CLN6 gene therapy to the brain of CLN6-deficient mice (red, blue) can be manipulated with targeted drugs to prevent the cell from CLN6 gene therapy to the brain of CLN6-deficient micenclf (red, blue) doubles the Across the consortium as a whole, the knowledge and resources have been shared freely, doubles the lifespan compared with untreated CLN6 mice (Cln6 , lifespangrey). compared with untreated CLN6 mice (Cln6nclf, grey). damaging itself. We hope to use our proteomics data to discover a way most notably the exclusive CLN7 mice shared by the University of Hamburg, forging new After the treatment, the CLN6 animals live as long as mice without of preventing CLN7 neurons from self-inflicted damage under disease- collaborations that will continue as the remaining questions are resolved and new projects After the condition treatment, (wild the type, CLN6 wt, control, animals black) live as long as mice without the condition induced stress. start. (wild type, wt, control, black) Professor Tristan McKay

“BATCure has allowed us to create a hub for Batten disease gene therapy expertise across four institutes at University College London, drawing in additional funding from other sources to develop therapies for two (hopefully soon, three) further forms of Batten Disease.

Across the consortium as a whole, the knowledge and resources have been shared freely, most notably the exclusive CLN7 mice shared by the University of Hamburg, forging new collaborations that will continue as the remaining questions are resolved and new projects start.” MMU team with the BDFA hosted a laboratory open day for affected families and Dr. Sander Smith, Institute of Ophthalmology, UCL professionals in March 2017.

The McKay lab were tasked with generating stem cells from Batten disease patient cells, which had been previously taken with consent. From this we can “reprogramme” the cells to produce induced pluripotent stem cells (iPSC) which have two unique properties that make them ideal to study Batten disease.

1) they can grow and divide indefinitely, meaning they are an inexhaustible research resource 2) in the lab they have the capacity to mature into any functional cell type in the human body.

Consequently, iPSC from a patient with Batten disease, can be made in the lab to become brain neurons, cells that protect neurons in the brain (glial cells) or even heart cells. We have now generated the largest repository of Batten disease iPSC lines in the world and these cells are available to all academic researchers worldwide working to find a cure for Batten disease.

