AT-GTX-502 / Amicus - LARVOL DELTA

Advances in AAV9 Gene Therapy for CLN3 – Update on the Phase I/II Clinical Trial Indicating Lasting Efficacy at 5 Years Post Dosing and Next Steps in Program Development (ASGCT 2025) - "Juvenile neuronal ceroid lipofuscinosis (JNCL), also called CLN3 Batten Disease, is a debilitating autosomal recessive neurodegenerative disorder affecting children with onset around 4-10 years of age...Additional preclinical efforts have positioned this program optimally for further development to bring this therapy to patients with urgent need. Disease Focus of Abstract:Central Nervous System Disorders"

Clinical • Gene therapy • P1/2 data • CNS Disorders • Epilepsy • Gene Therapies • Metabolic Disorders

Splice-Switching Antisense Oligonucleotide Drug Discovery for CLN3 Batten Disease (ASGCT 2025) - "Together our results suggest that SSO-mediated exon skipping is a promising therapeutic approach for multiple CLN3 Batten disease-causing variants. Disease Focus of Abstract:Genetic Diseases"

CNS Disorders • Epilepsy • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Ophthalmology • Pediatrics • Rare Diseases

Evidence of the impact of CLN2 and CLN3 Batten disease on families in the United Kingdom. (PubMed, Orphanet J Rare Dis) - "This study contributes novel UK specific data on family experiences and unmet needs in CLN2 and CLN3 disease. More needs to be done to ensure NCLs are diagnosed early, and timely local support services are made available to protect quality of life for both the affected children and their families."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Epilepsy

Elevated lysosomal pH contributes to altered sphingolipid signaling and defective photoreceptor outer segment (POS) phagocytosis in a stem cell-derived model of CLN3 Batten disease. (ARVO 2025) - "Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Ophthalmology • ASAH1

Recombinant acid ceramidase can rescue photoreceptor outer segment loss in an iPSC model of CLN3-Batten disease (ARVO 2025) - "Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Ophthalmology • ASAH1

Speech, Language and Non-verbal Communication in CLN2 and CLN3 Batten Disease. (PubMed, J Inherit Metab Dis) - "Challenging behaviours were common in CLN3 (11/17, 65%), but less frequent in CLN2 (4/16, 25%) disease. Individuals with Batten disease require tailored speech therapy incorporating communication partner training utilising environment adaptations and informal communication behaviours."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Genetic and Cellular Basis of Impaired Phagocytosis and Photoreceptor Degeneration in CLN3 Disease. (PubMed, Invest Ophthalmol Vis Sci) - "CLN3 Batten disease (also known as juvenile neuronal ceroid lipofuscinosis) is a lysosomal storage disorder that typically initiates with retinal degeneration but is followed by seizure onset, motor decline and premature death...CLN3Δ7-8/Δ7-8 mutation (which affects ≤85% of patients) affects both RPE and POS and leads to photoreceptor cell loss in CLN3 disease. Furthermore, both primary RPE dysfunction and mutant POS independently contribute to impaired POS phagocytosis in CLN3 disease."

Journal • CNS Disorders • Epilepsy • Lysosomal Storage Diseases • Metabolic Disorders • Ophthalmology • Rare Diseases

Genetic and cellular basis of impaired phagocytosis and photoreceptor degeneration in CLN3 disease. (PubMed, bioRxiv) - "CLN3 Batten disease (also known as Juvenile Neuronal Ceroid Lipofuscinosis; JNCL) is a lysosomal storage disorder that typically initiates with retinal degeneration but is followed by seizure onset, motor decline and premature death...CLN3 Δ 7-8/ Δ 7-8 mutation (that affects up to 85% patients) affects both RPE and POSs and leads to photoreceptor cell loss in CLN3 disease. Furthermore, both primary RPE dysfunction and mutant POS independently contribute to impaired POS phagocytosis in CLN3 disease."

Journal • CNS Disorders • Epilepsy • Lysosomal Storage Diseases • Metabolic Disorders • Ophthalmology • Rare Diseases

The parent and family impact of CLN3 disease: an observational survey-based study. (PubMed, Orphanet J Rare Dis) - "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."

