Dr. Lee’s laboratory at UCONN was created exclusively for GSD research, where scientists work

toward developing cures through preclinical research using animal models of GSDs.

The lab raises awareness about GSD and gene therapy among research communities, collaborating

with research groups around the world. The lab is central to the clinical GSD program team at UConn

Health/Connecticut Children’s Medical Center, and participates in monthly "Bench to Bedside"

meetings to discuss findings from both basic sciences and clinical cares.

Ongoing Research Project on GSD-Ia

Evaluation of AAV-neutralizing antibody digesting enzyme in murine model of Glycogen Storage

Disease Type Ia:

To date in the Phase 3 clinical trial of AAV8-mediated GSD-Ia gene therapy, the cohorts that received

the gene therapy have shown sustained efficacy. While this is positive, it is also clear that it is not a

permanent cure. Going forward, all patients will require redosing. However, as normal response to

any kinds of virus, human body produces “neutralizing antibody” against the AAV8 gene therapy, and

it disables the gene therapy. Therefore, the cohorts who received the first dose should have the

neutralizing antibodies to the AAV gene therapy, so the second dose will not work for the cohorts

Additionally, a large number of GSD-Ia patients carry pre-existing neutralizing antibodies against

AAV8; these individuals have already been excluded from the current clinical trial.

Thanks to The Children's Fund for Glycogen Storage Disease Research, the lab has initiated a project

to evaluate neutralizing antibody-digesting enzymes in GSD-Ia gene therapy. The redosing efficacy of

AAV8-hG6PC will be evaluated in a GSD-Ia mouse model. Once an optimized condition is identified

in the preclinical model, the lab will offer recommendations for the clinical translation of the GSD-Ia

gene therapy.

Future Project Under Development:

AAV-mediated treatment allows for the delivery of a functional copy of G6Pase-α to liver cells.

However, there is a significant obstacle for pediatric patients because of their rapid hepatic growth.

To ensure stable G6PC expression despite early intervention, the lab is working on a novel concept

for a gene therapy vector that introduces a functional copy of G6Pase-α into a designated location

without disturbing other genetic information. We are hopeful that this new development will lead to

gene therapy for the infant and pediatric populations with GSD-Ia.

Explanaiton Notes

What is AAV8 mediated GSD 1a gene therapy?

It is a medical approach that uses a harmless virus to deliver and insert a corrected or therapeutic

gene (that is G6Pase-a enzyme for GSD-Ia) into a patient's cells. The AAV (adeno associated virus)

acts as a delivery vehicle, carrying the desired genetic material into the patient's cells so that they

can produce the missing or corrected G6Pase-a enzyme. There are several different kinds of AAV. In

the GSD-Ia case, we need to deliver the gene into the liver, so we use AAV8, because AAV8 is the

best for liver gene delivery.