Another month has passed, which means 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.
CLINICAL PROGRAM UPDATES
Clinical Trial Tracker
Stay up-to-date with the latest clinical trial and natural history study news with our Clinical Studies Chart on the BDSRA Foundation’s website. Check it out by clicking here.
Collaborations Pharmaceuticals, Inc. Awarded A new $3.9M SBIR Commercialization Readiness Pilot Grant For CLN1 Batten Disease
On March 7, Collaboration Pharmaceuticals announced it was awarded a new NIH grant that will be utilized for the ongoing development of its lead pipeline product, a recombinant human enzyme replacement therapy for CLN1 disease treatment. Currently in preclinical development, Collaboration Pharmaceuticals is actively manufacturing the protein in preparation for IND-enabling toxicity testing.
CEO Dr. Sean Ekins said in a press release, “We now propose in this project production of GMP (Good Manufacturing Practice) protein, continued development of quality procedures, prepare a clinical trial protocol, and submit an IND in collaboration with STC Biologics, Long Scientific LLC, RTI International and CTI Clinical Trial Services, Inc. respectively, in order to translate this potential treatment to the clinic.”
RESEARCH CONFERENCE NEWS
Save the Date: Translational Research Conference for the Management of NCLs
Held on alternate years to the International Congress on Neuronal Ceroid Lipofuscinosis (NCL Congress) this bi-annual meeting is for families, researchers, and industry experts to discuss gaps, lessons learned, and emerging therapeutic approaches in NCL preclinical and clinical research.
The 8th Translational Research Conference will be held in Chicago, at the Westin Chicago Lombard on November 20-22, 2024. There will be more details to follow.
To join the mailing list for updates on this Conference, please email ResearchEvents@sanfordhealth.org.
FAMILY REGISTER
Have you joined the Register yet?
In recent months, we’ve continued to have a wonderful response to our calls for families to join our Register. Let’s keep the momentum going!
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 – March 2024
Disruption of lysosomal nutrient sensing scaffold contributes to pathogenesis of a fatal neurodegenerative lysosomal storage disease
Bagh MB, et al. J Biol Chem. 2024 Feb;300(2):105641.
ABSTRACT
The ceroid lipofuscinosis neuronal 1 (CLN1) disease, formerly called infantile neuronal ceroid lipofuscinosis, is a fatal hereditary neurodegenerative lysosomal storage disorder. This disease is caused by loss-of-function mutations in the CLN1 gene, encoding palmitoyl-protein thioesterase-1 (PPT1). PPT1 catalyzes depalmitoylation of S-palmitoylated proteins for degradation and clearance by lysosomal hydrolases. Numerous proteins, especially in the brain, require dynamic S-palmitoylation (palmitoylation-depalmitoylation cycles) for endosomal trafficking to their destination. While 23 palmitoyl-acyl transferases in the mammalian genome catalyze S-palmitoylation, depalmitoylation is catalyzed by thioesterases such as PPT1. Despite these discoveries, the pathogenic mechanism of CLN1 disease has remained elusive. Here, we report that in the brain of Cln1-/- mice, which mimic CLN1 disease, the mechanistic target of rapamycin complex-1 (mTORC1) kinase is hyperactivated. The activation of mTORC1 by nutrients requires its anchorage to lysosomal limiting membrane by Rag GTPases and Ragulator complex. These proteins form the lysosomal nutrient sensing scaffold to which mTORC1 must attach to activate. We found that in Cln1-/- mice, two constituent proteins of the Ragulator complex (vacuolar (H+)-ATPase and Lamtor1) require dynamic S-palmitoylation for endosomal trafficking to the lysosomal limiting membrane. Intriguingly, Ppt1 deficiency in Cln1-/- mice misrouted these proteins to the plasma membrane disrupting the lysosomal nutrient sensing scaffold. Despite this defect, mTORC1 was hyperactivated via the IGF1/PI3K/Akt-signaling pathway, which suppressed autophagy contributing to neuropathology. Importantly, pharmacological inhibition of PI3K/Akt suppressed mTORC1 activation, restored autophagy, and ameliorated neurodegeneration in Cln1-/- mice. Our findings reveal a previously unrecognized role of Cln1/Ppt1 in regulating mTORC1 activation and suggest that IGF1/PI3K/Akt may be a targetable pathway for CLN1 disease.