We ourselves have been studying neural cells specified from iPSC lines generated from CLN7 patients. We have embarked on an exciting new study to map all the proteins expressed in CLN7 neural cells and compare them to unaffected neural cells, which will help us isolate groups of proteins that are either over or under-represented in CLN7 disease. The BATCure team at Professor Tristan McKay’s Lab at MMU We have created conditions that mimic the stresses that CLN7 neural cells are known to be under as (Professor in Stem Cell Biology) the disease progresses. This approach, called “proteomics”, is capable of identifying and detecting changes in the quantities of proteins known to be involved in maintaining the health of cells in stressful conditions. Some proteins function in the cell by sending signals to one another under certain conditions such as stress. Often these “signaling pathways” can be manipulated with targeted drugs to prevent the cell from damaging itself. We hope to use our proteomics data to discover a way of preventing CLN7 neurons from self-inflicted damage under disease-induced stress. Professor Tristan McKay All forms of Batten disease have a profound impact upon the brain and for many years we have mostly focused Orphazymeon these effectsis based into Copenhagen, better understand Denmark, anddisease specialises in novel All forms of Batten disease have a profound impact upon the brain and for therapies for rare degenerative diseases. Our approach is based on many years we have mostly focused on these effects to better understand mechanisms in order to best directaugmentation therapies. of the However,naturally occurring it is now protective clear thatresponses Batten that occur disease mechanisms in order to best direct therapies. However, it is disease has effects outside thein brain. cells in Perhapsresponse tobest stress. known Disease example causes stress is the responses early in cells and now clear that Batten disease has effects outside the brain. Perhaps best so our approach is to find ways that could prevent or help correct these known example is the early impact of CLN1 disease upon the spinal cord. impact of CLN1 disease upon theevents. spinal cord. Studying pathological changes is the study of disease and is often We develop small molecule inducers of chaperones, such as HSP70, and referred to as the bridge between science and medicine and our work Studying pathological changesin is late the 2018 study we completed of disease a phase and isII/III often clinical referred trial in Niemann-Pick to as the focused on when changes occur in the spinal cord and Peripheral bridge between science and medicineDisease Type and C, ouranother work very focused rare lysosomal on when storage changes disease. occur Being part Nervous System (PNS) in mouse models of CLN3, CLN6 and CLN7 in the spinal cord and PNS in mouseof the BATCure models has of given CLN3, us invaluable CLN6 and experience CLN7 disease. and new This partners is in the Batten disease field. disease. This is especially important, as these three forms are caused by AcureOmicsAcureOmics used used metabolomics metabolomics to to mutations in transmembrane proteins. We will need to more precisely Orphazyme is based in Copenhagen, Denmark,especially and specialises important, in novel therapies as these three forms are caused by mutations in identifyidentify disturbed disturbed biochemical biochemical pathways pathways Orphazyme is based in Copenhagen, Denmark, and specialises in novel therapies We have characterized the stress responses using cells which mimic target therapies than in an enzyme deficient form of Batten disease like for rare degenerative diseases. Our approachtransmembrane is based on augmentation proteins. of the We will need to more precisely target therapies than in an inin CLN3, CLN3, CLN6 CLN6 and and CLN7 CLN7 diseases. diseases. This This for rare degenerative diseases. Our approach is based on augmentation of the a wide spectrum of clinical presentations for Batten disease, kindly CLN2 disease. naturally occurring protective responses that occur in cells in response to stress. knowledgeknowledge is is being being used used to to both both help help naturally occurring protective responses thatenzyme occur in deficientcells in response form to of stress. Batten provided disease by other like partnersCLN2 disease. in the BATCure consortium. Our studies have Disease causes stress responses in cells and so our approach is to find ways that assessassess and and design design novel novel treatments treatments that that Disease causes stress responses in cells and so our approach is to find ways that generated data that indicate a similar responsiveness of these model Our results show that spinal pathology occurs in all three forms, but this act to normalise the disturbed could prevent or help correct these events. cells as found in our work in other rare lysosomal storage diseases. act to normalise the disturbed could prevent or help correct these events.Our results show that spinal pathology occurs in all three forms, but this occurs to occurs to different extents and progresses at different rates according biochemical pathway. This work will to disease subtype. All follow a similar pattern with the nerve cell loss biochemical pathway. This work will While it is too early to tell whether this new knowledge has any potential “It was an incredible experience contribute to improving how the effect We develop small molecule inducers of chaperones,different such extents as HSP70, and and progresses in late at different rates according to disease subtype. All occurring late in disease, but this starts earlier in CLN6 and CLN7 mice contribute to improving how the effect We develop small molecule inducers of chaperones, such as HSP70, and in late in the treatment of patients with Batten disease, our work has generated “It wasand an incredibleI am immensely experience grateful and I am of ongoing treatment is monitored.” 20182018 we we completed completed a aphase phase II/III II/III clinical clinical trial trial in in Niemann Niemann-Pick-Pick Disease Disease Type Type C, C, than in CLN3 mice. In general, spinal pathology occurs at all levels of of ongoing treatment is monitored.” follow a similar pattern with thenew nerve scientific cell insight loss thatoccurring will aid futurelate inresearch disease, efforts but to thiscombat this immenselyfor the grateful funding for that the allowedfunding that anotheranother very very rare rare lysosomal lysosomal storage storage disease. disease. Being Being part part of of the the BATCure BATCure has has given given the cord in all three mouse models but is more severe at specific levels us invaluable experience and new partners instarts the Batten earlier disease in CLN6field. and CLN7devastating mice than group in CLN3of diseases. mice. In general, spinal pathology allowedme me to tocomplete complete my myPhD PhD in in this Dr Kate Bennett us invaluable experience and new partners in the Batten disease field. of the of the cord. In comparison we have found much less evidence for Dr Kate Bennett collaborativethis collaborative and inspiring and research inspiring occurs at all levels of the cord in all three mouse modelsNikolaj but H.T.is more Petersen, severe Sr. Science at Manager any pathological effects in the sensory PNS and it may be that we need to ProfessorProfessor Torbjörn Torbjörn Lundstedt Lundstedt WeWe have have characterized characterized the the stress stress responses responses specificusing using cells cells levelswhich which mimic ofmimic the a awide ofwide the cord. In comparison weSenior have Scientist found Raffaella much less Magnoni, evidence Orphazyme environment,research which environment, included whichworking on look further afield in the PNS. We did find evidence of storage material in AssociateAssociate Professor Professor Katrin Katrin Lundstedt Lundstedt- - spectrumspectrum of of clinical clinical presentations presentations for for Batten Batten disease, disease, kindly kindly provided provided by by other other mouseincluded models fromworking labs on in mouse both modelsHamburg the heart of CLN3 mice, which may underlie some of the defects seen in EnkelEnkel for any pathological effects in the sensory PNS and it may be that we need to look partnerspartners in in the the BATCure BATCure consortium. consortium. Our Our studies studies have have generated generated data data that that and London.from labs Bi-annual in both progressHamburg meetings and human CLN3 disease. indicate a similar responsiveness of these modelfurther cells asafield found in in theour workPNS. in We did find evidence of storage material in the heart of indicate a similar responsiveness of these model cells as found in our work in alwaysLondon. drove home Bi-annual that weprogress were all All forms of Batten disease have a profound impact upon the brain and for many other rare lysosomal storage diseases. Now that we know that spinal pathology is presentyears we in everyhave mostly form offocused Batten on these effects to better understand disease other rare lysosomal storage diseases. CLN3 mice, which may underlie some of the defects seen in human CLN3 disease. workingmeetings together always towards drove a common home that goal. disease, we can try to treat this and it will be mechanismsimportant to in test order whether to best direct therapies. However, it is now clear that Batten Meetingwe families were all of working affected together children at disease has effects outside the brain. Perhaps best known example is the early WhileWhile it it is is too too early early to to tell tell whether whether this this new new knowledge knowledge has has any any potential potential in in the the also directing gene therapy to the spinal cord will prove more effective Now that we know that spinal pathology is present in every form of Batten disease, conferencestowards and a hearingcommon goal.their Meeting experiences impact of CLN1 disease upon the spinal cord. treatmenttreatment of of patients patients with with Batten Batten disease, disease, our our work work has has generated generated new new scientific scientific than just treating the brain alone. really inspired and motivated me when I’d insightinsight that that will will aid aid future future research research efforts efforts to towe combat combat can thistry this devastatingto devastating treat this group group and of of it will be importantLeitat to