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Progressive vision loss, and eventually blindness, are the hallmarks of juvenile neuronal ceroid lipofuscinosis (JNCL) or CLN3-Batten disease. New research shows how the mutation associated with the disease could potentially lead to degeneration of light sensing photoreceptor cells in the retina, and subsequent vision loss.

"The prominence and early onset of retinal degeneration in JNCL makes it likely that cellular processes that are compromised in JNCL are critical for health and function of the retina," said Ruchira Singh, Ph.D., an associate professor in the Department of Ophthalmology and Center for Visual Science and lead author of the study which appears in the journal Communications Biology. "It is important to understand how vision loss is triggered in this disease, what is primary and what is secondary, and this will allow us to develop new therapeutic strategies."

Batten disease is caused by a mutation in the CLN3 gene, which is found on chromosome 16. Most children suffering from JNCL have a missing part in the gene which inhibits the production of certain proteins. Rapidly progressive vision loss can start in children as young as 4, who eventually go on to develop learning and behavior problems, slow cognitive decline, seizures, and loss of motor control. Most patients with the disease die between the ages of 15 and 30.

It has been well established that vision loss in JNCL is due to degeneration of the light-sensing tissue in the retina. The vision loss associated with JNCL can precede other neurological symptoms by many years in some instances, which often leads to patients being misdiagnosed with other more common retinal degenerations. However, one of the barriers to studying vision loss in Batten disease is that mouse models of CLN3 gene mutation do not produce the retinal degeneration or vision loss found in humans. Additionally, examination of eye tissue after death reveals extensive degeneration of retinal cells which does not allow researchers to understand the precise mechanisms that lead to vision loss.

URMC is a hub for Batten disease research. The Medical Center is home to the University of Rochester Batten Center (URBC), one of the nation's premier centers dedicated to the study and treatment of this condition. The URBC is led by pediatric neurologist Jonathan Mink, M.D., Ph.D., who is a co-author of the study. Batten disease is also one of the key research projects that will be undertaken by the National Institute of Child Health and Human Development-supported University of Rochester Intellectual and Development Diseases Research Center.

To study Batten disease in patient's own cells, the research team reengineered skin cells from patients and unaffected family members to create human-induced pluripotent stem cells. These cells, in turn, were used to create retinal cells which possessed the CLN3 mutation. Using this new human cell model of the disease, the new study shows for the first time that proper function of CLN3 is necessary for retinal pigment epithelium cell structure, the cell layer in the retina that nourishes light sensing photoreceptor cells in the retina and is critical for their survival and function and thereby vision.

Singh points out that understanding how RPE cell dysfunction contributes to photoreceptor cell loss in Batten disease is important first step, and it will enable researchers to target specific cell type in the eye using potential future gene therapies, cell transplantation, and drug-based interventions.

Additional co-authors of the study include Cynthia Tang, Jimin Han, Sonal Dalvi, Kannan Marian, Lauren Winschel, Celia Soto, Chad Galloway, Whitney Spencer, Michael Roll, Lisa Latchney, Erika Augustine, Vamsi Gullapalli, and Mina Chung with URMC, David Williams and Stephanie Volland with the University of California, Los Angeles, Vera Boniha with the Cleveland Clinic, and Tyler Johnson with Sanford Research. The research was supported with funding from the National Eye Institute BrightFocus Foundation, the David Bryant Trust, the Foundation of Fighting Blindness, the Knights Templar Eye Foundation, the Retina Research Foundation, and Research to Prevent Blindness.

The principal project of the Intellectual and Developmental Disabilities Research Center (IDDRC) will focus on Batten disease, specifically CLN3 disease, also known as juvenile-onset Batten disease. Children with this rare genetic disorder start developing symptoms such as vision loss, impaired motor control, seizures, and dementia between 5-10 years of age. The University of Rochester Batten Center (URBC) is a recognized leader in research and treatment of this condition. With several potential gene therapies for Batten disease currently in advanced stages of development, URMC will focus on identifying biomarkers to evaluate the effectiveness of these experimental treatments.

"Even within individual families, we have learned that each diagnosed child may have a different disease experience in terms of the age of symptom onset, pattern of symptom progression, and the types of burdens experienced by them and their families," said Heather Adams, Ph.D., associate professor in the departments of Neurology and Pediatrics and coinvestigator of the UR IDDRC Principal Project. "We cannot miss any opportunity to learn from affected individuals."

Patients and families from across the U.S. come to URMC for care and to participate in research. While some visit labs in Rochester equipped to work with these patients and their families, in many instances a mobile URBC lab will travel to them. "Research is the main way that we feel like we contribute to the Batten community. We try to support research as much as we can. It is how we feel connected, doing what we can to help everyone's effort," said Bridget Patterson who lives in Virginia. Two of her four children, Nora and Gabriel, have Batten disease. "A disease like this really does affect the whole family. We have two other children that are not affected, but they feel the effects of the disease every day. I know that helping their lives be better too is one reason why we are involved in this research. If we can find a cure, a treatment, Nora and Gabriel would be the ones most dramatically impacted but it would help all of us."

