Greetings from the NCL 2023 Congress in Hamburg, Germany! This month’s research column is hot off the press from the premier international research meeting for Batten disease. With over 200 in-person delegates including scientists, clinicians, industry partners, patient advocacy groups, and families, it’s been an exciting week of presentations, discussions, and connecting with colleagues from all over the world. We will publish a full report on the latest discoveries and meeting highlights in next month’s addition. In the meantime, keep an eye out for a few snippets from President Amy Fenton Parker and me on our social media forums!

NCL RESEARCHERS CHALLENGE 2023:
MEET THE URBC TEAM

As part of this year’s Annual Family Conference program, we hosted the inaugural NCL Researchers Challenge. Batten disease researchers from all over the world were invited to enter a “3-minute thesis” style video presentation, summarizing their team’s main research approach, latest findings, and what the significance of these findings is for our Batten community. Conference registrants were invited to view and vote for their favorites. It was so wonderful to see the level of interest and engagement from both the research and family communities!

Congratulations to the University of Rochester Batten Center (URBC) team from Rochester, NY who were awarded first place. We recently conducted an interview with the team, and we’re delighted to showcase some of their key projects and discoveries below.

Meet the team below:

Top (pictured from left): Jennifer Vermilion, MD (URBC Director); Amy Vierhile, DNP, RN, PPCNP-BC (Lead Clinical Coordinator), Patricia Fenton, RN, CCRC (Coordinator).

Bottom (pictured from left): Heather Adams, Ph.D. (Neuropsychologist), Marianna Pereira-Freitas, BA (Coordinator).

ABOUT THE URBC

The URBC is a comprehensive Batten disease clinical and research center located at the University of Rochester Medical Center (URMC) in Rochester, New York. The URBC provides support and clinical services, contributes new knowledge, and works to find treatments that will slow, halt, or prevent disease in people with Batten disease. Here, the URBC team shares some insights into their research.

Can you tell us a bit about the research carried out at the URBC?

The University of Rochester Batten Center started studying Batten disease (i.e. Neuronal ceroid lipofuscinosis, or NCL) in 2002 and has had a very active research team over the past two decades. We have been looking at all forms of Batten disease; studying the various symptoms such as vision, cognitive function, motor movements, mood, sleep quality, and behavior. One of our major research studies entails gathering information from affected individuals and their families on the natural history of Batten disease. Importantly, these data have been used to help researchers and scientists when planning for treatment trials.

Natural history? This term may seem a little odd to some at first. Can you please explain what the term “natural history” means, in the context of Batten disease?

Natural history refers to how a disease and its symptoms unfold and progress over time. The URBC natural history research study follows affected individuals with any of the NCL forms. By observing affected individuals as they age, we can learn when particular symptoms begin and answer questions like: “Do those symptoms remain stable over time, worsen, or improve?” “What symptoms lead to disability?;” and “What factors might be related to fewer symptoms and/or less disability?” We also want to understand how symptoms, and their changes over time, impact an affected person’s quality of life, daily functioning, and family function. All of this information furthers our understanding of the progression of NCL disorders and helps to establish a baseline for comparison to disease-modifying treatments.  Also, understanding the disease’s natural history has helped us learn about differences between the various NCL types, or even within a particular NCL disorder (e.g. different patterns of progression for girls versus boys affected by CLN3 Batten disease).

Tell us about some of the specific research projects currently underway at URBC.

The core of the URBC research is our Natural History Study, which guides our work to understand how all forms of Batten disease develop and progress over time. At the heart of the Natural History study is the Unified Batten Disease Rating Scale (UBDRS), a disease-specific neurological exam used to measure the core symptoms of NCLs. This exam was developed at the URMC and has remained a standard for examining disease-specific related symptoms. With all this, we have learned much about how Batten disease changes over time, particularly when we can evaluate the same individuals multiple times over years. In addition, we conduct neuropsychological evaluations to assess attention, language, and memory and how thinking skills change over time as well. We ask parents, who are considered the experts of their affected child(ren), to help us learn about mood, behavior, adaptive function, and quality of life via parent reports. Through those different assessments, we increase our knowledge about Batten disease and have made various interesting discoveries over the years. Most of all, it has encouraged us to expand our research into other areas of Batten Disease.