has test contributed whether towards also the directing goals of the gene project through two main activities.families We of developedaffected and children at had a long day at the lab.” StudyingProfessor pathological Jon changes Cooper is the study of disease and is often referred to as the diseases.”diseases.” therapy to the spinal cord will Leitatprove has more contributed effectiveprovided towards new than theresearch just goals toolstreating of the such project as the special throughbrain antibodies two to other consortiumconferences members to help and to hearing their Nikolaj H.T. Petersen, Sr. Science Manager, Senior Scientist Raffaella Magnoni, bridge between science and medicine and our work focused on when changes occur Nikolaj H.T. Petersen, Sr. Science Manager, Senior Scientist Raffaella Magnoni, main activities. Weprogress developed their and research provided and ultimately new research to gain tools more such knowledge on Batten diseaseexperiences pathophysiology. really inspired and in the spinal cord and PNS in mouse models of CLN3, CLN6 and CLN7 disease. This is Orphazyme alone. All forms of Batten disease have a profound impact upon the brain and for many Orphazyme as special antibodiesOur tospecific other research consortium effort members has been focusedto help towardsto progress the discovery Charlott of newmotivated biomarkers Repschlager meby analysing when, PhD I’d student had a long especially important, as these three forms are caused by mutations in Professor Jon Cooper years we have mostly focused on these effects to better understand disease Marc at their research andurine ultimately samples to from gain patients. more knowledge We wanted on to Battenlook at diseasethe metabolites, proteinsday and at DNA the present lab.” in the transmembrane proteins. We will need to more precisely target therapies than in an mechanisms in order to best direct therapies. However, it is now clear that Batten AcureOmics used metabolomics to pathophysiology. Oururine specific to identify research differences effort in thathas beenmay be focused useful as towards markers for the disease in diagnosis, prognosis or enzyme deficient form of Batten disease like CLN2 disease. work in disease has effects outside the brain. Perhaps best known example is the early identify disturbed biochemical pathways Orphazyme is based in Copenhagen, Denmark,the discovery and specialises of newfollow biomarkers in-up. novel Among therapies by the analysing results, differences urine samples in the fromurine metabolites have been observed. It requires Barcelonapatients. We wantedfurther to look research at the to metabolites, confirm these. proteins and DNA present Charlott Repschlager impact of CLN1 disease upon the spinal cord. in CLN3, CLN6 and CLN7 diseases. This for rare degenerative diseases. Our approach is based on augmentation of the Our results show that spinal pathology occurs in all three forms, but this occurs to in the urine to identify differences in that may be useful as markers for naturally occurring protective responses that occur in cells in response to stress. PhD student different extents and progresses at different rates according to disease subtype. All knowledge is being used to both help the disease in diagnosis,Leitat had prognosis no previous or follow-up.experience Amongin research the on results, rare diseases, much less rare paediatric diseases, Studying pathological changes is the study of disease and is often referred to as the “It was an incredible experience and I am follow a similar pattern with the nerve cell loss occurring late in disease, but this assess and design novel treatments that Disease causes stress responses in cells anddifferences so our approach in the suchurine is asto metabolites Battenfind ways disease. thathave It beenrepresented observed. a scientific It requires challenge as well as opening up a new research field bridge between science and medicine and our work focused on when changes occur immensely grateful for the funding that starts earlier in CLN6 and CLN7 mice than in CLN3 mice. In general, spinal pathology allowed me to complete my PhD in this act to normalise the disturbed could prevent or help correct these events.further research toto confirm Leitat. We these. have been honoured to be surrounded by such expert scientists in the Batten disease in the spinal cord and PNS in mouse models of CLN3, CLN6 and CLN7 disease. This is At Cardiff university we used our expertise inoccurs how cellsat all withlevels Batten of the cord in all three mouse models but is more severe at collaborative and inspiring research research field and have learned a lot. The involvement of the collaborators went above and beyond especially important, as these three forms are caused by mutations in biochemical pathway. This work will disease communicate with each other comparedspecific to healthylevels of cells.the of the cord. In comparison we have found much less evidence environment, which included working on Leitat had no previous experience in research on rare diseases, much transmembrane proteins. We will need to more precisely target therapies than in an contribute to improving how the effect We develop small molecule inducers of chaperones, such asthe HSP70, scientific and activities. in late Communication between cells in an organ, likefor theany heartpathological for example, effects inis the sensory PNS and it may be that we need to look mouse models from labs in both Hamburg less rare paediatric diseases, such as Batten disease. It represented a enzyme deficient form of Batten disease like CLN2 disease. and London. Bi-annual progress meetings of ongoing treatment is monitored.” 2018 we completed a phase II/III clinical trial in Niemann-Pick Disease Type C, critical as it maintains the normal rhythm of thefurther heartbeat. afield in the PNS. We did find evidence of storage material in the heart of scientific challengeWe as intend well asto continueopening toup collaborate a new research closely, field as we to did Leitat. during these past 3 years, with UCL, University always drove home that we were all anotherMarc at work very in rareBarcelona lysosomal storage disease. Being part of the BATCure has given CLN3 mice, which may underlie some of the defects seen in human CLN3 disease. of Salamanca, Acuromics, The Royal Veterinary College and Universitaetsklinikum Hamburg-Eppendorf. Our results show that spinal pathology occurs in all three forms, but this occurs to working together towards a common goal. us invaluable experience and new partnersWe in have the Battenbeen honoured disease field.to be surrounded by such expert scientists in Using cells that our colleagues in BATCure provided a key finding Meeting families of affected children at It’s been a fulfilling and scientifically enriching relationship, with many encouraging results being different extents and progresses at different rates according to disease subtype. All Dr Kate Bennett the Batten disease research field and have learned a lot. The involvement is that CLN3 is providing an important role inNow maintaining that we know the ionic that spinal pathology is present in every form of Batten“It was disease, an incredible experienceconferences and Iand am hearing their experiences achieved, free sharing of scientific resources and profitable technical discussions. follow a similar pattern with the nerve cell loss occurring late in disease, but this Professor Torbjörn Lundstedt of the collaborators went above and beyond the scientific activities. balance of the lysosome, a part of the cell responsiblewe can try forto treat recycling this and and it will be important to test whether also directingimmensely gene grateful for thereally funding inspired that and motivated me when I’d We have characterized the stress responses using cells which mimic a wide starts earlier in CLN6 and CLN7 mice than in CLN3 mice. In general, spinal pathology Associate Professor Katrin Lundstedt- We intend to continue to collaborate closely, as we did during these communicating nutritional balance with the resttherapy of the to cell.the spinal We have cord alsowill prove more effective than just treating theallowed brain me to complete myhad PhD a long in thisday at the lab.” spectrum of clinical presentations for Batten disease, kindly provided by other occurs at all levels of the cord in all three mouse models but is more severe at collaborative and inspiring research Enkel past 3 years, with UCL,Marc UniversityMasa, Diagnostic of Salamanca, Working Group Acuromics, Manager, The LEITAT Royal identified some compounds that help cells strugglingalone. to specific levels of the of the cord. In comparison we have found much less evidence environment, which includedCharlott working Repschlager on , PhD student partners in the BATCure consortium. Our Veterinarystudies have College generated and Universitaetsklinikum data that Hamburg-Eppendorf. Professor Jon Cooper do this. for any pathological effects in the sensory PNS and it may be that we need to look mouse models from labs in both Hamburg indicate a similar responsiveness of theseIt’s model been cells a fulfilling as found and in scientifically our work in enriching relationship, with many and London. Bi-annual progress meetings further afield in the PNS. We did find evidence of storage material in the heart of other rare lysosomal storage diseases. encouraging results being achieved, free sharing of scientific resources always drove home that we were all CLN3 mice, which may underlieDr someEmyr of Lloyd-Evans the defects seen in human CLN3 disease. Guillermo Quintás at work in Valencia and profitable technical discussions. working together towards a common goal. School of Biosciences, Cardiff University Meeting families of affected children at While it is too early to tell whether this new knowledge has any potential in the Marc Masa, Diagnostic Working Group Manager Now that we know that spinal pathology is present in every form of Batten disease, conferences and hearing their experiences treatment of patients with Batten disease, our work has generated new scientific really inspired and motivated me when I’d LEITAT we can try to treat this and it will be important to test whether also directing gene insight that Guillermowill aid future Quintás research at work efforts in to combat this devastating group of therapy to the spinal cord will prove more effective than just treating the brain had a long day at the lab.”

