Impact Objectives • Create new models, tools and technologies for developing and testing therapies for

• Triage new compound treatments

• Provide a novel mechanism to fully involve patients and their families, and prepare all stakeholders for clinical trials

Coordinating a cure Batten disease is a group of neurodegenerative diseases that are life-limiting, and are made all the more tragic because they mainly affect children. Professor Sara Mole at University College London is coordinating BATCure, a project that aims to tackle the disease

Can you begin by of rare lysosomal diseases known as Batten CLN6 and CLN7 diseases. We will apply a explaining what disease. It will provide concerted, focused novel strategic approach to drug discovery, Batten disease is, and synergistic action by experts committed which has significant advantages over drug and what its effects to working together towards this common discovery programmes based on mode- are? goal. of-action approaches, and which is also integrated with gene therapy development. Batten disease How will the consortium behind BATCure Our innovative approach adapts and is a broad classification for more than achieve this goal? modifies the best aspects of the function- a dozen separate monogenic recessive based and physiology-based approaches disorders, also known as the neuronal BATCure will focus on therapeutic previously described to provide biological ceroid lipofuscinoses, which share common development for three types of Batten efficacy of compounds, and is tailored to clinical features. These features are caused disease, including the most common type meet the specific needs of Batten disease. by neuron loss within the central nervous – CLN3 disease – which affect at least half There is the required expertise within the system and the storage of autofluorescent of all cases. Therapeutic development has BATCure consortium for all planned activities material in most cell types, which has a been neglected for these types, with no and integration of disciplines at all stages. typical pattern in electron microscopy. clinical trials directly addressing the disease Batten disease mainly affects children, who in existence when we began this project. What inspired this project and how did you suffer progressive dementia, motor decline, Therapy for diseases caused by dysfunctional become the coordinator for it? visual failure and epilepsy. The disease intracellular transmembrane proteins course leads to a long period of complete requires a trans-disciplinary and therefore This is an EU collaborative research project, dependence on others, and is life-limiting. coordinated approach, and new and which is an ideal platform for collaborative Existing palliative treatment can help, but emerging technologies now allow this goal work. I watched out for a call that was cannot eliminate the burden of seizures to be addressed. Finally, it’s important to relevant to this type of work and on the and the progressively worsening effects on note that our strategic approach and the new day one was announced, I invited a small the whole body due to decreasing central therapies that are devised may benefit other group in London to meet and begin to plan nervous system influence and control. diseases, both rare and more common. a collaborative project. I then invited the required experts from across Europe to What are the key objectives of BATCure? We see drug and gene-based approaches engage with the project. as the most likely to be beneficial for The goal of BATCure is to develop effective those affected by CLN3 disease, as well treatments for patients living with a group as other types of Batten disease such as

www.impact.pub 37 Changing the outcomes of Batten disease Due to the rarity of the neurodegenerative conditions known collectively as Batten disease, not much is known about them from a general clinical or public perspective. BATCure aims to address part of this problem by developing therapeutics for three types of the disease

Batten disease was first described in granted nearly 6 million euros of European A PHASED APPROACH Sweden in 1826 and in the UK in 1903, but Union funding. The project is coordinated While there are many diseases under the the first genes involved in its onset were by Professor Sara Mole of University College umbrella term ‘Batten disease’, BATCure only identified in 1995. They were the first of London (UCL), UK, who has been working on focuses on three genetically distinct sub- many, because Batten disease is not a single Batten disease for more than two decades, types, which affect over 50 per cent of condition, but rather a group of diseases, and has already made progress towards the children and young adults living with the with over 400 mutations in 13 different development of new therapies. The project disease across Europe. The team is taking genes currently known to be involved in also has a large consortium of members a multifaceted approach to the project in the various forms. While relatively speaking selected from across Europe to provide the order to maximise their chances of success. Batten disease is rare, affecting approximately relevant expertise and resources that will be ‘The challenges of reaching therapies for 14,000 people worldwide with around 1,400 required to address each of the key objectives Batten disease are such that it requires new cases every year, it is a particularly tragic of the project. The lack of established tackling on multiple fronts,’ explains Mole. affliction as the majority of those affected treatments for Batten disease means the The team hopes to develop new gene are children. Those with the disease will consortium has a big job to do. As such there therapies, for example, but they are also experience devastating symptoms such as are several different aspects to their work, looking at whether it is possible to repurpose visual impairment and blindness, severe making collaboration absolutely crucial, and existing drugs. This may aid the design of epileptic seizures that are difficult to control, Mole feels that things are going smoothly so new compounds, and ultimately achieve the involuntary muscle spasms, speech loss, far. ‘Despite about half being new to Batten objective of finding effective treatments. swallowing difficulties and the deterioration disease and to each other, I’m pleased to say of motor skills. Ultimately, the disease is fatal, that all partners have been working together The work of BATCure is divided into and there are no established treatments. incredibly well,’ she enthuses. three phases: pre-discovery, discovery