There are 11 other currently known childhood-onset forms of Batten disease, genetically distinct from one another, and all have significant impacts on neurodevelopment. URBC is designated a Center of Excellence by the Batten Disease Support and Research Association.

Jonathan W. Mink, M.D., Ph.D., chief of Child Neurology at Golisano Children's Hospital, will lead the nation's largest organization of child neurologists.

Mink, who is also Frederick A. Horner, MD Endowed Professor in Pediatric Neurology, was voted president of the organization by fellow pediatric neurologists from around the U.S. He will assume the position of president-elect following the annual meeting of the Child Neurology Society in November.

Mink will succeed Golisano Children’s Hospital’s pediatrician-in-chief, Nina F. Schor, Ph.D., William H. Eilinger Chair of Pediatrics.

The Child Neurology Society is a non-profit professional association of 1,300 pediatric neurologists in the United States, Canada, and worldwide who are devoted to fostering the discipline of child neurology and promoting the optimal care and welfare of children with neurological and neurodevelopmental disorders.

“It’s a tremendous honor to be elected,” Mink said. “Child neurology is a changing field. There is a real opportunity to leverage our increasing diversity to reach out to students, trainees and patients in a way that we couldn’t before.”

In addition to Mink’s clinical practice and research, he directs the Division of Child Neurology in the Department of Neurology and is associate director of the Child Neurology Residency Program. He also serves on the executive board of the International Child Neurology Association, on the board of directors of the American Neurological Association, and the executive committee of the American Academy of Pediatrics Section on Neurology. He is a member of the National Advisory Neurological Disorders and Stroke Council of the NIH, a medical advisory to the Batten Disease Support and Research Association, and is also an associate editor of Neurology. He served as chair of the Child Neurology Society’s Scientific Program Committee from 2013 to 2015, where he and Schor collaborated to plan the 2014 and 2015 Annual Meetings.

“Nina was a terrific president of the Child Neurology Society. She’s a born leader, and I have learned some lessons on how she fulfilled her duties,” Mink said. “I think it’s tremendous for the University of Rochester. When I started here, there were four child neurologists. Now there are 15, and our residency program is one of the top-rated programs nationally.”

Mink trained in Pediatrics Neurology at St. Louis Children’s Hospital. He received his M.D. and Ph.D. from Washington University.

Mink is nationally recognized as a movement disorders specialist. He’s known for his research on Tourette syndrome and understanding brain mechanisms involved in the control of movement, along with disorders that cause involuntary movement. His research also includes clinical trials that impact the function of children with movement disorders.

Mink will serve one year as president-elect, two as president, and one as past president.

Ruchira Singh, Ph.D.

University of Rochester Medical Center scientist Ruchira Singh, Ph.D., received a grant from the Knights Templar Eye Foundation to investigate how neurodegenerative diseases, such as juvenile Batten disease, cause blindness.

Singh, assistant professor of Ophthalmology and Biomedical Genetics, will use the $60,000 grant to create a human model of Batten disease (CNL3) using patient’s own cells. The project may lead to better understand the disease mechanisms, aiding in the development of drug therapies to preserve vision in affected patients.

For the complete article, visit the URMC newsroom.

There are a number of recent and ongoing clinical trials in Batten Disease. Most of these are focused on asking if these potential new treatments are safe. After safety studies are completed, the next stage of clinical trials research is to learn if these or other interventions are effective. In order to answer this question, we will need a way to measure whether or not an intervention actually makes a meaningful difference in disease course.

Therefore, the URBC hosted a workshop titled, Outcome Measures and Infrastructure for Phase III Studies in JNCL (December 6-7, 2013). The workshop brought together experts in the clinical features of JNCL, experts from other fields (clinical trials in rare diseases, statistics, etc.), and Batten family representatives. Each expert was invited to bring trainee to accompany him/her, so that we can continue cultivating the next generation of researchers who are focused on Batten Disease. Our goals were to:

• Identify possible outcome measures for future clinical trials
• Develop a roadmap for further research to test and refine outcome measures
• Strengthen research collaborations to support outcome measure development

The University of Rochester Medical Center is currently recruiting subjects with JNCL for a clinical trial. This research study will focus on evaluating whether an investigational drug is safe and well tolerated in children with JNCL. Mycophenolate mofetil (also known as Cellcept) is a medication that suppresses the immune system. The study is 22 weeks long with a total of 8 in-person visits and 4 telephone contacts. Four visits require travel to University of Rochester Medical Center in Rochester, New York, and four visits are with your child’s local physician. Four contacts take place by telephone. Travel costs are covered by the study. Children enrolled in the study will take mycophenolate syrup twice a day, and will have blood drawn at each study visit to monitor safety.

More information on the trial can be found at ClinicalTrials.gov, Time Warner Cable News (Rochester, NY television affiliate) and the URMC Newsroom.

For further information, please contact Amy Vierhile at (585) 275-4762.