alone. diseases.” Valencia Charlott Repschlager, PhD student Nikolaj H.T. Petersen, Sr. Science Manager, Senior Scientist Raffaella Magnoni, Professor Jon Cooper

Orphazyme Leitat has contributed towards the goals of the project through two main activities. We developed and provided new research tools such as special antibodies to other consortium members to help to progress their research and ultimately to gain more knowledge on Batten disease pathophysiology. Our specific research effort has been focused towards the discovery of new biomarkers by analysing Marc at urine samples from patients. We wanted to look at the metabolites, proteins and DNA present in the work in urine to identify differences in that may be useful as markers for the disease in diagnosis, prognosis or follow-up. Among the results, differences in the urine metabolites have been observed. It requires Barcelona further research to confirm these.

Leitat had no previous experience in research on rare diseases, much less rare paediatric diseases, such as Batten disease. It represented a scientific challenge as well as opening up a new research field to Leitat. We have been honoured to be surrounded by such expert scientists in the Batten disease research field and have learned a lot. The involvement of the collaborators went above and beyond the scientific activities.

We intend to continue to collaborate closely, as we did during these past 3 years, with UCL, University of Salamanca, Acuromics, The Royal Veterinary College and Universitaetsklinikum Hamburg-Eppendorf. It’s been a fulfilling and scientifically enriching relationship, with many encouraging results being achieved, free sharing of scientific resources and profitable technical discussions.

Marc Masa, Diagnostic Working Group Manager, LEITAT

Guillermo Quintás at work in Valencia Untreated FDA#HIT1 FDA#HIT2

Cells

- / - CLN3 Our laboratory is focused on the study of lysosomal storage disorders (LSDs) and in the development of innovative therapeutics using cell-based high content imaging approaches for drug discovery. Together with other BATCure project partners (Sara Mole at UCL), our laboratory Compound hits reducing the accumulation of lipids in a cellular model of developed assays in a variety of cellular models of Batten disease to identify compounds with CLN3. CLN3-depleted cells were treated with DMSO (untreated condition), the potential to treat the disease. or with compound 1 or 2. Cells were fixed and stained and imaged.

We developed a cell-based primary assay, to measure lipid accumulation, a marker for disease, in human cells depleted of CLN3 and CLN7. We have identified FDA-approved compounds able We have conductedto reduce this studies accumulation on theas shown molecular opposite. basis of CLN7 disease Our laboratory is focused on the study of lysosomal storage disorders (LSDs) and in the development of innovative therapeutics using cell- using a mouseIn collaborationmodel for with the partners disease. at the OSI In led this by Profmodel. Maija theDambrova CLN7, we proteinare using compound is truncated leadinghits as reference to a non-functional structures to generate protein. analogs with improved potency in our assay. By testing based high content imaging approaches for drug discovery. Together these hits in secondary assays aimed to determine the mechanism of action, we found that lipid with other BATCure project partners (Sara Mole at UCL), our laboratory clearance might be mediated by activation of lysosomal and autophagic activity (the process developed assays in a variety of cellular models of Batten disease to We focused onthat the allows main for the question orderly degradation why andthe recycling loss ofof cellularthe CLN7 components) protein. leads identify compounds with the potential to treat the disease. to lysosomal Fromdysfunction this we are currentlyand subsequent testing one of the damage best compounds of neurons in a mouse especially model of CLN 7 in in the brain andcollaboration in the with eye. BATCure For partnerour analyses (Juan P. Bolanos, we USAL)used. cultured primary We developed a cell-based primary assay to measure lipid accumulation cells derivedDr from Diego theL. Medina, CLN7 Head mouse of the highmodel. content This screening revealed facility at that the Telethon many Instituteother of (a marker for disease) in human cells depleted of CLN3 and CLN7. proteins wereGenetics depleted and Medicine in the (TIGEM, absence Pozzuoli of-Italy), functional and Professor CLN7 of cell andbiology specific at the University We have identified FDA-approved compounds able to reduce this lipids accumulateof Naples, in Federico the brain. II, Italy. TheThe high High contentcontent screening screening team atteam the TIGEM at the facility. TIGEM facility accumulation as shown opposite. NCL Patient Registry In the frame of BATCure we have provided our CLN7 mouse model to In collaboration with partners at the Latvian Institute for Organic different research groups in the UK, Spain and Italy. The complementary Untreated= parti cipating countries FDA#HIT1 FDA#HIT2 Synthesis (OSI) led by Prof. Maija Dambrova, we are using compound hits We have conducted studies on the molecular basis of CLN7 as reference structures to generate analogs with improved potency in our Dr. Stephan Storch expertise and resources of the different BATCure partners in the fields disease using a mouse model for the disease. In this model Cells

