Capsida Shows New Evidence of IV Gene Therapy for STXBP1 Epilepsy

Capsida Biotherapeutics has unveiled new preclinical data highlighting the potential of their gene therapy candidate, CAP-002, for the treatment of neurological conditions linked to mutations in the syntaxin-binding protein 1 (STXBP1) gene. This innovative approach aims to address genetic epilepsy that, until now, has lacked effective therapeutic options.

Traditional adeno-associated virus (AAV) therapies have failed to achieve the necessary widespread neuronal transduction to correct diseases caused by STXBP1 mutations. CAP-002, however, represents a breakthrough as a next-generation intravenous (IV) gene therapy capable of achieving comprehensive neuronal expression across the brain while avoiding the liver.

Currently in IND-enabling studies, CAP-002 is anticipated to commence clinical trials in early 2025. This novel therapy's potential was underscored in a study co-authored by Mingshan Xue, Ph.D., from Baylor College of Medicine. The study demonstrated that IV administration of the STXBP1 gene in adult mice with one non-functional copy of the gene could rescue crucial phenotypic defects in a dose-dependent manner, achieving long-lasting effects. The rescue of neurological phenotypes such as epileptic seizures, motor deficits, and cognitive impairments was contingent on adequate STXBP1 supplementation in neurons throughout the brain, levels unattainable with older AAV serotypes like AAV9.

These promising results were presented at the 2024 Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT) in Baltimore, MD. Wu Chen, Ph.D., from Baylor College of Medicine, delivered the oral presentation, highlighting the significant advancements in understanding the therapeutic potential of engineered AAV gene therapies for genetic epilepsy due to STXBP1 mutations.

In addition, Capsida presented new data indicating that a single IV infusion of CAP-002 can result in brain-wide STXBP1 gene expression, effectively transducing up to 70% of neurons at therapeutic doses in non-human primates (NHPs). This level of gene expression is comparable to that which reversed disease phenotypes in mouse models, with no adverse clinical, histopathological, or immunogenic effects observed.

Dr. Susan Catalano, Capsida's Chief Scientific Officer, emphasized that these results demonstrate CAP-002's ability to cross the blood-brain barrier effectively in NHPs, achieving the necessary widespread brain transduction and STXBP1 protein expression to modify the disease. Coupled with significant liver detargeting, CAP-002 appears promising for reversing disease effects through less invasive IV administration. Capsida plans to advance this program to clinical development by mid-2025, offering hope to patients afflicted with this severe condition.

Genetic epilepsy resulting from STXBP1 mutations is a severe developmental and epileptic encephalopathy affecting approximately one in 30,000 children globally. It leads to severe developmental delays, intellectual disabilities, treatment-resistant seizures, and sudden unexpected death in epilepsy (SUDEP). The STXBP1 protein, critical for normal neurotransmission, is present in every neuron. Currently, there are no therapies that modify the course of this disease.

Capsida Biotherapeutics is a pioneering gene therapy company focused on treatments for central nervous system (CNS) disorders. Their portfolio includes disease-modifying therapies for genetic epilepsy due to STXBP1 mutations and Parkinson's disease linked to GBA mutations. Beyond their wholly owned programs, Capsida collaborates with prominent organizations like AbbVie, Lilly, and CRISPR Therapeutics, expanding their reach to various CNS and ophthalmology disorders. Founded in 2019 and backed by Versant Ventures and Westlake Village BioPartners, Capsida originated from the groundbreaking research of Viviana Gradinaru, Ph.D., at Caltech.