Access the article here.
Dem-Aging: autophagy-related pathologies and the “two faces of dementia”
Gammaldi, N. et al. Neurogenetics. 2024 Jan;25(1):39-46
ABSTRACT
Neuronal ceroid lipofuscinosis (NCL) is an umbrella term referring to the most frequent childhood-onset neurodegenerative diseases, which are also the main cause of childhood dementia. Although the molecular mechanisms underlying the NCLs remain elusive, evidence is increasingly pointing to shared disease pathways and common clinical features across the disease forms. The characterization of pathological mechanisms, disease modifiers, and biomarkers might facilitate the development of treatment strategies. The DEM-AGING project aims to define molecular signatures in NCL and expedite biomarker discovery with a view to identifying novel targets for monitoring disease status and progression and accelerating clinical trial readiness in this field. In this study, we fused multiomic assessments in established NCL models with similar data on the more common late-onset neurodegenerative conditions in order to test the hypothesis of shared molecular fingerprints critical to the underlying pathological mechanisms. Our aim, ultimately, is to combine data analysis, cell models, and omic strategies in an effort to trace new routes to therapies that might readily be applied in the most common forms of dementia.
Access the full article here.
Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease
Nayame, K. et al. Mol Cell. 2024 Feb 28:S1097-2765(24)00125-4.
ABSTRACT
Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. CLN3 loss leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage being robustly observed upon CLN3 loss, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome using human cell lines and mouse models. Mechanistically, GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2, which we establish to possess phospholipase B activity. GPDs effectively inhibit the rate-limiting lysophospholipase activity of these phospholipases. Consistently, lysosomes of CLN3-deficient cells and tissues accumulate toxic lysophospholipids. Our work establishes that the storage material in Batten disease directly disrupts lysosomal lipid homeostasis, suggesting GPD clearance as a potential therapeutic approach to this fatal disease.
Access the full article here.
Neuronal ceroid lipofuscinosis type 11 diagnosed patient with bi-allelic variants in GRN gene: case report and review of literature
Sürücü Kara I, et al. J Pediatr Endocrinol Metab. 2024 Jan 23;37(3):280-288
ABSTRACT
Objectives: Neuronal ceroid lipofuscinosis type 11 (NCL11) is a rare disease that presents with progressive cognitive decline, epilepsy, visual impairment, retinal atrophy, cerebellar ataxia and cerebellar atrophy. We present herein a case of NCL11 in a patient diagnosed with neuromotor developmental delay, epilepsy, bronchiolitis obliterans and hypothyroidism.
Case presentation: A 4-year-old male patient was admitted to our clinic with global developmental delay and a medical history that included recurrent hospitalizations for pneumonia at the age of 17 days, and in months 4, 5 and 7. Family history revealed a brother with similar clinical findings (recurrent pneumonia, hypothyroidism, hypotonicity, swallowing dysfunction and neuromotor delay) who died from pneumonia at the age of 22 months. Computed tomography of the thorax was consistent with bronchiolitis obliterans, while epileptic discharges were identified on electroencephalogram with a high incidence of bilateral fronto-centro-temporal and generalized spike-wave activity but no photoparoxysmal response. Cranial MRI revealed T2 hyperintense areas in the occipital periventricular white matter and volume loss in the white matter, a thin corpus callosum and vermis atrophy. A whole-exome sequencing molecular analysis revealed compound heterozygous c.430G>A (p.Asp144Asn) and c.415T>C (p.Cys139Arg) variants in the GRN gene.
Conclusions: The presented case indicates that NCL11 should be taken into account in patients with epilepsy and neurodegenerative diseases.
Access the article here.
Classic and Atypical Late Infantile Neuronal Ceroid Lipofuscinosis in Latin America: Clinical and Genetic Aspects, and Treatment Outcome with Cerliponase Alfa
Geulbert, N, et al, Mol Genet Metab Rep. 2024 Feb 1:38:101060.
