NCL RESEARCHERS CHALLENGE – CONGRATULATIONS TO OUR WINNERS!
As part of this year’s Annual Family Conference, we hosted the inaugural NCL Researchers Challenge. Batten disease researchers from all over the world were invited to enter a three-minute thesis-style video presentation, summarizing their team’s main research approach, the latest findings, and the significance of these findings 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!
We are delighted to announce the 3 winning entries:
1st place – The University of Rochester Batten Center team, Rochester NY
Topic: University of Rochester Batten Center Research Programs
2nd place – Dr. Joshua Dearborn, Washington University School of Medicine, St Louis MO
Topic: Medical Marijuana and Batten Disease
3rd place – Lottie Morison, Murdoch Children’s Research Institute, Melbourne Australia
Topic: Communication is connection: Understanding speech, language, and non-verbal communications in CLN2 and CLN3 disease
Our three winners will be featured in the Illuminator over the coming months. Stay tuned!
Videos are still available for viewing in the “Research Videos” section of the conference app.
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
Here are the latest developments in REGENXBIO’s first-in-human gene therapy programs for the treatment of CLN2 disease.
On August 2, REGENXBIO announced the first patient had been dosed in the Phase I/II ocular trial of RGX-381 at Great Ormond Street Hospital in the UK. RGX-381 is an investigational one-time AAV gene therapy for the treatment of ocular manifestations of CLN2 disease, using the NAV® AAV9 to deliver the TPP1 gene directly to the retina. Initial data from this trial is expected to be shared in 2024.
In addition, REGENXBIO’s program for brain/central nervous system (CNS)-targeted gene therapy, known as RGX-181, continues. Physicians in Brazil continue to follow the first child with CLN2 disease dosed with RGX-181 under a single patient investigator-initiated study. Initial interim data from this study, including 6-month results, was presented at the SSIEM (Society for the Study of Inborn Errors of Metabolism) Annual Symposium this week.
RGX-181 is an investigational one-time AAV therapeutic for the treatment of CLN2, using the NAV AAV9 vector to deliver the TPP1 gene directly to the CNS.
For further information, read the press release here or reach out to us at the BDSRA Foundation.
BATTEN DISEASE CENTERS OF EXCELLENCE
Applications are now open – until September 15!
We are proud to announce the launch of the Batten Disease Center of Excellence (CoE) program. This initiative aims to support the formation and ongoing provision of specialized Batten disease care centers across the United States. Health Systems and Academic Medical Centers are encouraged to apply for this designation. Ask your healthcare team/system to apply today.
For more information and to apply, click here.
Applications close September 15, 2023.
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
Sheep models proving valuable in Batten disease gene therapy research and development
This newsletter edition features two recently published papers from a New Zealand-based group, led by Professors Nadia Mitchell and David Palmer of Lincoln University. Over the past decade, this research team has discovered and characterized naturally occurring sheep models of CLN5 and CLN6 disease that each share key clinical features of the human conditions. These models represent ideal systems for testing the clinical efficacy of gene therapies.
The studies below describe some of the key natural history and IND-enabling safety and efficacy studies that contributed to the development of Neurogene’s NGN-101 therapy, currently in Phase 1/2 clinical trial for the treatment of CLN5 disease.
The paper, “Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses,” published in the journal Developmental Biology in late May, compared neurodegeneration, neuroinflammation, and lysosomal storage accumulation in CLN5-affected and CLN6-affected sheep brains from birth to end-stage disease at ≤24 months of age. The disease cascade was remarkably similar for both models and correlated with published clinical (human) data. The study identifies three potential therapeutic windows in affected sheep – pre-symptomatic (3 months), early symptomatic (6 months), and later disease stage (9 months of age). Beyond later-stage, the extensive loss of neurons was considered likely to diminish any chance of therapeutic benefit.
Mitchell and colleagues’ subsequent paper, “Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease,” published August 8, showed that low, moderate and high doses of gene therapy delayed CLN5 disease progression in affected sheep, extended survival and slowed stereotypical brain atrophy. The benefits were observed in those treated before symptom onset (pre-symptomatically) and those treated after symptom onset – particularly in the early symptomatic stage, and the evidence suggests higher doses are likely more effective.
Over the past decade, Professors Mitchell and Palmer and co-author Dr. Imke Tammen have all been recipients of BDSRA Australia research grants, which have contributed vital funds toward the development of these sheep models. Prof. Mitchell presented a summary of her team’s research at the U.S. BDSRA Annual Family Conference in July (conference registrants can view the video via the conference app).