Journal • Observational data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Epilepsy • Insomnia • Lysosomal Storage Diseases • Metabolic Disorders • Pediatrics • Rare Diseases • Sleep Disorder

Gene Therapy for Children With CLN3 Batten Disease (clinicaltrials.gov) - P1/2 | N=7 | Active, not recruiting | Sponsor: Amicus Therapeutics | Trial completion date: Sep 2023 ➔ Sep 2024 | Trial primary completion date: Jun 2023 ➔ Sep 2024

Gene therapy • Trial completion date • Trial primary completion date • CNS Disorders • Gene Therapies

Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach. (PubMed, Mol Ther Nucleic Acids) - "Behavioral and pathological analyses of these mice demonstrate a less severe phenotype compared with the CLN3 disease mouse model, providing evidence that antisense oligonucleotide-induced exon skipping can have therapeutic efficacy in treating CLN3 Batten disease. This model highlights how protein engineering through RNA splicing modulation can be an effective therapeutic approach."

Journal • Preclinical • CNS Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Pediatrics • Rare Diseases

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes. (PubMed, Dis Model Mech) - "Additionally, mutant miniswine present with retinal degeneration and motor abnormalities, similar to deficits seen in human patients. Taken together, the CLN3Δex7/8 miniswine model shows consistent and progressive Batten disease pathology and behavioral impairment mirroring clinical presentation, demonstrating its value in studying the role of CLN3 and safety/efficacy of novel disease modifying therapeutics."

Journal • Preclinical • CNS Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Ophthalmology • Pediatrics • Rare Diseases

The Batten disease protein CLN3 is important for stress granules dynamics and translational activity. (PubMed, J Biol Chem) - "Furthermore, loss of CLN3 function results in perturbations in SG dynamics, resulting in assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1. With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases, novel insights into the molecular basis of CLN3 Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease."

Journal • CNS Disorders • G3BP1

Therapeutic antisense oligonucleotides in mouse models of neurological disease (Neuroscience 2022) - "Treatment of Cln3Δex7/8 neonatal mice with this ASO resulted in the desired splicing effect throughout the central nervous system, improved motor coordination, reduced histopathological features of the disease in the brain, and extended life in a severe mouse model of the disease. Our results demonstrate that ASO-mediated reading frame correction is a promising therapeutic approach for CLN3 Batten disease and has important implications for the treatment of other neurological diseases."

Preclinical • Alzheimer's Disease • CNS Disorders • Parkinson's Disease

Identifying translatable retinal biomarkers of lysosome storage disorders through phenotypic characterization of CLN3 Batten’s disease mice (Neuroscience 2022) - "CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein...These pathological defects correlated with biochemical alterations in lysosome and autophagy biomarkers including elevated p62, LAMP1 and CatB as well as age-dependent protein aggregation. These data demonstrate the utility of the CLN3 in vivo mouse model for interrogating lysosome biology and identify translatable retinal biomarkers that can be used to support efficacy trials for therapeutic mechanisms targeting lysosome dysfunction."

Preclinical • CNS Disorders • LAMP1

Phenotyping the CLN3(Deltaex7/8)mouse model of Batten disease: fine motor kinematics and retinal function (Neuroscience 2022) - "CLN3 Batten Disease, juvenile NCL (neuronal lipofuscinosis), is an ultra-rare condition which becomes symptomatic between 5 to 15 yrs and is typically fatal by the late teens or early twenties...Parallel experiments utilizing OCT (retinal layer thickness), fundus autofluorescence, biochemical protein aggregation and autophagy biomarkers in the retina and brain were performed in separate cohorts (adjoining poster). Together, the data depict a model that recapitulates key aspects of retinal and motor dysfunction that occur in CLN3 Battens Disease that can be utilized to assess therapeutic interventions into the disease process."

Preclinical • CNS Disorders

A novel in vitro modeling system to evaluate the role of Glia and Neurons in CLN3 Batten disease (Neuroscience 2022) - "Additionally, to further study the effect of mutations in neurons, we generated induced neurons (iNs) from patients fibroblasts and are currently evaluating patient specific phenotypes. These in vitro culture systems are also being used for testing of new therapeutic strategies in order to accelerate development of novel treatments."