ABSTRACT
Introduction: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), is a neurodegenerative autosomal recessive disease caused by TPP1 gene variants, with a spectrum of classic and atypical phenotypes. The aim of treatment is to slow functional decline as early as possible in an attempt to improve quality of life and survival. This study describes the clinical characteristics as well as the response to treatment with cerliponase alfa.
Results: A total of 36 patients were observed (range of follow-up of 61-110 weeks post-treatment). At presentation, patients with the classic phenotype (n = 16) exhibited regression in language (90%), while seizures were the predominant symptom (87%) in patients with the atypical phenotype (n = 20). Median age of symptom onset and time to first specialized consultation was 3 (classical) and 7 (atypical) years, while the median time interval between onset of symptoms and treatment initiation was 4 years (classical) and 7.5 (atypical). The most frequent variant was c.827 A > T in 17/72 alleles, followed by c.622C > T in 6/72 alleles. All patients were treated with cerliponase alfa, and either remained functionally stable or had a loss of 1 point on the CLN2 scale, or up to 2 points on the Wells Cornel and Hamburg scales, when compared to pretreatment values.
Discussion and conclusion: This study reports the largest number of patients with CLN2 currently on treatment with cerliponase alfa in the world. Data show a higher frequency of patients with atypical phenotypes and a high allelic proportion of intron variants in our region. There was evidence of long intervals until first specialized consultation, diagnosis, and enzyme replacement therapy. Follow-up after the initiation of cerliponase alfa showed slower progression or stabilization of the disease, associated with adequate clinical outcomes and stable functional scores. These improvements were consistent in both clinical phenotypes.
Access the full article here.
Identification of New Modulators and Inhibitors of Palmitoyl-Protein Thioesterase 1 for CLN1 Batten Disease and Cancer
Puhl, AC, et al. ACS Omega. 2024 Feb 28;9(10):11870-11882.
ABSTRACT
Palmitoyl-protein thioesterase 1 (PPT1) is an understudied enzyme that is gaining attention due to its role in the depalmitoylation of several proteins involved in neurodegenerative diseases and cancer. PPT1 is overexpressed in several cancers, specifically cholangiocarcinoma and esophageal cancers. Inhibitors of PPT1 lead to cell death and have been shown to enhance the killing of tumor cells alongside known chemotherapeutics. PPT1 is hence a viable target for anticancer drug development. Furthermore, mutations in PPT1 cause a lysosomal storage disorder called infantile neuronal ceroid lipofuscinosis (CLN1 disease). Molecules that can inhibit, stabilize, or modulate the activity of this target are needed to address these diseases. We used PPT1 enzymatic assays to identify molecules that were subsequently tested by using differential scanning fluorimetry and microscale thermophoresis. Selected compounds were also tested in neuroblastoma cell lines. The resulting PPT1 screening data was used for building machine learning models to help select additional compounds for testing. We discovered two of the most potent PPT1 inhibitors reported to date, orlistat (IC50 178.8 nM) and palmostatin B (IC50 11.8 nM). When tested in HepG2 cells, it was found that these molecules had decreased activity, indicating that they were likely not penetrating the cells. The combination of in vitro enzymatic and biophysical assays enabled the identification of several molecules that can bind or inhibit PPT1 and may aid in the discovery of modulators or chaperones. The molecules identified could be used as a starting point for further optimization as treatments for other potential therapeutic applications outside CLN1 disease, such as cancer and neurological diseases.
Read the full article here.
The parent and family impact of CLN3 disease: an observational survey-based study
Schulz A, et al. Orphanet J Rare Dis. 2024 Mar 18;19(1):125 .
ABSTRACT
Background: CLN3 disease (also known as CLN3 Batten disease or Juvenile Neuronal Ceroid Lipofuscinosis) is a rare pediatric neurodegenerative disorder caused by biallelic mutations in CLN3. While extensive efforts have been undertaken to understand CLN3 disease etiology, pathology, and clinical progression, little is known about the impact of CLN3 disease on parents and caregivers. Here, we investigated CLN3 disease progression, clinical care, and family experiences using semi-structured interviews with 39 parents of individuals with CLN3 disease. Analysis included response categorization by independent observers and quantitative methods.