assay. By testing these hits in secondary assays aimed to determine the - of gene therapy, small molecule screening, metabolic reprogramming / the CLN7 protein is truncated leading to a non-functional - mechanism of action, we found that lipid clearance might be mediated by and neuropathology contributed much to the progress of our project. Our CLN3 protein. Our laboratory is focused on the study of lysosomal storage disorders (LSDs) and in the Norway Germany activation of lysosomal and autophagic activity (the process that allows USA development of innovative therapeutics using cell-based high content Inimaginggrid Helland, MD approachesRon Crforystal, M D PhD Angela Schulz, MD , Co-ordinator interactions at project update meetings were inspiring. Oslo University Hospital Weill Cornell Medical College University of Hamburg Denmark drug discovery. Together with other BATCure project partners (Sara Mole at UCL), our laboratoryArgentina Italy for the orderly degradation and recycling of cellular components). From Jon R. Ostergaard, MD Ines Noher de Halac, MD CompoundAlessandro Simonati M Dhits reducing the accumulation of lipids in a cellular model of Aarhus University Hospital Universidad Nacional de Cordoba CompoundUniversity of Verona hits reducing the accumulation of lipids in We focused on the main question whydeveloped the loss assays of in the a variety CLN7 of cellular models of Batten disease to identify compounds with CLN3.UK CLN3-depletedIndia cells were treated with DMSO (untreated condition), France Brazil Ruth Williams, MD Pratibha Singhi, MD Catherine Caillaud MD PhD this we are currently testing one of the best compounds in a mouse model Charles Lourenco, MD PhD a cellularGSTT, London modelPG IMofER, C hCLN3.andigarh CLN3-depleted cells were the potential to treat the disease. INSERM, Paris or with compound 1 or 2. Cells were fixed and stained and imaged. protein leads to lysosomal dysfunction and subsequent University of São Paulo Finland We hope that our research will contribute to a better understandingTurk eyof treatedLaura Aber gwith DMSO (untreated condition), or with Meral Topcu, MD PhD Folkhälsan, Helsinki of CLN7 in collaboration with BATCure partner (Juan P. Bolanos, USAL). damagethe mechanisms of neurons especially involved in the in brainWeCLN7 developed and disease ina cell the-based eye. and primary For hopefully assay, to measure will lipid accumulation, lay theUniver sitabasisy Ch markerildren’s Hospital, An kafor ra disease, compound 1 or 2. Cells were fixed and stained and our analyses we used cultured primaryin human cells cellsderived depleted from of CLN 3the and CLN7. We have identified FDA-approved compounds able imaged. for treatment options in the nearto reduce future. this accumulation as shown opposite. Dr Diego L. Medina, Head of the high content screening facility CLN7 mouse model. This revealed that many other proteins In collaboration with partners at the OSI led by Prof. Maija Dambrova, we are using compound were depleted in the absence of functional CLN7 and specific at the Telethon Institute of Genetics and Medicine hits as reference structures to generate analogs withOur improved role potencyat The in Universitätsklinikumour assay. By testing Hamburg-Eppendorf (UKE), lipids accumulate in the brain. these hits in secondary assays aimed toDr. determine Stephan the mechanism Storch, of action, UKE we found that lipid (TIGEM, Pozzuoli-Italy), and Professor of cell biology at the clearance might be mediated by activation of lysosomalbeing and a clinicalautophagic centreactivity (the with process long -standing expertise in the that allows for the orderly degradation and recycling of cellular components). University of Naples, Federico II, Italy diagnosis and management of neuronal ceroid liopfuscinosis In the frame of BATCure we have provided our CLN7 mouse From this we are currently testing one of the best(NCL), compounds Batten in a mouse disease model involvedof CLN7 in regular and holistic assessment of model to different research groups incollaboration the UK, Spainwith BATCure and partner Italy. (Juan P. Bolanos, USAL). patients, for example by MRI and psychiatric assessments. Untreated FDA#HIT1 FDA#HIT2 TheOur complementary role at The expertise Universitätsklinikum and resourcesDr Diego L. ofMedina, Hamburg-Eppendorf the Headdifferent of the high content screening (UKE), facility atbeing the Telethon Institute of

BATCurea clinical partners centre in the with fields long-standing of geneGenetics therapy, and expertiseMedicine small molecule(TIGEM, in Pozzuoli the -Italy), diagnosis and Professor and of cell biology at the University

of Naples, Federico II, Italy. Cells Dr Angela Schulz, a paediatrician and has runThe theHigh contentNCL clinic screening at team the at the TIGEM facility. - /

screening, metabolic reprogramming and neuropathology - management of neuronal ceroid lipofuscinoses (NCL), BattenUKE Children’s disease Hospital for more than 10 years and coordinates contributed much to the progress of our project. Our CLN3 involved regular and holistic assessment of patients, for theexample recruitment by MRI of NCL patients, collection of patient data for interactions at project update meetings were inspiring. Our laboratory is focused on the study of lysosomal storage disorders (LSDs) and in the and psychiatric assessments. natural history studies for the project. Shedevelopment also coordinates of innovative the therapeutics using cell-based high content imaging approaches for

international DEM-CHILD NCL patient database.drug discovery . Together with other BATCure project partners (Sara Mole at UCL), our laboratory Compound hits reducing the accumulation of lipids in a cellular model of We hope that our research will contribute to a better developed assays in a variety of cellular models of Batten disease to identify compounds with CLN3. CLN3-depleted cells were treated with DMSO (untreated condition),

understandingDr Angela ofSchulz, the mechanisms a paediatrician involved inand CLN7 has disease run the NCL clinic at the the potential to treat the disease. Metabolism comprises all chemicalor with compound changes 1 or 2. Cells occurring were fixed and within stained and cells imaged . “Collecting patient data is “ Collecting patient data is vital for clinical trials but is important andUKE hopefully Children’s will lay Hospitalthe basis for for treatment more than options 10 years in the and coordinates the We developed a cell-based primary assay, to measure lipid accumulation,in a finely a marker balanced for disease, and coordinated manner. Amongst other things, vital for clinical trials but for many other reasons - current patient data can identify early nearrecruitment future. of NCL patients, collection of patient data for natural history in human cells depleted of CLN3 and CLN7. We have identified FDA-approved compounds able indicators of disease and help improve diagnosis”to reduce this accumulation as shown opposite. metabolism ensures the energy supply required by cells to make tissues is important for many other Dr. Stephan Storch, UKE studies for the project. She also coordinates the international DEM-CHILD and organs to work properly. Neurons are brain cells requiring a vast reasons - current patient data In collaboration with partners at the OSI led by Prof. Maija Dambrova, we are using compound NCL patient database. hits as reference structures to generate analogs with improvedand potency continuous in our assay. Byamount testing of energy to sustain neurotransmission, i.e. the Metabolism comprises all chemical changes occurring within cells in a finely balanced and these hits in secondary assays aimed to determine the mechanism of action, we found that lipid can identify early indicators coordinated manner. Amongst other things, metabolism ensures the energy supply required by work that neurons do to keep the brain alive. In essence, our contribution clearance might be mediated by activation of lysosomal and autophagic activity (the process cells to make tissues and organs to work properly. Neurons are brain cells requiring a vast and within the BATCure consortium was to identify that neurons affected of disease and help improve continuous amount of energy to sustain neurotransmission, i.e. the work that neurons do to that allows for the orderly degradation and recycling of cellular components). keep the brain alive. diagnosis.” From this we are currently testing one of the best compoundsby inBatten a mouse disease model of CLN undergo7 in profound changes in metabolism strongly

