Retinoid-Activating Gene Therapy for the Treatment of Amyotrophic Lateral Sclerosis
Abstract
This proposal seeks to develop a novel gene based therapy for the treatment of amyotrophic lateral sclerosis (ALS), the most common motor neuron disease for which no cures currently exist. Here, we will target the retinoic acid (RA) signaling pathway as a means of neuroprotection. RA is an important signaling molecule involved in a host of vital functions in the central nervous system (CNS). Vitamin A is converted into RA which then acts on retinoic acid receptors to control the transcription of a numerous genes. RA levels are controlled mainly by its degradation via cytochrome p450 family 26 (CYP26) enzymes (CYP26A1, CYP26B1, and CYP26C1). Genetic and protein studies have shown that members of the retinoid signaling pathway are alternatively expressed in neurodegenerative conditions including in post-mortem tissues of ALS patients and animal models of ALS. Our previous work demonstrated that activation of the RA signaling pathway was neuroprotective in preclinical models of ALS. However, our pharmaceutical approaches still had high obstacles to overcome for clinical development. We seek to build on previous work to address our overarching hypothesis: Increased retinoid signaling activity in the central nervous system is neuroprotective and can reduce ALS symptoms and disease progression. We will use an adeno-associated virus (AAV) technology in order to deliver short hairpin RNA as a way to reduce the expression of retinoic acid degrading enzymes CYP26A1, CYP26B1, and CYP26C1. By utilizing a genetic approach we will overcome disadvantages of a traditional pharmaceutical approach such as limited blood-brain barrier penetration, rapid clearance of drugs, and off-target effects. Employing a genetic approach will allow us to produce a robust, site-specific, and long-lasting effect. We will reduce CYP26 enzyme levels specifically in the spinal cord and motor cortex, the sites most affected by ALS progression. This proposal will generate preclinical data to demonstrate proof-of-concept of targeting CYP26 enzymes as an ALS intervention. Further, it will demonstrate the advantages of utilizing a genetic approach to activate neuroprotective pathways. Our aims will be to (1) Establish proper dosing paradigms of viral vectors to achieve optimal RA signaling. (2) Measure the neuroprotective effects of CYP26 reduction in an ALS mouse model. (3) Validate biomarkers that are responsive to retinoid activation to demonstrate the therapeutic action of our treatment. Successful completion of this project will enable us to progress our retinoid activating therapy towards use in clinical trials. As retinoid signaling has been demonstrated to modulate a host of pathogenic mechanisms such as response to oxidative stress, neuroinflammation, and synaptic function, its potential has wide applicability to different forms of ALS, either sporadic or familial. Together, these studies will help simultaneously validate the use of RA activating strategies for the treatment of ALS and the use of AAV technology for the delivery of novel therapeutic approaches.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310206
Entities
People
- David Medina
Organizations
- United States Army