Results: Parents reported patterns of disease progression that aligned with previous reports. Insomnia and thought- and mood-related concerns were reported frequently. “Decline in visual acuity” was the first sign/symptom noticed by n = 28 parents (70%). A minority of parents reported “behavioral issues” (n = 5, 12.5%), “communication issues” (n = 3, 7.5%), “cognitive decline” (n = 1, 2.5%), or “seizures” (n = 1, 2.5%) as the first sign/symptom. The mean time from the first signs or symptoms to a diagnosis of CLN3 disease was 2.8 years (SD = 4.1). Misdiagnosis was common, being reported by n = 24 participants (55.8%). Diagnostic tests and treatments were closely aligned with observed symptoms. Desires for improved or stabilized vision (top therapeutic treatment concern for n = 14, 32.6%), cognition (n = 8, 18.6%), and mobility (n = 3, 7%) dominated parental concerns and wishes for therapeutic correction. Family impacts were common, with n = 34 (81%) of respondents reporting a financial impact on the family and n = 20 (46.5%) reporting marital strain related to the disease.
Conclusions: Collectively, responses demonstrated clear patterns of disease progression, a strong desire for therapies to treat symptoms related to vision and cognition, and a powerful family impact driven by the unrelenting nature of disease progression.
Access the full article here.
A recessive CLN3 variant is responsible for delayed-onset retinal degeneration in Hereford cattle
Reith, RR, et al. J Vet Diagn Invest. 2024 Mar 22:10406387241239918.
ABSTRACT
Thirteen American Hereford cattle were reported blind with presumed onset when ~12-mo-old. All blind cattle shared a common ancestor through both the maternal and paternal pedigrees, suggesting a recessive genetic origin. Given the pedigree relationships and novel phenotype, we characterized the ophthalmo-pathologic changes associated with blindness and identified the responsible gene variant. Ophthalmologic examinations of 5 blind cattle revealed retinal degeneration. Histologically, 2 blind cattle had loss of the retinal photoreceptor layer. Whole-genome sequencing (WGS) of 7 blind cattle and 9 unaffected relatives revealed a 1-bp frameshift deletion in ceroid lipofuscinosis neuronal 3 (CLN3; chr25 g.26043843del) for which the blind cattle were homozygous and their parents heterozygous. The identified variant in exon 16 of 17 is predicted to truncate the encoded protein (p. Pro369Argfs*8) battenin, which is involved in lysosomal function necessary for photoreceptor layer maintenance. Of 462 cattle genotyped, only blind cattle were homozygous for the deletion. A query of WGS data of > 5,800 animals further revealed that the variant was only observed in related Hereford cattle. Mutations in CLN3 are associated with human juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease, which results in early-onset retinal degeneration and lesions similar to those observed in our cases. Our data support the frameshift variant of CLN3 as causative of blindness in these Hereford cattle, and provide additional evidence of the role of this gene in retinal lesions, possibly as a model for human non-syndromic JNCL.
Access the full article here.
Natural History of Neuronal Ceroid Lipofuscinosis Type 6, Late Infantile Disease
O’Neal, M. et al. Pediatr Neurol. 2024 Mar 1:154:51-57.
ABSTRACT
Background: Mutations in the CLN6 gene cause late infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disease of childhood onset. Clinically, individuals present with progressive motor and cognitive regression, ataxia, and early death. The aim of this study is to establish natural history data of individuals with classic, late-infantile-onset (age less than five years) CLN6 disease.
Methods: We analyzed the natural history of 25 patients with late-infantile-onset CLN6, utilizing the Hamburg motor-language scale to measure disease progression. The key outcomes were CLN6 disease progression, assessed by rate of decline in motor and language clinical domain summary scores (0 to 6 total points); onset and type of first symptom; onset of first seizure; and time from first symptom to complete loss of function.
Results: Median age of total motor and language onset of decline was 42 months (interquartile range 36 to 48). The estimated rate of decline in total score was at a slope of -1.20 (S.D. 0.30) per year, after the start of decline. Complete loss of both motor and language function was found to be, on average, 88.1 months (S.D. 13.5).
Conclusions: To our knowledge, this is the largest international study that monitors the longitudinal natural history and progression of CLN6 disease. These data may serve as a template for future interventional trials targeted to slow the progression of this devastating disease.
Access the article here.