We are also about to launch a new study to learn more about sleep dysfunction in individuals with CLN2 and CLN3 diseases. For instance, we are interested in overall sleep quality and problems with falling asleep, staying asleep, and excessive daytime sleepiness.

Another study we are conducting is focused on CLN3 disease and is led by Dr. Erika Augustine (the study’s Principal Investigator). Dr. Augustine is now based at Kennedy Krieger Institute in Baltimore, MD, though remains a close collaborator with and member of the URBC as well. Two of the study’s goals include finding sensitive clinical assessments to measure how patients feel and function, and to establish rigorous methods that could be used to evaluate patients consistently across multi-site studies.

Lastly, we are also one of two sites in the world currently conducting a CLN5 gene therapy study!

Tell us about some of those discoveries!

  • As mentioned above, we were able to demonstrate that boys and girls with CLN3 Batten disease have different patterns of disease progression; on average, girls may develop symptoms about a year later than boys, but the progression of their physical symptoms happens more rapidly.
  • We used our natural history dataset to learn whether individuals taking the drug flupirtine experienced a clinical benefit from this medication. We did not find any significant differences between those who did and did not take this drug.
  • The UBDRS data, collected over many years, allowed us to quantify the rate of physical declines in CLN3 Batten disease.
  • A study completed by one of our former medical students explored marital quality for parents of children with any form of Batten disease. We discovered ways in which parents across many different affected families learn about Batten disease and how they share information and support one another.
  • Our studies have contributed to our understanding of parents’ knowledge about genetic testing and their preferences related to testing affected and unaffected family members, including other children in the family.
  • Two of our studies that were completed long before the start of the COVID-19 public health emergency (studies conducted in 2011 and 2015) demonstrated the feasibility and reliability of telemedicine assessments for use in our natural history research. This allowed for a quick, easy, and successful transition to remote assessments beginning in Spring 2020.
  • We increased our understanding of the different seizure types that are seen in individuals affected with CLN3 Batten disease.

What role do families play in your research?

Family participation is essential for us to carry out vital research. Input from families increases our knowledge about Batten disease and can affect the research we do by improving upon what we already know and provide novel perspectives. Not all of our research is carried out in Rochester, but also when we come to the BDSRA Foundation’s Annual Family Conference. Every year, our team travels to see the families and affected children, granting us the opportunity to conduct some of our research there in person. We are so grateful that the BDSRA Foundation and families have welcomed us into their space. We have also, over the years, conducted research “house calls”, visiting affected families right in their homes. This is also beneficial to families to ease the burden of travel (i.e. financial stress, physical/medical challenges to travel, time away from home, etc.).

We have been attending the conference every year since 2002 and enjoy sitting down with families to learn from them, hear about their experiences, and discuss whatever questions they bring to us. In fact, those questions have led to some really interesting discoveries. For example, our discovery regarding the different rates of progression in CLN3 disease between affected boys and girls came from a family member, who had brought this topic up the year prior. This reinforces the idea that parents and other family members are the real experts in the affected individual’s life and the experience of living with Batten disease.

In our upcoming study about sleep dysfunction in CLN2 and CLN3 Batten disease, parents will be directly involved with data collection activities since all of the research will be conducted in the home setting. This is another example of how parents, and other caregivers, play a critical role in capturing a holistic view of Batten disease.

Why does URBC’s research matter?

Our research matters because it helps us learn more about the issues and concerns faced by parents, siblings, other family members, and affected children living with Batten disease. By continually conducting research, we uncover more about Batten Disease and how to best respond to the needs of the community. With the goal of learning how to better treat different symptoms in affected individuals, we ultimately hope to discover cures for these diseases.

How can families get involved?

Families can get involved in research by visiting the University of Rochester Batten Center website: www.rochesterbatten.urmc.edu. On this page, families can find our contact information and sign up for our contact registry and learn about past and upcoming research studies. Among many educational resources on the page, we post updates to keep individuals informed of what’s happening at URBC!

