Grant Award Focuses on Vectors Used for Gene Therapy


Recombinant adeno-associated virus (rAAV) vectors are used to introduce genes as part of gene therapy, which aims to treat diseases by introducing genes that repair, regulate or replace a defective or missing gene. Because rAAV vectors can direct long-term gene expression when introducing the genes to cells, they are attractive vectors for gene therapy in patients. However, a lack of knowledge about how rAAV vectors work has prevented investigators from designing new strategies to improve their use.

Recognizing the potential of this delivery mechanism for gene therapy, the National Institutes of Health has awarded Children's Hospital a 5-year, $1.8 million grant to study how the genes introduced by rAAV vectors are incorporated into cells. In order for gene therapy to be effective, the rAAV genome that includes the therapeutic gene must enter the cell and become stabilized. Weidong Xiao, Ph.D. will lead the study with the long-term goal of developing new strategies to enhance rAAV transduction efficiency, improving the rAAV safety profile and making rAAV gene transfer more cost-effective.

Dr. Xiao and his colleagues will study the stability of rAAV genomes in various forms, single-stranded or double-stranded DNA; linear or circular. Single-stranded DNA is not stable and often signals cells to repair or degrade it, or to undergo apoptosis. The researchers also propose that the newly formed double-strand DNA may not be stable either.

In current studies, more than 99 percent of initial vectors were wasted before stabilization. Dr. Xiao and his team hope to understand the cellular mechanisms that promote rAAV genome stabilization over degradation. Understanding more about this process may help investigators searching for novel strategies to reduce the dose of rAAV in gene therapy clinical trials.

In addition, Dr. Xiao's team will study the frequency of rAAV integration into host chromosomes. They believe that rAAV genomes may remain as a unit of genetic material that is not integrated into chromosomes, known as an episome. By designing a novel strategy, they plan to accurately measure the integration frequency of rAAV vectors. Understanding the frequency of rAAV integration will help investigators design strategies to improve the safety profile for rAAV vectors.