It’s time for research updates! BDSRA Foundation’s Head of Research & Medical Affairs Dr. Ineka Whiteman breaks down Batten disease clinical program updates, research news & opportunities, and resources in her monthly column, as seen in BDSRA’s monthly newsletter, The Illuminator.
CLN1 Natural History Study Global Roundtable
On May 23, the BDSRA Foundation hosted a virtual roundtable meeting with 19 key stakeholders across four continents taking part in a robust discussion on the future direction of CLN1 natural history studies.
It was encouraging to see such active participation and equal voices around the table, with representatives from the CLN1 family community (U.S., Europe, and Scandinavia), patient advocacy groups (BDSRA Canada, BDSRA Australia, BDFA UK, and Taylor’s Tale), industry partners (JCR Pharmaceuticals, Taysha Gene Therapies, and Collaboration Pharmaceuticals), and clinical centers involved in CLN1 natural history studies, including University Medical Center Hamburg-Eppendorf, Germany; Rush University Medical Center, Chicago, IL; Kennedy Krieger Institute, Baltimore, MD; Nationwide Children’s Hospital, Columbus, OH; and University of Rochester Batten Center (URBC), Rochester, NY.
Industry partners briefly shared updates on their pipeline programs, including those in clinical and preclinical stages. This laid the foundation for the following discussions, reinforcing the need for and importance of robust natural history data in driving CLN1 therapeutic development. Existing CLN1 natural history data collected through respective studies in the U.S. and Germany were then presented to the group. Discussions that followed focused on critical learnings and insights gained from these studies, brainstorming how to best complement and/or fortify those current datasets across continents, countries, and sites, and how to engage and collaborate with CLN1 patients and families worldwide effectively. Participants agreed that natural history study activities moving forward must be consistent and unified across continents and sites to ensure the best outcomes for our patient community. The next big step will be enacting the key ideas and potential solutions discussed. There is more to come, and we look forward to sharing further developments soon!
Help Shape The Future of Batten Disease Research – Community Survey Phase 2 Opening Soon
Over the past two weeks, you may have seen announcements on social media and in your inboxes seeking your input on the topics and questions YOU feel should be prioritized by Batten disease researchers and research funders.
We are delighted to partner with Kennedy Krieger Institute on this two-phase Research Priority Setting project and want to thank all those who participated in the Phase 1 survey.
We’re halfway there!
In Phase 2, we will collate all the responses received in Phase 1 and produce a summarized list of research questions. This list will be sent around in a second survey, and we will ask stakeholders to rank the list of research questions in order of importance to YOU. Those rankings will determine the “top priority research” questions that will help inform and drive research priorities and future investment in Batten disease. You may participate in Survey 2 whether you completed Survey 1 or not. Whether you’re a parent, clinician, researcher, industry representative, policy maker, educator, allied health, or support worker, we are seeking input from all stakeholders.
Your role in the Batten disease community is important, and your response matters.
So please keep an eye out for the Phase 2 survey coming to your inboxes and social media channels soon! And as always, thank you for your support and dedication to our shared mission.
Warm regards,
CLINICAL PROGRAM UPDATES
Clinical Trial Tracker
Keep up-to-date with the latest clinical trial and natural history study news with our Clinical Studies Chart on BDSRA’s website. Check it out by clicking here.
REGENXBIO CLN2 gene therapy program preliminary data presented at ARVO
As REGENXBIO continues to actively explore partnership opportunities to enable the ongoing development of its CLN2 gene therapy programs (see previous announcements on this by clicking here), preliminary data from the RGX-381 ocular gene therapy program was presented at the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting held May 5-9 in Seattle. Associate Professor Rob Henderson, an Ophthalmic Surgeon at Great Ormond Street Hospital UK, presented the latest data from four patients treated in the Phase 1/2 study, A First-in-Human Study in Pediatric Patients With Ocular CLN2 Disease (NCT05791864).
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 and natural history opportunities.
The Register also enables BDSRA to understand more 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 in the U.S. and internationally.
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!
RESEARCH OPPORTUNITIES
Characterizing Sleep in Batten Disease
Principal Investigator: Heather Adams, Ph.D.