CLINICAL PROGRAM UPDATES

Clinical Trial Tracker

Have you seen our NEW chart tracking clinical trials for Batten disease? Learn more with this Toolbox Tuesday video. View the chart by clicking here and watch the video below for more information.

Gene therapy studies for CLN2 disease – REGENXBIO

Further to the developments we shared on REGENXBIO’s CLN2 gene therapy programs in the August Illuminator, we want to share REGENXBIO announced the topline preliminary 6-month data from the ‘RGX-181’ brain-targeted gene therapy program at SSIEM (Society for the Study of Inborn Errors of Metabolism) Annual Symposium in Jerusalem on August 31. In this investigator-initiated study in Brazil, physicians treated one child with CLN2 disease dosed with RGX-181 under a single patient investigator-initiated study. Initial interim data from this study showed:

  • One-time administration of RGX-181 was well tolerated, achieved sustained gene expression and demonstrated clinically meaningful improvements across multiple measures including reduced (86%) seizure frequency.
  • Investigators observed encouraging neurodevelopmental skill acquisition at 6 months.

To read more head to: Initial Clinical Data of First Pediatric CLN2 Patient Dosed with RGX-181 Presented at SSIEM Annual Symposium.

FAMILY REGISTER 

Have you joined the Register yet?

The BDSRA Foundation Family Register is a vital tool that enables us to keep you informed of ongoing Batten disease research, including future clinical research opportunities.

The Register also enables the BDSRA Foundation to better understand the prevalence of Batten disease, including the different subtypes and geographical locations. This helps us tailor our education and support activities according to the needs of our families. The Register is open to all current and bereaved families.

The information collected in this form is kept STRICTLY CONFIDENTIAL. Your involvement in this survey is entirely voluntary, and you may request to be removed from the list at any time. The form takes just a few minutes to complete and can be accessed by clicking here.

Thank you for participating in this important initiative!

PUBLICATION SUMMARIES

Assessment of CLN2 disease gene therapy in primate model

In 2020, Sondhi and colleagues published results from an investigative gene therapy study for the treatment of CLN2 disease. In that study, 8 children with mild to moderate CLN2 disease were treated with intraparenchymal administration (infusion of drug into the brain tissue via burr holes in the skull) of an AAV viral serotype encoding the human CLN2 gene, known as AAVrh.10hCLN2. Researchers concluded that the treatment “slowed the progression of disease in children with CLN2 disease, [however], improvements in vector design and delivery strategies will be necessary to halt disease progression using gene therapy.”

In their latest study, Assessment of Safety and Biodistribution of AAVrh.10hCLN2 Following Intracisternal Administration in Nonhuman Primates for the Treatment of CLN2 Batten disease, published in August, the research team assessed whether the less invasive intracisternal delivery route (infusion into cisterna magna compartment at the base of the skull) would be safe and provide a wider distribution of the TPP-1 enzyme. The study was conducted in nonhuman primates (NHP) with intracisternal delivery to the cerebral spinal fluid of AAVrh.10hCLN2. Overall, results indicate that delivery of the investigational gene therapy via the intracisternal route is safe, and the doses administered led to widely distributed TPP-1 in the brain and cerebrospinal fluid (CSF) at levels that are potentially therapeutic.

An exciting new role for the CLN5 gene

Lysosomes play a crucial role in maintaining neuronal health in childhood and in age-related neurodegenerative diseases. Lysosomal function is potently enhanced by an enigmatic lipid known as bis(monoacylglycero)phosphate (BMP). Alterations in BMP levels are linked to neurodegeneration, and its accumulation is increasingly recognized as a ‘firefighter’ response to lysosomal dysfunction. However, the enzyme responsible for BMP production has remained unknown for decades, hindering understanding and translational potential. In this study, The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase, Uche Medoh and colleagues now show that the gene CLN5, the loss of which causes CLN5 Batten disease, encodes the long-sought BMP synthase. This discovery establishes the groundwork for future research on the fundamental aspects of BMP and its therapeutic applications in CLN5 disease, other NCL subtypes, and potentially other neurodegenerative conditions.