Gene therapy and genome editing for type I glycogen storage diseases
Type I glycogen storage diseases (GSD-I) consist of two major autosomal recessive disorders, GSD-Ia, caused by a reduction of glucose-6-phosphatase-α (G6Pase-α or G6PC) activity and GSD-Ib, caused by a reduction in the glucose-6-phosphate transporter (G6PT or SLC37A4) activity. The G6Pase-α and G6PT...
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| Format: | Article |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Molecular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmmed.2023.1167091/full |
| _version_ | 1797855071751372800 |
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| author | Janice Y. Chou Brian C. Mansfield |
| author_facet | Janice Y. Chou Brian C. Mansfield |
| author_sort | Janice Y. Chou |
| collection | DOAJ |
| description | Type I glycogen storage diseases (GSD-I) consist of two major autosomal recessive disorders, GSD-Ia, caused by a reduction of glucose-6-phosphatase-α (G6Pase-α or G6PC) activity and GSD-Ib, caused by a reduction in the glucose-6-phosphate transporter (G6PT or SLC37A4) activity. The G6Pase-α and G6PT are functionally co-dependent. Together, the G6Pase-α/G6PT complex catalyzes the translocation of G6P from the cytoplasm into the endoplasmic reticulum lumen and its subsequent hydrolysis to glucose that is released into the blood to maintain euglycemia. Consequently, all GSD-I patients share a metabolic phenotype that includes a loss of glucose homeostasis and long-term risks of hepatocellular adenoma/carcinoma and renal disease. A rigorous dietary therapy has enabled GSD-I patients to maintain a normalized metabolic phenotype, but adherence is challenging. Moreover, dietary therapies do not address the underlying pathological processes, and long-term complications still occur in metabolically compensated patients. Animal models of GSD-Ia and GSD-Ib have delineated the disease biology and pathophysiology, and guided development of effective gene therapy strategies for both disorders. Preclinical studies of GSD-I have established that recombinant adeno-associated virus vector-mediated gene therapy for GSD-Ia and GSD-Ib are safe, and efficacious. A phase III clinical trial of rAAV-mediated gene augmentation therapy for GSD-Ia (NCT05139316) is in progress as of 2023. A phase I clinical trial of mRNA augmentation for GSD-Ia was initiated in 2022 (NCT05095727). Alternative genetic technologies for GSD-I therapies, such as gene editing, are also being examined for their potential to improve further long-term outcomes. |
| first_indexed | 2024-04-09T20:16:38Z |
| format | Article |
| id | doaj.art-87473fe601a84b738c42b80b030eac14 |
| institution | Directory Open Access Journal |
| issn | 2674-0095 |
| language | English |
| last_indexed | 2024-04-09T20:16:38Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Medicine |
| spelling | doaj.art-87473fe601a84b738c42b80b030eac142023-03-31T07:00:06ZengFrontiers Media S.A.Frontiers in Molecular Medicine2674-00952023-03-01310.3389/fmmed.2023.11670911167091Gene therapy and genome editing for type I glycogen storage diseasesJanice Y. ChouBrian C. MansfieldType I glycogen storage diseases (GSD-I) consist of two major autosomal recessive disorders, GSD-Ia, caused by a reduction of glucose-6-phosphatase-α (G6Pase-α or G6PC) activity and GSD-Ib, caused by a reduction in the glucose-6-phosphate transporter (G6PT or SLC37A4) activity. The G6Pase-α and G6PT are functionally co-dependent. Together, the G6Pase-α/G6PT complex catalyzes the translocation of G6P from the cytoplasm into the endoplasmic reticulum lumen and its subsequent hydrolysis to glucose that is released into the blood to maintain euglycemia. Consequently, all GSD-I patients share a metabolic phenotype that includes a loss of glucose homeostasis and long-term risks of hepatocellular adenoma/carcinoma and renal disease. A rigorous dietary therapy has enabled GSD-I patients to maintain a normalized metabolic phenotype, but adherence is challenging. Moreover, dietary therapies do not address the underlying pathological processes, and long-term complications still occur in metabolically compensated patients. Animal models of GSD-Ia and GSD-Ib have delineated the disease biology and pathophysiology, and guided development of effective gene therapy strategies for both disorders. Preclinical studies of GSD-I have established that recombinant adeno-associated virus vector-mediated gene therapy for GSD-Ia and GSD-Ib are safe, and efficacious. A phase III clinical trial of rAAV-mediated gene augmentation therapy for GSD-Ia (NCT05139316) is in progress as of 2023. A phase I clinical trial of mRNA augmentation for GSD-Ia was initiated in 2022 (NCT05095727). Alternative genetic technologies for GSD-I therapies, such as gene editing, are also being examined for their potential to improve further long-term outcomes.https://www.frontiersin.org/articles/10.3389/fmmed.2023.1167091/fulladeno-associated virus vectorCRISPR/ Cas9 systemgene therapygene editingglucose-6-phosphatase-αglucose-6-phosphate transporter |
| spellingShingle | Janice Y. Chou Brian C. Mansfield Gene therapy and genome editing for type I glycogen storage diseases Frontiers in Molecular Medicine adeno-associated virus vector CRISPR/ Cas9 system gene therapy gene editing glucose-6-phosphatase-α glucose-6-phosphate transporter |
| title | Gene therapy and genome editing for type I glycogen storage diseases |
| title_full | Gene therapy and genome editing for type I glycogen storage diseases |
| title_fullStr | Gene therapy and genome editing for type I glycogen storage diseases |
| title_full_unstemmed | Gene therapy and genome editing for type I glycogen storage diseases |
| title_short | Gene therapy and genome editing for type I glycogen storage diseases |
| title_sort | gene therapy and genome editing for type i glycogen storage diseases |
| topic | adeno-associated virus vector CRISPR/ Cas9 system gene therapy gene editing glucose-6-phosphatase-α glucose-6-phosphate transporter |
| url | https://www.frontiersin.org/articles/10.3389/fmmed.2023.1167091/full |
| work_keys_str_mv | AT janiceychou genetherapyandgenomeeditingfortypeiglycogenstoragediseases AT briancmansfield genetherapyandgenomeeditingfortypeiglycogenstoragediseases |