Research sponsor: Batten Disease Support, Research, & Advocacy Foundation
The University of Rochester Batten Center is conducting a study of sleep function in individuals with CLN2 and CLN3 Batten disease.
What is involved?
Affected individuals will provide saliva samples to test melatonin concentration, and wear an actigraph (a wrist-watch style activity monitor). Parents/caregivers will assist the affected individual with study activities and will complete questionnaires.
Who may be eligible?
Affected individuals who…
- have a confirmed genetic or enzyme-based diagnosis of CLN2 or CLN3 disease
- have any symptoms of CLN2 or CLN3 disease
- are at least 2 years old
- live at home with at least one primary caregiver
- have not taken oral melatonin in the past 2 weeks (before study participation begins), or have only taken it occasionally (no more than 3 times per week)
No travel is required! All study activities will take place at your own home. This study is open to families currently residing in the U.S.
The affected child & parent will receive $200 (total for household) for participation in the research.
If you are interested in learning more about the study, please contact the study team at Batten@URMC.Rochester.edu or call Study Coordinator, Marianna Pereira-Freitas at: (585) 274-0205.
PUBLICATION HIGHLIGHTS – May 2024
A needle in a haystack? The impact of a targeted epilepsy gene panel in the identification of a treatable but rapidly progressive metabolic epilepsy: CLN2 disease
Lourenço CM, et al. Arq Neuropsiquiatr. 2024 May; 82(5):1-8.
ABSTRACT
Background: Neuronal ceroid lipofuscinoses (NCL) are a group of autosomal recessive, inherited, lysosomal, and neurodegenerative diseases that causes progressive dementia, seizures, movement disorders, language delay/regression, progressive visual failure, and early death. Neuronal ceroid lipofuscinosis type 2 (CLN2), caused by biallelic pathogenic variants of the TPP1 gene, is the only NCL with an approved targeted therapy. The laboratory diagnosis of CLN2 is established through highly specific tests, leading to diagnostic delays and eventually hampering the provision of specific treatment for patients with CLN2. Epilepsy is a common and clinically-identifiable feature among NCLs, and seizure onset is the main driver for families to seek medical care.
Objective: To evaluate the results of the Latin America Epilepsy and Genetics Program, an epilepsy gene panel, as a comprehensive tool for the investigation of CLN2 among other genetic causes of epilepsy.
Methods: A total of 1,284 patients with epilepsy without a specific cause who had at least 1 symptom associated with CLN2 were screened for variants in 160 genes associated with epilepsy or metabolic disorders presenting with epilepsy through an epilepsy gene panel.
Results: Variants of the TPP1 gene were identified in 25 individuals (1.9%), 21 of them with 2 variants. The 2 most frequently reported variants were p.Arg208* and p.Asp276Val, and 2 novel variants were detected in the present study: p.Leu308Pro and c.89 + 3G > C Intron 2.
Conclusion: The results suggest that these genetic panels can be very useful tools to confirm or exclude CLN2 diagnosis and, if confirmed, provide disease-specific treatment for the patients.
Access the article by clicking here.
A novel homozygous CLN6 Tyr142Cys variant in a nonconsanguineous family with Kufs disease
Chen B, et al. Neurol Sci. 2024 May 21. Epub ahead of print.
ABSTRACT
Background: Neuronal ceroid lipofuscinoses are a genetically heterogeneous group of inherited lysosomal storage disorders. Kufs disease is the predominant form of neuronal ceroid lipofuscinosis in adults, but it’s rare and challenging to diagnose.
Case description: The proband initially presented with cognitive deterioration and parkinsonian traits. At 35, he was admitted to hospital following a tonic-clonic seizure. Brain magnetic resonance imaging showed atrophy of the cerebral cortex and cerebellum, enlarged ventricles, and thinned corpus callosum. The proband’s younger brother and sister were also affected, and the clinical phenotype within the family was consistent. Whole-exome Sequencing of the proband revealed a novel homozygous mutation in CLN6 (NM_017882: c.425A > G, p. Tyr142Cys). Co-segregation analysis revealed that two other affected individuals carried a homozygous mutation at the same locus, with both parents exhibiting heterozygous mutations of c.425A > G.
