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.
The Annual Family Conference is Almost Here!
This past month has been a flurry of activity as we have put the finishing touches on a host of science, clinical, and research activities for the conference.
The scientific and clinical program will feature in-person presentations from local and international researchers, interactive Ask-A-Doc sessions with Centers of Excellence Directors and senior clinicians, the latest clinical trial and pipeline updates, including a Q&A with our industry partners, concurrent sessions on “Behavior, Cognition, and Learning,” and “Palliative Care: Debunking the Stigmas,” and an “Ask Me Anything,” session with scientists who are excited to share a collection of laboratory gadgets and items for a true “hands-on” research experience.
Please also check out the “NCL Researchers Challenge” videos in the conference app. Global researchers will present their latest findings in three-minute presentations, and attendees may watch and vote for their favorites.
This year, we are excited to present several on-site research study opportunities for our families. We encourage registrants to check out the Research Study Information flyers here, and we warmly invite you to sign up for any studies that you and your family are interested in. You may sign up in advance or at the Research Study Registration table at the conference. Your participation is vital for advancing research as we all work together on the “Path to a Cure.”
During the Dinner Dance on Saturday evening, July 13, we’ll have special announcements you won’t want to miss!
I can’t wait to see so many of you in St. Louis!
Help Shape The Future Of Batten Disease Research – Community Survey Phase 2 Opening Soon
Last month, we were so encouraged by the response to Phase 1 of our Research Priority Setting project. Through this survey, we received more than 400 research questions that participants felt should be priorities for Batten disease researchers and research funders.
We have now collated a summarized list of popular research questions and will distribute a second survey in July. We’re asking stakeholders to choose the “Top 10” research questions important 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.
Again, whether you’re a parent, clinician, researcher, industry representative, policy maker, educator, allied health, or support worker, we want input from all stakeholders.
Your role in the Batten disease community is crucial, and your response matters.
So please keep an eye out for the Phase 2 survey coming through to your inboxes and socials 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.
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 – June 2024
Targeting autophagy impairment improves the phenotype of a novel CLN8 zebrafish model
Marchese M, et al. Neurobiol Dis. 2024 Jul;197:106536.
ABSTRACT
CLN8 is an endoplasmic reticulum cargo receptor and a regulator of lysosome biogenesis whose loss of function leads to neuronal ceroid lipofuscinosis. CLN8 has been linked to autophagy and lipid metabolism, but much remains to be learned, and there are no therapies acting on the molecular signatures in this disorder. The present study aims to characterize the molecular pathways involved in CLN8 disease and, by pinpointing altered ones, to identify potential therapies. To bridge the gap between cell and mammalian models, we generated a new zebrafish model of CLN8 deficiency, which recapitulates the pathological features of the disease. We observed, for the first time, that CLN8 dysfunction impairs autophagy. Using autophagy modulators, we showed that trehalose and SG2 are able to attenuate the pathological phenotype in mutant larvae, confirming autophagy impairment as a secondary event in disease progression. Overall, our successful modeling of CLN8 defects in zebrafish highlights this novel in vivo model’s strong potential as an instrument for exploring the role of CLN8 dysfunction in cellular pathways, with a view to identifying small molecules to treat this rare disease.
Access the article here.
Phenotypic/Genotypic Profile of Children with Neuronal Ceroid Lipofuscinosis in Southern Brazil
Santos BV, et al. Neuropediatrics. 2024 Jun 10. Epub ahead of print.
ABSTRACT
Introduction: Neuronal ceroid lipofuscinoses (CLNs) are a group of lysosomal storage disorders of genetic origin, characterized by progressive neurodegeneration and intracellular accumulation of autofluorescent lipopigment. Thirteen genes related to CLNs are currently described, showing genetic and allelic heterogeneity, most of them with an autosomal recessive pattern. Due to the few descriptions of cases related to CLNs in Brazil, it is necessary to describe the phenotypic and genotypic characteristics of these patients. This study aims to evaluate the genotypic profile and correlate it with the phenotypic characteristics of patients with CLN in a children’s hospital.
Methods: This study was performed as a descriptive cross-sectional study with analysis of medical records, imaging, and laboratory tests of patients who had a confirmed molecular diagnosis of CLN.
Results: The sample consisted of 11 patients from nine families with different subtypes of CLNs (CLN2, 5, 6, 7, and 8), with CLN2 being the most prevalent in the study. A total of 16 mutation variants were identified in genes associated with the five CLNs described in this study, with typical and atypical clinical phenotypes depending on the subtype and its variants.
Conclusion: Novel mutations identified in the patients in this study showed phenotypes of rapid and severe progression in the CLN2 patient and similar characteristics in CLN6 and CLN7 patients, as previously described in the literature.
Access the article here.
Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis
He H, et al. Ann Neurol. 2024 Jun 15. Online ahead of print.
ABSTRACT
Objective: The aim of this study was to explore the pathogenesis of CLCN6-related disease and to assess whether its Cl–/H+-exchange activity is crucial for the biological role of ClC-6.
Methods: We performed whole-exome sequencing on a girl with development delay, intractable epilepsy, behavioral abnormities, retinal dysfunction, progressive brain atrophy, suggestive of neuronal ceroid lipofuscinoses (NCLs). We generated and analyzed the first knock-in mouse model of a patient variant (p.E200A) and compared it with a Clcn6-/- mouse model. Additional functional tests were performed with heterologous expression of mutant ClC-6.
Results: We identified a de novo heterozygous p.E200A variant in the proband. Expression of disease-causing ClC-6E200A or ClC-6Y553C mutants blocked autophagic flux and activated transcription factors EB (TFEB) and E3 (TFE3), leading to autophagic vesicle and cholesterol accumulation. Such alterations were absent with a transport-deficient ClC-6E267A mutant. Clcn6E200A/+ mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC-6E200A, but not loss of ClC-6 in Clcn6-/- mice, increased lysosomal biogenesis by suppressing mTORC1-TFEB signaling, blocked autophagic flux through impairing lysosomal function, and increased apoptosis. Carbohydrate and lipid deposits accumulated in Clcn6E200A/+ brain, while only lipid storage was found in Clcn6-/- brain. Lysosome dysfunction, autophagy defects, and gliosis were early pathogenic events preceding neuron loss.
Interpretation: CLCN6 is a novel genetic cause of NCLs, highlighting the importance of considering CLCN6 mutations in the diagnostic workup for molecularly undefined forms of NCLs. Uncoupling of Cl– transport from H+ countertransport in the E200A mutant has a dominant effect on the autophagic/lysosomal pathway.
Access the article here.
Intraventricular Cerliponase Alfa Treatment in a Patient with Advanced Neuronal Ceroid Lipofuscinosis Type 2
Nakashima S, et al. Intern Med. 2024 Jun 15;63(12):1807-1812.
ABSTRACT
Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive lysosomal disease caused by decreased activity of the enzyme tripeptidyl peptidase 1 (TPP1) due to pathogenic variants in the TPP1 gene. Cerliponase alfa, a recombinant proenzyme form of TPP1, has shown efficacy in preventing motor and language function decline in early-stage CLN2. However, the safety and effects of this therapy in advanced-stage CLN2 are unclear. We herein report a case of intraventricular cerliponase alfa treatment for over a year in a patient with advanced-stage CLN2. The results suggest the safety and potential efficacy of treatment at an advanced stage of CLN2.
Access the article here.
