California-based Capsida Biotherapeutics has reported promising preclinical results for CAP-002, its gene therapy for developmental and epileptic encephalopathy (DEE) caused by mutations in the syntaxin-binding protein 1 (STXBP1) gene. The research demonstrated the therapy’s ability to reduce seizures, improve cognitive and motor function and restore brain activity in animal studies, signaling hope for patients with this rare and severe condition.
Addressing a Devastating Disease
The protein STXBP1 is required for healthy neurotransmission and is present in every neuron in the brain. Mutations in the STXBP1 gene disrupt protein production and, therefore, neurotransmission, causing STXBP1-developmental and epileptic encephalopathy. This debilitating neurodevelopmental disorder is the most severe form of epilepsy and affects approximately one in 26,000 children globally. It is often observed starting in infancy and is characterized by treatment-resistant seizures, intellectual disabilities, speech and motor impairments and a higher risk of sudden unexpected death in epilepsy (SUDEP). Patients often experience co-occurring conditions, including sleep problems, movement disorders and autism spectrum disorder. No approved therapies currently exist, leaving patients and families with limited options.
Promising Results in Preclinical Studies
CAP-002 uses Capsida’s proprietary adeno-associated virus (AAV) vector technology, leveraging an engineered AAV capsid platform to deliver a functional STXBP1 gene throughout the brain. The vector is designed to cross the blood-brain barrier, allowing for lower dosing and a broader therapeutic window than traditional gene therapy approaches.
In human neurons cultured in the lab, CAP-002 enabled the restoration of STXBP1 protein levels and the correction of neuronal network activity. These results align with the preclinical mouse studies, suggesting the therapy’s potential to treat all manifestations of STXBP1-DEE, including seizures, motor abnormalities and cognitive impairments.
The researchers evaluated the effects of three different doses of CAP-002 in a mouse model of STXBP1-DEE. The results, presented at the American Epilepsy Society annual meeting, show dose-dependent efficacy. CAP-002 reversed cognitive and motor deficits and significantly reduced seizures, with effects lasting up to one year after treatment.
In non-human primates (NHPs), the therapy achieved widespread brain distribution, restoring STXBP1 protein levels in 70% of neurons while minimizing effects on non-target organs like the liver. Compared to traditional AAV9 vectors, drug delivery with Capsida’s engineered capsid platform demonstrated 20 times lower liver targeting and 143 times lower expression in dorsal root ganglia, improving safety and tolerability.
Expanding the Scope of Gene Therapy
Capsida’s engineered capsid platform represents a new frontier in central nervous system therapies. By enhancing neuron transduction while reducing off-target effects, this approach offers hope for other severe neurological diseases. Beyond STXBP1-DEE, Capsida is advancing treatments for Parkinson’s disease associated with glucocerebrosidase (GBA) gene mutations and Friedreich’s ataxia. The company plans to begin clinical trials for both treatments by mid-2025.
Hope for Patients and Families
CAP-002 has received Orphan Drug Designation from the U.S. Food and Drug Administration, and Capsida has completed a pre-Investigational New Drug meeting with the agency. The company is preparing to initiate clinical trials in the first half of 2025.
For families affected by STXBP1-DEE, the promise of CAP-002 is significant. “STXBP1-DEE is a life-altering condition for patients and their families,” said Peter Anastasiou, CEO of Capsida Biotherapeutics. “These new data demonstrate the potential of CAP-002 to safely address all of the manifestations of the disease, and we look forward to progressing this program into the clinic in the first half of 2025.”
As the field of gene therapy advances, Capsida’s innovative approach and the promising preclinical results demonstrated by CAP-002 could mark the beginning of a new era in treating genetic epilepsy and other difficult-to-treat, serious neurological disorders.
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