PDCD RESEARCH

Our roadmap to a first in-human clinical trial for AAV9 gene replacement for PDHA1

A vast majority of PDCD patients (80-88%) have a mutation on their PDHA1 gene. PDHA1 was shown to be a good candidate for gene therapy using an adeno associated virus (AAV2) to express the protein in vitro nearly 15 years ago; however research was discontinued due to lack of funding. Since then, AAV technology, which is used as the delivery method to express PDHA1 in cells that are deficient, has advanced rapidly. The current generation of AAV vectors, AAV9, are safe and effective at crossing the blood-brain barrier. An AAV9 vector is currently used in an FDA-approved gene therapy of spinal muscular atrophy (SMA) in infants and children.

The Gray Lab at UTSW will initiate a proof of concept mice model study to determine efficacy of this approach on November 1, 2022. This project will last 20-24 months and cost $500,000.

Current status of PDHA1 research:

  • PDHA1 can be expressed in cells that are missing the protein, showing that gene therapy could be a viable approach for this disease

  • AAV technology is used to deliver and express PDHA1. Newer version of AAV can effectively target the Central Nervous System (CNS) and skeletal muscles at lower doses than the first generation AAVs.

  • Mouse models with PDH deficiency already exist to easily test this AAV9 approach in vivo

  • AAV9 vectors have been used as FDA-approved gene therapy for SMA, one example of many AAVs currently being investigated for gene therapy approaches

Proposed preclinical research to clear FDA approval for a first-in-human clinical trial

  • Test AAV9 efficacy in PDH deficient mouse model and show improvement in disease

  • Provide data on efficacy and toxicity to FDA to get fast-track review for a first-in-human clinical trial

“Dr. Gray and Dr. Chen are not heroes, but superheroes in saving lives. I owe everything to them, they gave my family hope and my son a better life.”
— Terry Pirovolakis, Rare Disease Dad and Founder of Cure SPG50

Board Site Visit to UTSW Gray Lab, June 2023

What is Gene Therapy?

Sometimes the whole or part of a gene is defective or missing from birth. This is typically referred to as a genetically inherited mutation. Most children with PDCD have a spontaneous (meaning, not inherited) mutation that happens at conception.

Depending on what is wrong, scientists can do one of several things in gene therapy:

  • They can replace a gene that is missing or is causing a problem.

  • They can add genes to the body to help treat disease.

  • Or they can turn off genes that are causing problems.

To insert new genes directly into cells, scientists use a vehicle called a “vector.” Vectors are genetically engineered to deliver the necessary genes for treating the disease.

Vectors need to be able to efficiently deliver genetic material into cells, and there are different kinds of vectors. Viruses are currently the most commonly used vectors in gene therapies because they have a natural ability to deliver genetic material into cells. Before a virus can be used to carry therapeutic genes into human cells, it is modified to remove its ability to cause infectious disease.

Below is a video from the FDA explaining how gene therapy works.