Cone specific promoter for use in gene therapy of retinal degenerative diseases

Frank M. Dyka, Sanford L. Boye, Renee C. Ryals, Vince A. Chiodo, Shannon E. Boye, William W. Hauswirth

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Achromatopsia (ACHM) is caused by a progressive loss of cone photoreceptors leading to color blindness and poor visual acuity. Animal studies and human clinical trials have shown that gene replacement therapy with adeno-associate virus (AAV) is a viable treatment option for this disease. Although there have been successful attempts to optimize capsid proteins for increased specificity, it is simpler to restrict expression via the use of cell type-specific promoters. To target cone photoreceptors, a chimeric promoter consisting of an enhancer element of interphotoreceptor retinoid-binding protein promoter and a minimal sequence of the human transducin alpha-subunit promoter (IRBPe/GNAT2) was created. Additionally, a synthetic transducin alpha-subunit promoter (synGNAT2/GNAT2) containing conserved sequence blocks located downstream of the transcriptional start was created. The strength and specificity of these promoters were evaluated in murine retina by immunohistochemistry. The results showed that the chimeric, (IRBPe/ GNAT2) promoter is more efficient and specific than the synthetic, synGNAT2/ GNAT2 promoter. Additionally, IRBPe/GNAT2-mediated expression was found in all cone subtypes and it was improved over existing promoters currently used for gene therapy of achromatopsia.

Original languageEnglish (US)
Pages (from-to)695-701
Number of pages7
JournalAdvances in experimental medicine and biology
Volume801
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Achromatopsia
  • Adeno-associated virus
  • Chimeric promoter
  • Cone photoreceptors
  • Gene replacement therapy
  • Targeted expression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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