BATCure is a project that has the ambitious and inspiring objective of developing The challenges of reaching therapies for Batten disease effective treatments for patients with three types of Batten disease. It began in January are such that it requires tackling on multiple fronts 2016 and will run for three years, having been

38 www.impact.pub is understandable to a certain extent, as obviously rare diseases by their very affect fewer people, it may be an oversight. Such diseases can often provide key insights into fundamental biology, and therefore funding and research support for them can have a broad impact that goes beyond a specific disease.

Given the nature of the disease and the total lack of treatments, BATCure is offering a rare glimpse of hope for those affected and their families. The collaborative working and science that is behind the project offers huge potential that is already on its way to being realised.

BATCure Consortium at UCL and pre-clinical. There are a total of eight was an unexpected result and is unusual in Project Insights experimental work packages, each led by an terms of experience with gene therapy for expert in that specific area and supported by other genetic causes of blindness. FUNDING other partners, aiming to address a single Looking ahead to the end of the project, it is European Union’s Horizon 2020 objective that forms the wider project. The hoped that BATCure will be continued and research and innovation programme under grant agreement No 666918 first three packages focus on developing that funding will be secured for clinical trials new models, identifying therapeutic target to capitalise on the work that has already PARTNERS pathways and establishing new monitoring been undertaken. The team also wants University College London (UCL) • and diagnostic techniques. Moving beyond similar work to be applied to other types of Acureomics • Latvijas Organiskas this, the team will look at the wider natural Batten disease, should funding be secured. Sintezes Instituts • Cardiff history of the brain, identify new compound Despite having 14 consortium members University • Fondazione Telethon • leads and determine therapeutic potential spread across seven different countries, the Universitaetsklinikum Hamburg- using zebrafish. As the work progresses, the BATCure team is working efficiently together Eppendorf • Pronexus • Manchester Metropolitan University • Royal team will assess gene therapy for the brain, towards its goals, and they all have long Veterinary College • Universidad eye and other organs, and also deliver a new term ambitions regarding this disease. Salamanca • Orphazyme • Kings small molecule therapy to mice. College London • Acondicionamiento BREAKING NEW GROUND Tarrasense Associacion (LEITAT) • Alongside the research side of the project Batten disease is particularly distressing Batten Disease Family Association are two supporting work packages. These due to its degenerative nature. As a child include the management of the project and with the disease gets older, they slowly lose CONTACT the involvement of patient organisations. all of their abilities and become completely Sara Mole Many partners contribute to multiple work dependent on families and carers. Existing Project Leader packages and all the work packages rely on treatment is only palliative, and can do little input from other partners, so collaboration more than address certain symptoms. The E: [email protected] and sharing of information and data are disease is also very rare, and this presents T: +44 (0)20 7679 7257 built into the project. a number of further challenges for those W: www.batcure.eu affected and their families. It is often local PROJECT LEADER BIO THE PATH TO DISCOVERY physicians who are the first point of call Professor Sara Mole is a Great Ormond As the project has been running since for patients, yet most will never have seen Street Hospital Children’s Charity January 2016, there will soon be an a case of Batten disease. This may extend Professor at University College evaluation of the preliminary results to the amount of time before a patient is given London. Her main research interest is assess what is to be expected over the rest their diagnosis. Parents may have to give the neuronal ceroid lipofuscinoses or of its term. While this has not yet taken up work in order to provide round-the-clock Batten disease, a group of inherited place, the group has already made findings care, and social support may be required neurodegenerative diseases that affect homeostasis. that will inform their work. One example to try to lessen the emotional, physical and of this is in the treatment applied in mice. financial burden. Significantly, they found that in one of the types under study, to treat the loss of Furthermore, rare diseases like Batten photoreceptor cells – involved in the onset disease are always up against the challenge of blindness – it is necessary to target cells of funding. There is not as much money in the middle layer of the retina rather than available to support research into them, the photoreceptor cells themselves. This meaning progress is often slow. While this

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