| First Author | Arnaoutova I | Year | 2021 |
| Journal | Mol Ther | Volume | 29 |
| Issue | 4 | Pages | 1602-1610 |
| PubMed ID | 33359667 | Mgi Jnum | J:320697 |
| Mgi Id | MGI:6879400 | Doi | 10.1016/j.ymthe.2020.12.027 |
| Citation | Arnaoutova I, et al. (2021) Correction of metabolic abnormalities in a mouse model of glycogen storage disease type Ia by CRISPR/Cas9-based gene editing. Mol Ther 29(4):1602-1610 |
| abstractText | Glycogen storage disease type Ia (GSD-Ia), deficient in glucose-6-phosphatase-alpha (G6PC), is characterized by impaired glucose homeostasis and a hallmark of fasting hypoglycemia. We have developed a recombinant adeno-associated virus (rAAV) vector-mediated gene therapy for GSD-Ia that is currently in a phase I/II clinical trial. While therapeutic expression of the episomal rAAV-G6PC clinical vector is stable in mice, the long-term durability of expression in humans is currently being established. Here we evaluated CRISPR/Cas9-based in vivo genome editing technology to correct a prevalent pathogenic human variant, G6PC-p.R83C. We have generated a homozygous G6pc-R83C mouse strain and shown that the G6pc-R83C mice manifest impaired glucose homeostasis and frequent hypoglycemic seizures, mimicking the pathophysiology of GSD-Ia patients. We then used a CRISPR/Cas9-based gene editing system to treat newborn G6pc-R83C mice and showed that the treated mice grew normally to age 16 weeks without hypoglycemia seizures. The treated G6pc-R83C mice, expressing >/= 3% of normal hepatic G6Pase-alpha activity, maintained glucose homeostasis, displayed normalized blood metabolites, and could sustain 24 h of fasting. Taken together, we have developed a second-generation therapy in which in vivo correction of a pathogenic G6PC-p.R83C variant in its native genetic locus could lead to potentially permanent, durable, long-term correction of the GSD-Ia phenotype. |
