Chimeric RNA/DNA oligonucleotide-based gene therapy

Li-Wen Lai, Yeong Hau H Lien

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background. Chimeric RNA/DNA oligonucleotides, emerging as a potential strategy for gene therapy, have been shown to induce site-specific correction of point mutations in several genetic disease models. Methods. Six recent studies of chimeric RNA/DNA oligonucleotide-based gene therapy in genetic disease models are reviewed. Chimeric RNA/DNA oligonucleotides, complementary to 25 to 30 residues of genomic DNA flanking the mutation site with the exception of a mismatch in the center, were delivered via different routes and delivery vehicles to target different tissues and organs. Corrections of the mutation at genotypic and phenotypic levels were assessed using various methods, including allele-specific polymerase chain reaction assay, restriction enzyme digestion, colony-lifting assays, sequencing, Northern and Western blot analyses, enzyme activity assay, immunohistochemical staining, and functional studies. Results. The gene correction frequency varied, ranging from less than 1% to more than 40%. This represented several magnitudes higher conversion rate compared with homologous recombination frequency, which is in the range of 10-5 to 10-6. The resulting phenotype changes lasted longer than one year in some studies. Conclusion. Chimeric RNA/DNA oligonucleotide-based gene therapy has the potential to develop into powerful therapeutic modality for genetic diseases. It can offer permanent expression and normal regulation of corrected genes in appropriate cells or tissues. Further efforts to elucidate the mechanisms of chimeric RNA/DNA oligonucleotide-based gene therapy are warranted in order to increase the efficacy and safety of this method.

Original languageEnglish (US)
JournalKidney International
Volume61
Issue numberSUPPL. 1
StatePublished - 2002

Fingerprint

Oligonucleotides
Genetic Therapy
Inborn Genetic Diseases
RNA
DNA
Genetic Models
Enzyme Assays
Mutation
Homologous Recombination
Point Mutation
Gene Frequency
Northern Blotting
Digestion
Complementary DNA
Western Blotting
Alleles
Staining and Labeling
Phenotype
Safety
Polymerase Chain Reaction

Keywords

  • Carbonic anhydrase II
  • Crigler-Najjar syndrome type I
  • Duchenne muscular dystrophy
  • Dystrophin
  • Fabry disease
  • Genetic disease
  • Homologous pairing
  • Mismatch repair
  • Tyrosinase
  • UDP-glucuronosyltransferase

ASJC Scopus subject areas

  • Nephrology

Cite this

Chimeric RNA/DNA oligonucleotide-based gene therapy. / Lai, Li-Wen; Lien, Yeong Hau H.

In: Kidney International, Vol. 61, No. SUPPL. 1, 2002.

Research output: Contribution to journalArticle

Lai, Li-Wen ; Lien, Yeong Hau H. / Chimeric RNA/DNA oligonucleotide-based gene therapy. In: Kidney International. 2002 ; Vol. 61, No. SUPPL. 1.
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AB - Background. Chimeric RNA/DNA oligonucleotides, emerging as a potential strategy for gene therapy, have been shown to induce site-specific correction of point mutations in several genetic disease models. Methods. Six recent studies of chimeric RNA/DNA oligonucleotide-based gene therapy in genetic disease models are reviewed. Chimeric RNA/DNA oligonucleotides, complementary to 25 to 30 residues of genomic DNA flanking the mutation site with the exception of a mismatch in the center, were delivered via different routes and delivery vehicles to target different tissues and organs. Corrections of the mutation at genotypic and phenotypic levels were assessed using various methods, including allele-specific polymerase chain reaction assay, restriction enzyme digestion, colony-lifting assays, sequencing, Northern and Western blot analyses, enzyme activity assay, immunohistochemical staining, and functional studies. Results. The gene correction frequency varied, ranging from less than 1% to more than 40%. This represented several magnitudes higher conversion rate compared with homologous recombination frequency, which is in the range of 10-5 to 10-6. The resulting phenotype changes lasted longer than one year in some studies. Conclusion. Chimeric RNA/DNA oligonucleotide-based gene therapy has the potential to develop into powerful therapeutic modality for genetic diseases. It can offer permanent expression and normal regulation of corrected genes in appropriate cells or tissues. Further efforts to elucidate the mechanisms of chimeric RNA/DNA oligonucleotide-based gene therapy are warranted in order to increase the efficacy and safety of this method.

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KW - Mismatch repair

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