In essence, our contribution within the BATCure consortium was to identify that neurons collaboration with BATCure partner (Juan P. Bolanos, USAL). influencing energy supply. affected by Batten disease undergo profound changes in metabolism strongly influencing energy supply. Dr Diego L. Medina, Head of the high content screening facility at the Telethon Institute of Dr. Angela Schulz Genetics and Medicine (TIGEM, Pozzuoli-Italy), and Professor of cell biology at the University ProfessorProfessor Juan Juan Bolanos Bolanos (seated) and (seated) his team at theand Institute his of Inside cells, mitochondria are little “engines” that optimize metabolism of Naples, Federico II, Italy. NCL InsidePatient cells, Registry mitochondria are little “engines” that optimize metabolism to produce energy in a teamFunctional at theBiology Institute and Genomics of (IBFG), Functional University of Salamanca.Biology Dr. to produce energy in a highly efficientThe High way. content Using screening a teammouse at the TIGEMmodel facility. highly efficient way. Using a mouse model of Batten disease, in particular, the CLN7 type, we and IreneGenomics Lopez-Fabuel (IBFG),(first on the right)University is the BATCure of postdoc. observed that neurons accumulate inside very large (swelled) mitochondria, which of Batten disease, in particular, the CLN7 type, we observed that unfortunately are damaged and cannot function correctly. Salamanca.My laboratory had Dr. never Irene been involved Lopez-Fabuel in Batten Disease (first research on theso joiningright) the isBATCure the consortiumBATCure was postdoc challenging and at the same neurons accumulate inside very large (swelled) mitochondria, which time encouraging, as metabolism was never previously associated to This problem further contributes to the loss of neuronal energy= participating supply and, countries eventually, to degeneration. Importantly, we found a specific metabolic alteration (a target) in CLN7 Batten Batten Disease. unfortunately are damaged and cannot function correctly. disease mice that may account for many of the energetic problems that take place within The opportunity to collaborate with widely regarded experts, from damaged neurons. We are currently developing a pharmacological approach to try rescue this basic researchers to clinical experts, in Batten disease within the UK and the rest of Europe brought to our group the new dimension of effect. This problem further contributes to the loss of neuronal energy supply translational research.

Thanks to this experience, we have now got further funding to and, eventually, to degeneration. Importantly, we found a specific Professor Juan Bolaños , Research Leader based at the Institute of Functional Biology and investigate other metabolic aspects of Batten disease and this has Genomics now become a new research line within my laboratory. metabolic alteration (a target) in CLN7 Batten disease mice that may

account for many of the energetic problems that take place within damaged neurons. We are currently developing a pharmacological approach to try to rescue this effect.

Norway USA Germany Ingrid Helland, MD Ron Crystal, MD PhD Angela Schulz, MD , Co-ordinator Oslo University Hospital Weill Cornell Medical College University of Hamburg Professor Juan Bolaños , Research Leader Denmark Argentina Italy Jon R. Ostergaard, MD Ines Noher de Halac, MD Alessandro Simonati MD based at the Institute of Functional Biology and Genomics Aarhus University Hospital Universidad Nacional de Cordoba University of Verona UK India France Brazil Ruth Williams, MD Pratibha Singhi, MD NCL Patient Registry Catherine Caillaud MD PhD Charles Lourenco, MD PhD GSTT, London PGIMER, Chandigarh INSERM, Paris University of São Paulo Finland Turkey Laura Aberg Meral Topcu, MD PhD Folkhälsan, Helsinki University Children’s Hospital, Ankara = participating countries We have conducted studies on the molecular basis of CLN7 disease using a mouse model for the disease. In this model the CLN7 protein is truncated leading to a non-functional Metabolism comprises all chemical changes occurring within cells in a finely balanced and coordinated manner. Amongst other things, metabolism ensures the energy supply required by protein. cells to make tissues and organs to work properly. Neurons are brain cells requiring a vast and Norway USA Germany Ingrid Helland, MD continuousRon Crys tamountal, MD PhD of energyAngela toSchulz , sustainMD , Co-ordinator neurotransmission, i.e. the work that neurons do to Oslo University Hospital Weill Cornell Medical College University of Hamburg Denmark Argentina Italy Jon R. Ostergaard, MD keep the brain alive. Ines Noher de Halac, MD Alessandro Simonati MD Aarhus University Hospital Universidad Nacional de Cordoba University of Verona We focused on the main question why the loss of the CLN7 UK India France Brazil Ruth Williams, MD Pratibha Singhi, MD Catherine Caillaud MD PhD Charles Lourenco, MD PhD GSTT, London PGIMER, Chandigarh INSERM, Paris protein leads to lysosomal dysfunction and subsequent In essence,University oourf São Pau locontributionFi nlwithinand the BATCure consortium was to identify that neurons Turkey Laura Aberg Meral Topcu, MD PhD affected by Batten disease undergoFolkhälsan, Helsinki profound changes in metabolism strongly influencing University Children’s Hospital, Ankara damage of neurons especially in the brain and in the eye. For energy supply. our analyses we used cultured primary cells derived from the Professor Juan Bolanos (seated) and his team at the Institute of Inside cells, mitochondria are little “engines” that optimize metabolism to produce energy in a Functional Biology and Genomics (IBFG), University of Salamanca. Dr. CLN7 mouse model. This revealed that many other proteins highly efficient way. Using a mouse model of Batten disease, in particular, the CLN7 type, we Irene Lopez-Fabuel (first on the right) is the BATCure postdoc. were depleted in the absence of functional CLN7 and specific observed that neurons accumulate inside very large (swelled) mitochondria, which Our role at The Universitätsklinikum Hamburg-Eppendorf (UKE), lipids accumulate in the brain. unfortunately are damaged and cannot function correctly. My laboratory had never been involved in Batten Disease research being a clinical centre with long-standing expertise in the so joining the BATCure consortium was challenging and at the same This problem further contributes to the loss of neuronal energy supply and, eventually, to time encouraging, as metabolism was never previously associated to diagnosis and management of neuronal ceroid liopfuscinosis Batten Disease. In the frame of BATCure we have provided our CLN7 mouse degeneration. Importantly, we found a specific metabolic alteration (a target) in CLN7 Batten (NCL), Batten diseasedisease involved mice that regular may account and for holistic many of theassessment energetic problems of that take place within The opportunity to collaborate with widely regarded experts, from model to different research groups in the UK, Spain and Italy. damaged neurons. We are currently developing a pharmacological approach to try rescue this basic researchers to clinical experts, in Batten disease within the UK and the rest of Europe brought to our group the new dimension of patients, for exampleeffect. by MRI and psychiatric assessments. The complementary expertise and resources of the different translational research.

