Optimizing Ribozymes for Somatic Cell Gene Therapy

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Abstract

Therapeutic ribozymes are created through a multistep process that requires trial and error. There are few established rules governing ribozyme design, but guidelines are emerging. It is not yet known whether hammerheads and hairpins, the two ribozymes most widely studied as potential gene therapy agents, have the inherent capability to ablate single genes. Their capacity for specificity and selectivity remains to be explored through rigorous experimentation. These experiments require a battery of control molecules, the characteristics of which are outlined here. Methods for completing the steps in the ribozyme development process, from the selection of a target gene to the quantitation of RNA levels, are also presented and discussed.

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Most cited references 10

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Membranoproliferative glomerulonephritis associated with hepatitis C virus infection.

David Gretch, H Yamabe, L Corey … (1993)

Hepatitis C virus (HCV) infection causes both acute and chronic liver disease and is also associated with mixed cryoglobulinemia. Whether HCV is also associated with renal disease, as is the hepatitis B virus, is not known. We describe the clinical, pathologic, virologic, and immunologic features of eight patients with HCV infection who were referred to nephrologists for glomerulonephritis. Four patients were treated with interferon alfa. All eight patients had proteinuria, and seven had decreased renal function. Renal biopsy in all patients revealed membranoproliferative glomerulonephritis, characterized by the deposition of IgG, IgM, and C3 in glomeruli. Electron microscopy of the biopsy specimens showed cryoglobulin-like structures in three of four patients. All eight patients had HCV RNA detected in their serum, elevated serum aminotransferase concentrations, and hypocomplementemia, and the majority had cryoglobulins and circulating immune complexes in their serum. Cryoprecipitates from the three patients who were tested contained HCV RNA and IgG anti-HCV antibodies to the nucleocapsid core antigen (HCVc or c22-3). IgM rheumatoid factors, present in all patients, bound anti-HCV IgG in all six patients tested. Four patients received interferon alfa for 2 to 12 months; all had evidence of decreased HCV replication and improvement of their renal and liver disease. Chronic HCV infection is associated with cryoglobulinemia and membranoproliferative glomerulonephritis. The pathogenesis is unknown, but may relate to deposition within glomeruli of immune complexes containing HCV, anti-HCV IgG, and IgM rheumatoid factors.

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A small catalytic oligoribonucleotide.

O C Uhlenbeck (2016)

A 19-nucleotide RNA fragment can cause rapid, highly specific cleavage of a 24-nucleotide RNA fragment under physiological conditions. Because each 19-mer can participate in many cleavage reactions, this molecule has all the properties associated with an RNA enzyme.

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Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin.

R R Proia, T Butters, Jerry R. Dwek … (1997)

The glycosphingolipid (GSL) lysosomal storage diseases result from the inheritance of defects in the genes encoding the enzymes required for catabolism of GSLs within lysosomes. A strategy for the treatment of these diseases, based on an inhibitor of GSL biosynthesis N-butyldeoxynojirimycin, was evaluated in a mouse model of Tay-Sachs disease. When Tay-Sachs mice were treated with N-butyldeoxynojirimycin, the accumulation of GM2 in the brain was prevented, with the number of storage neurons and the quantity of ganglioside stored per cell markedly reduced. Thus, limiting the biosynthesis of the substrate (GM2) for the defective enzyme (beta-hexosaminidase A) prevents GSL accumulation and the neuropathology associated with its lysosomal storage.

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Author and article information

Journal

Journal ID (publisher-id): EXN

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 1998

Publication date (Print): February 1998

Publication date (Electronic): 04 February 1998

Volume: 6

Issue: 1

Pages: 78-83

Affiliations

^a Divisions of Liver Diseases (Department of Medicine) and Abdominal Organ Transplantation (Department of Surgery) and ^b Division of Nephrology (Department of Medicine), The Mount Sinai Medical Center, New York, N.Y., USA

Article

Publisher ID: 20508 Other ID: Exp Nephrol 1998;6:78–83

DOI: 10.1159/000020508

SO-VID: 8adf49ad-bf16-4677-b09d-0ceac87b3862

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Optimizing Ribozymes for Somatic Cell Gene Therapy

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Abstract

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Karger: Nephrology

Most cited references 10

Membranoproliferative glomerulonephritis associated with hepatitis C virus infection.

A small catalytic oligoribonucleotide.

Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin.

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