AAV-Based Mitochondrial Gene Therapy: A Novel Approach to Slowing Neurodegeneration
This invention comprises recombinant adeno-associated viral (AAV) vectors engineered to simultaneously deliver and overexpress key mitochondrial import complex proteins (TIM17, TIM23, and TIM50) directly to neurons. By restoring mitochondrial protein import function in vulnerable neuronal populations, this approach addresses a fundamental driver of neurodegeneration and has demonstrated the ability to slow disease progression in preclinical models of Huntington's disease.
Description
Mitochondrial dysfunction is a well-established hallmark of numerous neurodegenerative diseases. A critical but underappreciated mechanism involves the inhibition of mitochondrial protein import, the process by which the vast majority of mitochondrial proteins are transported into the organelle from the cytoplasm. In Huntington's disease, mutant huntingtin protein (mHTT) directly binds to the TIM23 import complex, impairing this process. Importantly, research underlying this invention demonstrated that the striatum, the brain region most vulnerable in Huntington's disease — naturally contains lower baseline levels of TIM23 complex subunits compared to other brain regions, providing a compelling mechanistic explanation for selective neuronal vulnerability. To address this deficit, a single-stranded AAV (ssAAV) vector was engineered to co-express three TIM import complex subunits (TIM17a, TIM23, and TIM50) under the control of a neuron-specific promoter (hSynapsin-1). The three coding sequences are linked via T2A self-cleaving peptides, enabling coordinated polycistronic expression of all three proteins from a single construct. The vector is packaged in AAV-PHP.eB capsids, which are capable of crossing the blood-brain barrier following systemic (intravenous) administration, enabling non-invasive, brain-wide delivery. Overexpression of these translocases was shown to accelerate mitochondrial protein import, protect cortical neurons from excitotoxic stress, and produce a trend toward improved survival and preservation of striatal neuronal markers in a mouse model of Huntington's disease.Applications
- Huntington's disease therapeutics: Direct application as a gene therapy for HD, a fatal disease with no currently approved disease-modifying treatment- Parkinson's disease: Mitochondrial protein import impairment has also been identified in Parkinson's disease (via α-Synuclein binding to TOM20), presenting an additional indication
- Broader neurodegenerative disease pipeline: Potential application across ALS, Alzheimer's disease, Friedreich's ataxia, and other diseases with established mitochondrial dysfunction
- Gene therapy platform licensing: The vector design, delivery approach, and polycistronic expression strategy represent a platform technology licensable for use in other CNS gene therapy programs
- Research tools and assays: The in-cell mitochondrial protein import assay developed alongside this technology represents a novel tool for drug discovery and screening in the neurodegeneration space
Advantages
- Addresses a root cause of neurodegeneration: Targets mitochondrial protein import deficiency, a mechanistic driver shared across multiple neurodegenerative diseases, rather than downstream symptoms- Brain-penetrant systemic delivery: AAV-PHP.eB capsid enables intravenous administration with efficient CNS transduction, eliminating the need for invasive intracranial injection
- Neuron-specific expression: Use of a CNS-specific promoter restricts transgene expression to neurons, reducing off-target effects in peripheral tissues
- Polycistronic single-vector design: All three therapeutic genes are delivered in a single construct, simplifying manufacturing and ensuring coordinated expression
- Broad therapeutic applicability: The mitochondrial import defect targeted by this technology has been identified in multiple neurodegenerative conditions, expanding the potential addressable disease space