BATCure partners in the fields of gene therapy, small molecule Thanks to this experience, we have now got further funding to Dr Angela Schulz, a paediatricianProfessor Juan Bolaños and ,has Research run Leader the NCLbased clinicat the Institute at the of Functional Biology and investigate other metabolic aspects of Batten disease and this has screening, metabolic reprogramming and neuropathology Genomics now become a new research line within my laboratory. UKE Children’s Hospital for more than 10 years and coordinates contributed much to the progress of our project. Our the recruitment of NCL patients, collection of patient data for interactions at project update meetings were inspiring. natural history studies for the project. She also coordinates the

international DEM-CHILD NCL patient database. We hope that our research will contribute to a better

understanding of the mechanisms involved in CLN7 disease “ Collecting patient data is vital for clinical trials but is important and hopefully will lay the basis for treatment options in the for many other reasons - current patient data can identify early near future. indicators of disease and help improve diagnosis” Dr. Stephan Storch, UKE

Metabolomics is the large-scale study of small molecules, commonly At The Latvian Institute of Organic Synthesis, (OSI) we have many years known as metabolites, within cells, biofluids, tissues or organisms. experience and expertise in making new compounds specifically AcureOmics used their expertise in this field to identify disturbed designed to treat a variety of diseases. TIGEM and UCL carried out drug biochemical pathways in CLN3, CLN6 and CLN7 diseases. This screens in cellular models of Batten disease to identified promising knowledge is being used to both help assess and design novel treatments compounds. We then redesigned the best ones using a medicinal that act to normalise the disturbed biochemical pathway. chemistry approach, with the aim to improve their properties. As a result, 121 new compounds were synthesised and then further tested by our This work will contribute to improve how the effect of ongoing treatment BATCure partners. is monitored. In Batten disease, it is important to know how well these new compounds can enter the brain (bioavailability). We used mouse models of Batten Dr Kate Bennett disease to measure this to identify the best candidates for further testing Professor Torbjörn Lundstedt by ourselves and our partners. We also assessed any potential toxic Associate Professor Katrin Lundstedt-Enkel effects of the new compounds.

Another approach is to look at the metabolic profiles, in models of the disease, AcureOmics lead the way. This involved new drugs we had developed and those suggested by the results from several partners, Dr. Kate Bennett in the lab in Sweden. The team at OSI “go orange” on Batten disease awareness day in 2017! TIGEM, UCL, and Pronexus Analytical. We were interested in whether the administered drugs change the blood metabolite profile in a favourable way in our different models of Batten disease.

Participation of OSI researchers in the BATCure project brought us to the rare disease field and the challenges in relation to the drug discovery programs for such diseases where no cure is currently available and a single drug target is difficult to identify. Our collaboration with those in the group to accumulate data about the mechanisms of a disease, combined AtAt The withThe Latvian Latvianour drug Institute Institute discovery of of Organic Organic approaches Synthesis, Synthesis, has (OSI) (OSI) provided we we have have evidencemany many that this is a yearsyearsway experience experience forward toand and new expertise expertise treatments. in in making making new new compounds compounds AcureOmics supporting the BDFA for Batten disease awareness day. AdministrationAdministration specificallyspecifically designed designed to to treat treat a a variety variety of of diseases. diseases. TIGEM TIGEM and and UCLUCL“I carriedcarriedenjoyed out out communicating drug drug screens screens in in withcellular cellular the models models BDFA of of BattenandBatten I amdisease disease now sharing this toto identified identified promising promising compounds. compounds. We We then then redesigned redesigned the the bestexperience, ones using aabout medicinal the chemistryinvolvement approach, of patient with organisationthe aim to in a research AcureOmics used metabolomics to best ones using a medicinal chemistry approach, with the aim to improveproject, their with properties. my colleagues As a result, here 121 in newLatvia compounds and internationally. were It is identify disturbed biochemical pathways Orphazyme is based in Copenhagen, Denmark, and specialises in novel therapies improve their properties. As a result, 121 new compounds were synthesisedmotivating and and then makes further the tested research by these questions BATCure partners. we are trying to solve in CLN3, CLN6 and CLN7 diseases. This We are a preclinical contract researchfor organization rare degenerative (CRO) diseases. offering Our approach is based on augmentation of the SamplingSampling synthesised and then further tested by these BATCure partners. knowledge is being used to both help advanced services and collaborativenaturally projects occurring in Central protective Nervous responses System that occur in cells in response to stress. more meaningful.” assess and design novel treatments that (CNS) pharmacology, neurochemistryDisease and bioanalysis.causes stress responses Our mission in cells and is so our approach is to find ways that InIn Batten Batten disease, disease, it it is is important important to to know know how how well well these theseProf new new Maija Dambrova, OSI could prevent or help correct these events. act to normalise the disturbed to serve and research organisations and pharmaceutical companies to compoundscompounds can can the the enter enter brain brain (bioavailability). (bioavailability). We We used used mouse mouse biochemical pathway. This work will modelsmodels of of Batten Batten disease disease to to measure measure this this to to identify identify the the best best Prof. Maija Dambrova, Head of the Laboratory of Pharmaceutical contribute to improving how the effect accelerate the process of drug discovery,We develop evaluate small moleculemechanisms inducers of of drug chaperones, such as HSP70, and in late Prof. Maija Dambrova, Head of the Laboratory of Pharmaceutical candidates for further testing by ourselves and our partners. We Pharmacology and the OSI researchers make “orange synthesis” for of ongoing treatment is monitored.” actions. 2018 we completed a phase II/III clinical trial in Niemann-Pick Disease Type C, Sample preparation candidates for further testing by ourselves and our partners. We Pharmacology and the OSI researchers make “orange synthesis” for Sample preparation also assessed any potential toxic effects of the new compounds. the Batten Disease Awareness Day, June 2018 another very rare lysosomal storage disease. Being part of the BATCure has given also assessed any potential toxic effects of the new compounds. the Batten Disease Awareness Day, June 2018 us invaluable experience and new partners in the Batten disease field. Dr Kate Bennett Pronexus core expertise is focused on studies using in vivo microdialysis,