Preclinical • CNS Disorders • Epilepsy

Glycerophosphoinositol is Elevated in Blood Samples From CLN3 pigs, Cln3 Mice, and CLN3-Affected Individuals. (PubMed, Biomark Insights) - "CLN3 Batten disease is a rare pediatric neurodegenerative lysosomal disorder caused by biallelic disease-associated variants in CLN3...GPI, in particular, shows consistent elevations across a diverse cohort of individuals with CLN3. This raises the potential to use these biomarkers as a blood-based diagnostic test or as an efficacy measure for disease-modifying therapies."

Journal • Preclinical • CNS Disorders • Metabolic Disorders • Pediatrics

Phenotypic screening of small molecules for the treatment of CLN3 Batten disease (ACS-Fall 2022) - "Batten disease is a form of genetic neuronal ceroid lipofuscinosis (NCL) disorder that usually manifests in infancy to teenage years. Several molecules were synthesized by modifying flupirtine/retigabine templates. Initial studies show that these compounds translate their neuroprotective effect to CLN3 patient induced pluripotent stem cell (iPSC)-derived neurons by activating autophagy, ameliorate induced apoptosis by Bcl-2 and rescue mitochondrial dysfunction via enhancing the clearance of accumulated subunit c of ATP synthase."

IO biomarker • Alzheimer's Disease • CNS Disorders • Dementia • Epilepsy • Gene Therapies • Metabolic Disorders • BCL2

Investigating photoreceptor outer segment phagocytosis by retinal pigment epithelium in CLN3-Batten (ARVO 2022) - "Purpose: CLN3-Batten disease is a lysosomal storage disorder that leads to retinal degeneration and vision loss... Using in vitro and in vivo models of CLN3-Batten, we show that CLN3Δ7/8 mutation (that affects ~75% patients) is independently sufficient for promoting both impaired POS phagocytosis and retinal degeneration in CLN3-Batten."

Ophthalmology

[VIRTUAL] New Targets & Approaches to Targeting Monogenic Neurodegenerative Diseases (CNSS 2021) - "• Exploring the therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease • What is the clinical progress in rare monogenic neurodegenerative conditions? • Broadening the therapeutic landscape for ASOs in the treatment of neurodegenerative diseases"

Alzheimer's Disease • CNS Disorders

Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease. (PubMed, Nat Med) - "ASOs also induced exon skipping in cell lines derived from patients with CLN3 Batten disease. Our findings demonstrate the utility of ASO-based reading-frame correction as an approach to treat CLN3 Batten disease and broaden the therapeutic landscape for ASOs in the treatment of other diseases using a similar strategy."

Journal • Preclinical • CNS Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

A tailored Cln3 mouse model for testing therapeutic interventions in CLN3 Batten disease. (PubMed, Sci Rep) - "Similar to previously characterized Cln3 mutant mouse lines, this novel model shows pathological deficits throughout the CNS including accumulation of lysosomal storage material and glial activation, and has limited perturbation in behavioral measures. Thus, at the molecular and cellular level, this mouse line provides a valuable tool for testing nonsense suppression therapies or read through compounds in CLN3 disease in the future."

Journal • Preclinical • CNS Disorders • Epilepsy • Lysosomal Storage Diseases • Ophthalmology • Pediatrics • Rare Diseases

Gene therapy targeting the inner retina rescues the retinal phenotype in a mouse model of CLN3 Batten disease. (PubMed, Hum Gene Ther) - "In contrast, the treatment of photoreceptors, which are lost in patients at late disease stages, was not therapeutic in Cln3Δex7/8 mice, underlining the notion that CLN3 disease is primarily a disease of the inner retina with secondary changes in the outer retina. These data indicate that bipolar cells play a central role in this disease and identify this cell type as an important target for ocular AAV-based gene therapies for CLN3 disease."

Journal • Preclinical • Bipolar Disorder • CNS Disorders • Epilepsy • Lysosomal Storage Diseases • Ophthalmology • Rare Diseases

Gene Therapy for Children With CLN3 Batten Disease (clinicaltrials.gov) - P1/2; N=7; Active, not recruiting; Sponsor: Amicus Therapeutics; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed