Correction of metabolic abnormalities in a mouse model of glycogen storage disease type Ia by CRISPR/Cas9-based gene editing
- PMID: 33359667
- PMCID: PMC8058440
- DOI: 10.1016/j.ymthe.2020.12.027
Correction of metabolic abnormalities in a mouse model of glycogen storage disease type Ia by CRISPR/Cas9-based gene editing
Abstract
Glycogen storage disease type Ia (GSD-Ia), deficient in glucose-6-phosphatase-α (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-α 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.
Published by Elsevier Inc.
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References
-
- Chou J.Y., Matern D., Mansfield B.C., Chen Y.T. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. Curr. Mol. Med. 2002;2:121–143. - PubMed
-
- Chou J.Y., Jun H.S., Mansfield B.C. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose-6-phosphate transporter complexes. J. Inherit. Metab. Dis. 2015;38:511–519. - PubMed
-
- Greene H.L., Slonim A.E., O’Neill J.A., Jr., Burr I.M. Continuous nocturnal intragastric feeding for management of type 1 glycogen-storage disease. N. Engl. J. Med. 1976;294:423–425. - PubMed
-
- Chen Y.T., Cornblath M., Sidbury J.B. Cornstarch therapy in type I glycogen-storage disease. N. Engl. J. Med. 1984;310:171–175. - PubMed
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