Professor Torbjörn Lundstedt which is a way to mimic a blood vessels, and in experimental models of Another approach is to look at the metabolic profiles, in models of the disease, for which our partners at AcureOmics We have characterized the stress responses using cells which mimic a wide Another approach is to look at the metabolic profiles, in models of the disease, for which our partners at AcureOmics Associate Professor Katrin Lundstedt- CNS and metabolic disorders. spectrum of clinical presentations for Batten disease, kindly provided by other leadlead the the way. way. This This involved involved new new drugs drugs we we had had developed developed and and those those suggested suggested by by the the results results from from several several partners, partners, Enkel TIGEM, UCL, and Pronexus Analytical. We were interested in whether the administered drugs change the blood partners in the BATCure consortium. Our studies have generated data that Bioanalytics TIGEM, UCL, and Pronexus Analytical. We were interested in whether the administered drugs change the blood We offer a range of assays and servicesindicate for aquantification similar responsiveness of of these model cells as found in our work in Bioanalytics metabolitemetabolite profile profile in in a a favourable favourable way way in in our our different different models models of of Batten Batten disease. disease. neurotransmitters, metabolites, drugs,other neuropeptides rare lysosomal storage and proteins diseases. in biological samples such as plasma, urine and tissue extracts. Our role ParticipationParticipation of of OSI OSI researchers researchers in in the the BATCure BATCure project project brought brought us us to to the the rare rare disease disease field field and and the the challenges challenges in in relation relation While it is too early to tell whether this new knowledge has any potential in the was to evaluate whether the selected potential therapeutic compound, toto the the drug drug discovery discovery programs programs for for such such diseases diseases where where no no cure cure is is currently currently available available and and a a single single drug drug target target is is difficult difficult developed by our partners would betreatment able to ofalter patients the withbiomarker Batten disease, our work has generated new scientific insight that will aid future research efforts to combat this devastating group of toto identify. identify. Our Our collaboration collaboration with with those those in in the the group group to to accumulate accumulate data data about about the the mechanisms mechanisms of of a a disease, disease, combined combined molecules we had identified as importantdiseases.” in the disease progression. withwith our our drug drug discovery discovery approaches approaches has has provided provided evidence evidence that that this this is is a a way way forward forward to to new new treatments. treatments. Senior scientist Fu-Hua Wang, MD, Nikolaj H.T. Petersen, Sr. Science Manager, Senior Scientist Raffaella Magnoni, DataData analysis analysis PhD in the surgery room. We studied the effect of the compoundOrphazyme in the brains of the CLN7 mouse model and compared this to the levels in the wild type mice. We were not able to detect a difference and further work is needed. One explanation may be that the drug needs to be given earlier in the disease course or at higher dose.

Dr Jan Kehr, Pronexus Analytical

Prof. Maija Dambrova, Head of the Laboratory of Pharmaceutical Pharmacology and the OSI researchers make “orange synthesis” for the Batten Disease Awareness Day, June 2018

At The Latvian Institute of Organic Synthesis, (OSI) we have many years experience and expertise in making new compounds Administration specifically designed to treat a variety of diseases. TIGEM and UCL carried out drug screens in cellular models of Batten disease to identified promising compounds. We then redesigned the best ones using a medicinal chemistry approach, with the aim to improve their properties. As a result, 121 new compounds were Sampling synthesised and then further tested by these BATCure partners.

In Batten disease, it is important to know how well these new compounds can the enter brain (bioavailability). We used mouse models of Batten disease to measure this to identify the best Prof. Maija Dambrova, Head of the Laboratory of Pharmaceutical candidates for further testing by ourselves and our partners. We Pharmacology and the OSI researchers make “orange synthesis” for Sample preparation also assessed any potential toxic effects of the new compounds. the Batten Disease Awareness Day, June 2018

Another approach is to look at the metabolic profiles, in models of the disease, for which our partners at AcureOmics lead the way. This involved new drugs we had developed and those suggested by the results from several partners, TIGEM, UCL, and Pronexus Analytical. We were interested in whether the administered drugs change the blood Bioanalytics metabolite profile in a favourable way in our different models of Batten disease.

Participation of OSI researchers in the BATCure project brought us to the rare disease field and the challenges in relation to the drug discovery programs for such diseases where no cure is currently available and a single drug target is difficult to identify. Our collaboration with those in the group to accumulate data about the mechanisms of a disease, combined with our drug discovery approaches has provided evidence that this is a way forward to new treatments. Data analysis