To learn more about the studies, click here.
Disease course may be slowed by ‘exon skipping’ in CLN3 disease
A gene-based technology that acts like a tiny ‘molecular patch’ over faulty DNA or RNA segments is a potential therapeutic solution showing promise in the treatment of Batten disease. Recent research led by Dr. Jessica Centa and Prof. Michelle Hastings at the Rosalind Franklin University of Medicine and Science in Chicago showed these ‘molecular patches,’ known as antisense oligonucleotides or ASOs, restore the production of the healthy gene product and lead to clinical improvement in a mouse model of CLN3 Batten disease.
To validate this therapeutic approach, Centa and team have now generated a mouse model that expresses the same gene product induced by the ASO molecule, whereby faulty gene sequences (around exons 5, 7, and 8) are effectively removed or ‘skipped,’ resulting in the production of a correct, functional CLN3 protein. Behavioral and pathological analyses of these mice demonstrate a less severe phenotype compared with the CLN3 disease mouse model, providing evidence that ASO-induced exon skipping can have a therapeutic effect on CLN3 disease. The study entitled, “Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach,” was published in Molecular Therapy: Nucleic Acids on June 3.
Prof. Hastings presented some of this research at the U.S. BDSRA Annual Family Conference in July. Conference registrants can view the video via the conference app in the agenda section (see Saturday General Session – An Overview of NCL Science).
Biomarker discovery in CLN3: Intriguing findings in cerebrospinal fluid studies
Biological markers or ‘biomarkers’ are important tools for evaluating the presence and progression of disease, and objectively measuring the efficacy of potential therapeutics. Validated biomarkers are a significant unmet need in NCL clinical research and are an area of focus for several research groups around the world. In this study, “Cerebrospinal Fluid Protein Biomarker Discovery in CLN3,” a team led by Dr. Forbes Porter and Dr. An Dang Do at the National Institutes of Health (NIH) in Bethesda Maryland, performed proteomic discovery studies using cerebrospinal fluid (CSF) samples from CLN3-affected individuals. Twenty-five candidate biomarkers for CLN3 disease were identified, including a number of “new and intriguing candidates” warranting further investigation. Read more here.
Dr. Dang Do presented a summary of her team’s research at the U.S. BDSRA Annual Family Conference in July (conference registrants can view the video via the conference app).
A novel miniature pig model of CLN3 disease
Mouse models of CLN3 Batten disease have improved our understanding of the cell biology and disease mechanisms of CLN3 disease, and have been important on the path to therapeutic development. Mouse models do however have limitations in their ‘translatability’ to the human experience of the disease. For example, differences in the size and anatomy of the brain, life span, and the inconsistent, subtle behavior deficits that can be difficult to evaluate in CLN3 mouse models, limit their utility in preclinical studies. This new study, “A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes,” characterizes a novel animal model of CLN3 disease – the miniature pig that has the most common CLN3 disease-causing mutation in humans – the 1 kb deletion or ‘exon 7-8’ deletion. In these CLN3-affected pigs, progressive neuron loss is observed in some regions of the brain and the retina, particularly in later stages of the disease. Hallmarks cell pathologies are also observed in several brain regions. Additionally, affected pigs present with gait abnormalities, similar to deficits seen in human patients. Taken together, the minipig model may have utility in furthering research and development for CLN3 disease.
To learn more, click here.
New cellular roles for CLN3 protein identified in cell study
A Texas-based research team has identified new cellular roles for the CLN3 protein, the loss of which contributes to lysosomal impairment and neurodegeneration in CLN3 disease.
The study led by Alessia Calgani at Baylor College of Medicine in Houston showed that loss of CLN3 protein in cell cultures leads to improper targeting and trafficking of essential enzymes needed for the function of lysosomes. Lysosomes are cellular compartments that act as ‘garbage trucks,’ degrading and removing proteins and other cellular waste. Calgani and colleagues showed that reduced lysosome function in CLN3-deficient cells in turn disrupts key pathways needed to create new, healthy lysosomes, therefore explaining global lysosomal dysfunction in CLN3 disease. The study, “Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation,” was published on July 3 in the journal Nature Communications.
Dr. Calgani presented a summary of her team’s research at the U.S. BDSRA Annual Family Conference in July (conference registrants can view the video via the conference app). A more detailed summary can be found by clicking here.
