Glycogen storage disease type Ib (GSD-Ib) is an autosomal recessive disorder caused by deficiencies in glucose-6-phosphate transporter (G6PT), a ubiquitously expressed endoplasmic reticulum (ER) protein that translocates G6P from the cytoplasm into the ER lumen. Inside the ER, G6P is hydrolyzed to glucose and phosphate by either the liver/kidney/intestine-restricted glucose-6-phosphatase-α (G6Pase-α or G6PC) or the ubiquitously expressed G6Pase-β. G6PT and G6Pase are functionally co-dependent and form the G6PT/G6Pase complexes. The G6PT/G6Pase-α complex maintains interprandial blood glucose homeostasis, while the G6PT/G6Pase-β complex maintains neutrophil/macrophage homeostasis and function. Therefore, GSD-Ib is not only a metabolic – but also an immune disorder – characterized by impaired glucose homeostasis, neutropenia, and myeloid dysfunction.
Allowing GSD-Ib to go untreated in juveniles can lead to metabolic and immune abnormalities – including fasting hypoglycemia and frequent infections. In severe cases it can be deadly. Currently, treatments include strict dietary therapies coupled with granulocyte colony stimulating factor therapy. However, these therapies fail to address several possible long-term complications – such as hepatocellular adenoma, which develops in 75% of GSD-I patients over 25 years-old.
This invention consists of two novel gene therapy vectors for the treatment of GSD-Ib that include recombinant nucleic acid molecules having a human G6PT coding sequence operably linked to either a human G6PC promoter/enhancer (GPE) sequence, or a minimal G6PT promoter/enhancer (miGT) sequence, respectively. Both have shown capable of protecting against age-related insulin resistance and obesity. These vectors are available for licensing and/or co-development: The qualified license applicant will have a capability to arrange: (i) the conduct of preclinical research, (ii) regulatory submissions to the FDA, (iii) clinical testing, and (iv) commercial manufacturing related to the development of a therapy for GSD1b.
- The invention offers the first opportunity to treat GSD-Ib by gene therapy; they are anticipated to be the most efficacious therapy and will offer patients a chance to live a relatively normal life
- Liver-directed gene transfer and expression corrects metabolic abnormalities and prevents hepatocellular adenoma (HCA) development with low potential safety concerns
- These vectors have shown capable of protecting against age-related insulin resistance and obesity
- Gene therapy approach might prevent long-term complications arising due to recurrent hypoglycemia and related biochemical abnormalities
- Gene therapy for GSD-Ib
- Hepatocellular adenoma
- Rare, pediatric metabolic disease