Niemann–Pick disease is a severe pediatric lysosomal storage disorder caused by a profound deficiency of acid sphingomyelinase (ASM), which prevents the proper metabolism of sphingomyelin. This leads to widespread lipid accumulation and progressive tissue damage. Patients with Type B (NPD-B) primarily exhibit systemic manifestations, including hepatosplenomegaly, with a highly variable clinical course. In contrast, Type A (NPD-A) is characterized by rapid and devastating neurodegeneration, typically leading to death within the first 2–3 years of life.

Our long-term goal is to shift the clinical trajectory of Type A toward a milder, Type B–like phenotype. To achieve this, we are developing a gene therapy approach based on a single cisternal administration of an adeno-associated viral (AAV) vector encoding human ASM. Our objective is to demonstrate that this strategy can effectively target the central nervous system and provide meaningful therapeutic benefit for the neurological manifestations of NPD-A.

Monoamine oxidase A (MAOA) deficiency is a rare neurogenetic disorder characterized by impaired degradation of monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine. The resulting neurotransmitter imbalance is associated with significant behavioral dysregulation, altered neurodevelopment, and disruptions in neuroimmune function. Despite its profound impact, effective therapeutic strategies targeting the central nervous system remain limited.

Our research focuses on developing a gene therapy approach to restore MAOA function in the brain. Using an adeno-associated viral vector encoding human MAOA. This approach is designed to achieve widespread and sustained expression within targeted brain regions while minimizing systemic exposure. Our objective is to evaluate the extent to which localized restoration of MAOA activity can normalize neurotransmitter levels, improve behavioral outcomes, and rescue associated neuropathological and neuroimmune alterations.

This work is in collaboration with UTSW (Gray Lab) and funded by MAO Deficiencies Foundation

GM1 gangliosidosis is a rare, autosomal recessive lysosomal storage disorder caused by mutations in the GLB1 gene, leading to deficient β-galactosidase activity and the progressive accumulation of GM1 gangliosides in the central nervous system. This results in severe neurodegeneration, with clinical severity ranging from rapidly progressive infantile forms to more slowly evolving juvenile and adult-onset phenotypes. Current treatment options are limited to supportive care, and existing gene therapy approaches—particularly systemic and cerebrospinal fluid (CSF)-based delivery—face significant challenges in achieving widespread and uniform CNS distribution.

This project aims to overcome these limitations by developing a targeted gene therapy strategy optimized for intracranial delivery. Leveraging magnetic resonance-guided convection-enhanced delivery (MR-CED), we focus on enabling broad vector dissemination through axonal transport pathways. This approach is designed to achieve efficient transduction of both cortical and subcortical networks, critical for sensory, motor, and cognitive function.

Alzheimer’s disease (AD) is marked by early synaptic dysfunction and progressive degeneration of the entorhinal–hippocampal circuitry that underlies learning and memory. Although delivery of neurotrophic factors has emerged as a promising therapeutic strategy, current AAV-based approaches rely on direct injections into medial temporal lobe structures that are often severely atrophic and surgically challenging to access in AD patients.

This project explores the olfactory bulb (OB) as a novel and minimally invasive entry point to these vulnerable networks. The OB has direct anatomical and functional connections to the entorhinal cortex, piriform cortex, and hippocampal-associated regions, positioning it as a strategic gateway to modulate memory-related circuits.