Investigating Batten disease JONA PROFESSOR Professor Jonathan Mink discusses a rare childhood neurological disorder – Batten disease – delving into its peculiarities, the difficulties associated with studying rare diseases, methods of clinical evaluation and potential future treatment options THA Batten disease explained N MINK Could you discuss some of the ongoing Neuronal ceroid lipofuscinoses clinical trials evaluating disease-modifying (NCLs) are a group of lysosomal storage therapies? diseases characterised by the accumulation of a lipopigment in neurons. There are at least Disease-modifying therapies currently 12 different forms of NCL, the most prevalent of undergoing investigation in human trials which is the juvenile form (JNCL, or Batten disease), include gene therapy, enzyme-replacement due to mutations in the CLN3 gene. therapy and immunomodulation. For the forms of Batten disease that involve Batten disease is characterised by rapidly soluble enzymes (eg. CLN1 and CLN2 progressive blindness beginning between four and diseases), gene and enzyme-replacement seven years, followed by progressive dementia, therapy are promising strategies. In juvenile epilepsy and premature death (usually in neuronal ceroid lipofuscinoses (JNCL, or the third decade). Incidence is estimated CLN3 disease), the protein is membrane-bound to be about two per 100,000 live and poorly understood, so therapy directed at births in the US. replacing the mutant protein is less feasible. However, work by David Pearce, PhD of the Sanford Children’s Health Research Center You employ standardised measures to has shown that children and mouse models disease, another rare childhood neurological conduct your evaluations. How do you with CLN3 disease have antibody-mediated disease. Our systematic approach to accommodate the unique phenotype of autoimmunity. In mice, suppression of the quantifying disease progression puts us in a Batten disease? immune response is protective. We are currently strong position to test treatment efficacy. performing a phase II clinical trial of the Wherever possible we aim to use standardised immunosuppressant mycophenolate mofetil in It is becoming increasingly apparent measures that do not require adaptation; children with CLN3 disease. that many neurodegenerative diseases for example, assessment tools that do not have an inflammatory component. If necessitate examination of visual stimuli. Due to the rarity of the condition, the Batten immunomodulation can slow CLN3 disease However, when adaptations are necessary we disease research community is relatively progression, it could provide important insights carefully document and maintain them. small. As such, do you find collaboration is an into the treatment of other lysosomal storage integral part of your work? disorders that affect the nervous system. We developed the Unified Batten Disease Rating Scale (UBDRS) and used iterative Collaboration is of critical importance in What are the main hurdles to developing methods to assure reliability. Even after a rare disease research generally and in Batten effective treatments? decade of evaluations, we continue to learn disease research specifically. Collaboration is how to further refine our assessments to necessary to develop consensus about how to At this time, potential treatments are more improve the sensitivity of the methods, prioritise treatment trials; develop agreement likely to slow or halt disease progression especially during the latter stages of disease. on meaningful endpoints for clinical trials; than reverse it. In addition to the difficulty of and enrol sufficient numbers of subjects in identifying and testing such a treatment, this The Pediatric Quality of Life Family Impact clinical trials. poses the challenge of identifying potential Module assesses the health-related candidates as early in the disease course as quality of life of parents and family Batten disease shares challenges with other possible, in order to have the best outcome – in relation to the child’s health. What lysosomal storage disorders. To what extent requiring early diagnosis. conclusions were you able to draw from will your research advance knowledge on your research? these rare diseases? Can you describe some of the greatest achievements your team has made to date? These results show the considerable impact Our approach to studying the natural of the disease upon the wellbeing of the history of JNCL has significant potential to Our greatest achievements have been family. Batten disease does not just affect a inform research on other rare childhood conducting the largest longitudinal study child, but an entire family system. The results neurodegenerative diseases. We have of the natural history of any form of NCL, also suggest that the care we provide must developed a disease-specific rating scale that developing the methodology and infrastructure take into consideration the needs of the can be modified for other diseases. In fact, for clinical trials in Batten disease and initiating family as a whole. it has already been employed for Wolfram the first controlled clinical trial in JNCL. WWW.RESEARCHMEDIA.EU 85 PROFESSOR JONATHAN MINK Rare disease clinical trials The University of Rochester Medical Center, a Batten disease Center of Excellence, is conducting the first controlled clinical trial for the juvenile form of the disease. It is hoped their work characterising the course of the condition will improve diagnosis and treatment, benefiting child patients and their families alike discovered an immune component SCALE OF DISEASE to JNCL, a monumental finding for a disease about which so little is The Unified Batten Disease Rating Scale understood. URBC researchers take a (UBDRS) was developed by the URBC to provide quantitative approach to the study of a consistent and disease-specific method of JNCL progression, which will inform evaluating children with JNCL. It is a multi- neurobiological investigations and component system, comprising a physical clinical trials. exam, medical history review and questioning about symptoms. The UBDRS is used both as There are many challenges associated part of clinical evaluation and as a research tool. with studying Batten disease: like all rare diseases, the number of affected The Scale is modelled after scales in similar people willing to enter clinical trials adult disorders and has four subscales: physical is small; those who are willing need impairment, seizures, behaviour and functional From left to right: Heather Adams, Sara Defendorf, Lisa de Blieck, Jonathan Mink, to be diagnosed early, which can capability. Since 2002, 120 children have Frederick Marshall, Amy Vierhile, Paul Rothberg, Alyssa Thatcher, Erika Augustine. be a difficult proposition; and by been evaluated using the UBDRS, and many its rare nature, there are relatively return each year. Repeat evaluations allow the few people working on the disease. team to consistently track disease progression ALTHOUGH RELATIVELY RARE, neuronal Overcoming these many and varied obstacles over time. Ultimately, the system enables ceroid lipofuscinoses (NCLs) represent the requires collaboration, training a new generation the identification of symptoms which lead to most common neurodegenerative disorders of of rare disease researchers and leveraging existing disability and factors which are associated with childhood. The University of Rochester Medical resources. However, great advances in genetics fewer symptoms. Center (URMC) studies Batten disease, the most alongside growing knowledge of JNCL’s clinical common form of NCL. features suggest meaningful therapeutics could The URBC investigators have recently shown be available in the not too distant future. that the physical impairment subscale can NCLs are a broad class of diseases. Although be used remotely by a trained non-physician. they share some symptoms and pathology, there Telemedicine has real potential to be a valuable RESEARCH CATEGORIES are great differences in terms of age of onset, tool in NCL research and clinical assessment, a biochemistry and genetics; there are at least 20 The overarching aims of studies at URBC are to real benefit given the geographically scattered genes associated with Batten disease alone. The advance knowledge of the clinical manifestations nature of patients. most prevalent form of Batten disease is juvenile of Batten disease and to develop improved NCL (JNCL), which is linked to mutations in treatments. Under this umbrella, research CLINICAL TRIAL CLN3. CLN3 encodes Battenin, a ubiquitously is divided into four basic categories: natural expressed membrane protein localised to the history; neurobehavioural and neurocognitive The past 20 years of JNCL research has seen a lysosomal membrane. Although its function is features; determinants of JNCL severity; and shift from the bench to the bedside. Forming unknown, modelling studies suggest it may play experimental therapeutics. part of this transition, URBC has developed a a role in substrate trafficking along the lysosomal clinical research infrastructure, research cohort pathway in cells. Neurobehavioural assessment of patients with and disease-specific clinical outcome measure. JNCL is particularly demanding. Dementia and This pathway is hugely important to cellular vision loss in JNCL place limits on assessment, Designing and carrying out meaningful clinical transport and metabolism; lysosomes essentially as many intelligence tests evaluate both verbal trials is a major emphasis of URBC research.