Conclusion: Our study not only provides insights into the clinical presentation and development of the disease within the affected family but also expanded the mutational and phenotypical spectrum of the CLN6 gene.
Access the article by clicking here.
Exploring concurrent validity of the CLN2 Clinical Rating Scale: Comparison to PedsQL using cerliponase alfa clinical trial data
Specchio N, et al. PLoS One. 2024 May 22;19(5):e0302382.
ABSTRACT
Background: The CLN2 Clinical Rating Scale evaluates disease progression in CLN2 disease, an ultra-rare, neurodegenerative disorder with late infantile onset. To validate the Clinical Rating Scale, a comparison with the Pediatric Quality of Life Inventory (PedsQL) was conducted utilising clinical trial data investigating cerliponase alfa use in CLN2 disease.
Methods: Linear regression and mixed effects models were used to investigate the relationship between the Clinical Rating Scale and PedsQL using open-label, single-arm, phase 1/2 (NCT01907087) and ongoing extension study (NCT02485899) data of 23 children with CLN2 disease treated with cerliponase alfa for ≥96 weeks.
Results: Correlations between the four Clinical Rating Scale domains were low. Linear mixed effects analyses showed significant correlation between PedsQL and Clinical Rating Scale (Total score or motor-language [ML] score adjusted p-values <0.05), driven by the relationship with the PedsQL Physical domain. A statistically significant relationship was identified between the Clinical Rating Scale motor domain and PedsQL (Total score: adjusted p-value = 0.048, parameter estimate [PE] = 8.10; Physical domain score: adjusted p-value = 0.012; PE = 13.79).
Conclusions: Each domain of the Clinical Rating Scale provides unique information on disease state. Validity of the scale is supported by its relationship with the PedsQL. Among the four domains of the Clinical Rating Scale, motor has the highest correlation to PedsQL, suggesting motor function as a driver of patients’ quality of life. The lack of association between the remaining domains of the Clinical Rating Scale and PedsQL suggests that additional disease-specific measures may be needed to fully capture the quality of life impact of CLN2 disease.
Access the article by clicking here.
A current view of mitochondria damage and the diversity of lipopigment inclusions in neuronal ceroid lipofuscinose type 2 from rectal biopsy
Felczak P, et al. Folia Neuropathol. 2024;62(1):21-31.
ABSTRACT
Case report – Neuronal ceroid lipofuscinoses (NCLs) are a growing group of neurodegenerative storage diseases, in which specific features are sought to facilitate the creation of a universal diagnostic algorithm in the future. In our ultrastructural studies, the group of NCLs was represented by the CLN2 disease caused by a defect in the TPP1 gene encoding the enzyme tripeptidyl-peptidase 1. A 3.5-year-old girl was affected by this disease. Due to diagnostic difficulties, the spectrum of clinical, enzymatic, and genetic tests was extended to include analysis of the ultrastructure of cells from a rectal biopsy. The aim of our research was to search for pathognomonic features of CLN2 and to analyse the mitochondrial damage accompanying the disease. In the examined cells of the rectal mucosa, as expected, filamentous deposits of the curvilinear profile (CVP) type were found, which dominated quantitatively. Mixed deposits of the CVP/fingerprint profile (FPP) type were observed less frequently in the examined cells. A form of inclusions of unknown origin, not described so far in CLN2 disease, were wads of osmophilic material (WOMs). They occurred alone or co-formed mixed deposits. In addition, atypically damaged mitochondria were observed in muscularis mucosae. Their deformed cristae had contact with inclusions that looked like CVPs. Considering the confirmed role of the c subunit of the mitochondrial ATP synthase in the formation of filamentous lipopigment deposits in the group of NCLs, we suggest the possible significance of other mitochondrial proteins, such as mitochondrial contact site and cristae organizing system (MICOS), in the formation of these deposits. The presence of WOMs in the context of searching for ultrastructural pathognomonic features in CLN2 disease also requires further research.
Access the article by clicking here.
