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

doi:10.1007/978-1-4614-3209-8_87

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 journal › Article › peer-review

16 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 language	English (US)
Pages (from-to)	695-701
Number of pages	7
Journal	Advances in experimental medicine and biology
Volume	801
DOIs	https://doi.org/10.1007/978-1-4614-3209-8_87
State	Published - 2014
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1007/978-1-4614-3209-8_87

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title = "Cone specific promoter for use in gene therapy of retinal degenerative diseases",

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.",

keywords = "Achromatopsia, Adeno-associated virus, Chimeric promoter, Cone photoreceptors, Gene replacement therapy, Targeted expression",

author = "Dyka, {Frank M.} and Boye, {Sanford L.} and Ryals, {Renee C.} and Chiodo, {Vince A.} and Boye, {Shannon E.} and Hauswirth, {William W.}",

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T1 - Cone specific promoter for use in gene therapy of retinal degenerative diseases

AU - Dyka, Frank M.

AU - Boye, Sanford L.

AU - Ryals, Renee C.

AU - Chiodo, Vince A.

AU - Boye, Shannon E.

AU - Hauswirth, William W.

N1 - Publisher Copyright: © Springer Science+Business Media, LLC 2014.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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KW - Gene replacement therapy

KW - Targeted expression

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

Abstract

Keywords

ASJC Scopus subject areas

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