Gene therapy for long-term treatment of GSDIa

Unmet Need

Glycogen storage disease type Ia (GSDIa), or von Gierke disease, is a rare heritable metabolic disorder that impacts the liver and kidneys due to an inability to break down glycogen. An estimated 1 in 50,000 births in the US are diagnosed with GSDIa. Patients experience life threatening low blood sugar, enlargement of the liver, and increased fat and urea in the blood. These symptoms can have long terms effects that include impaird growth, renal failure, and liver cancer. The current standard of care for GSDIa involves adding uncooked cornstarch to meals to help patients maintain normal blood sugar. Gene therapy has been explored as a potential treatment, however there have been problems with the duration of the therapeutic effect due to vector loss and unsustained transgene expression. There is a need for a safe, effective, and long-term genetic therapy for treatment of GSDIa to prevent the buildup of glycogen and give patients the ability to grow and live normally.

Technology

Duke inventors have developed a novel gene therapy for GSDIa. This is intended to be used as a one-time, stand alone treatment to increase glucose-6-phosphatase function in GSDIa. Specifically, the technology uses CRISPR-Cas9 mediated genome editing, delivered via a single adeno-associated virus (AAV) vector, to expresses Streptococcus pyogenes Cas9 and a donor vector that expresses a gRNA and G6PC transgene. Additionally, the drug bezafibrate was used to increase virus transduction, transgene expression, and editing efficacy due to the addition of a zinc finger nuclease. This treatment has shown favorable integration and safety with a frequency of transgene integration of almost 6% in mouse liver and an almost complete loss of Cas9 DNA after 12 weeks. Researchers have demonstrated this technology in-vivo in both mouse and canine studies.

Other Applications

The method for this gene therapy could also be adapted to other heritable metabolic disorders characterized by deficiency in enzymatic activity such as Pompe disease, Gaucher disease, Hunter syndrome, Metachromatic leukodystrophy, and Tay-Sachs disease.

Advantages

• Stable and safe genome editing treatment for GSDIa
• Universal treatment for all pathogenic variants of glucose-6-phosphatase deficiency
• Rare disease status can classify gene therapy as orphan drug, fast-tracking FDA approval