Prohibitin Gene Therapy for the Treatment of Alzheimer's Disease

Background & Unmet Need

• Alzheimer’s Disease (AD) affects over 5 million Americans annually and is the most common form of age-related cognitive impairment
• AD is linked to the formation of plaques in the brain by the synaptic protein amyloid-beta precursor protein (APP) through poorly understood mechanisms
• AD onset is also associated with mitochondrial dysfunction that may contribute to cognitive impairment
• Prohibitin (PHB1) is involved in mitochondrial lipid maturation and stabilized respiratory chain supercomplexes to promote respiratory functions in neural cells
• PHB1 gene silencing increases vulnerability of neurons to injury
• Unmet Need: Novel therapeutic strategies for AD

Technology Overview

• The Technology: Method to treat AD through upregulation of PHB1
• Discovery: Baseline PHB1 expression in reduced in Tg2576 mice, a mouse model of AD
• PHB1 knockout mice exhibit significant behavioral abnormalities, and display features consistent with neurodegeneration (e.g., protein aggregation, Tau hyperphosphorylation)
• The inventors also identified a novel regulatory mechanism for PHB1, based on nitric oxide (NO) mediated protein S-nitrosylation on residue Cys69
• PHB1 Cys69 S-nitrosylation is significantly reduced in the brains of APP mice and AD patients
• PoC Data: Administration of an AAV-based gene therapy to increase PHB1 expression induced functional improvements in AD symptoms and increased synaptic long-term potentiation (LTP)

Technology Applications

• Targeted gene therapy to reverse cognitive impairments in AD
• Method for up-regulating prohibitin expression in neurodegenerative diseases associated with mitochondrial dysfunction

Technology Advantages

• Applicable to multiple neurodegenerative diseases linked to mitochondrial function (e.g., AD, Creutzfeldt-Jakob disease)
• Selectively targets gene expression in a single brain region
• MOA operates by increasing expression of an endogenous protein