Transient photoreceptor deconstruction by CNTF enhances rAAV-Mediated cone functional rescue in late stage CNGB3-achromatopsia

András M. Komáromy, Jessica S. Rowlan, Amanda T Parton Corr, Shelby L. Reinstein, Sanford L. Boye, Ann E. Cooper, Amaliris Gonzalez, Britt Levy, Rong Wen, William W. Hauswirth, William A. Beltran, Gustavo D. Aguirre

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Achromatopsia is a genetic disorder of cones, and one of the most common forms is a channelopathy caused by mutations in the β-subunit, CNGB3, of the cone cyclic nucleotide-gated (CNG) channel. Recombinant adeno-associated virus of serotype 5 (rAAV5)-mediated gene transfer of human CNGB3 cDNA to mutant dog cones results in functional and structural rescue in dogs <0.5 years of age, but treatment is minimally effective in dogs >1 year. We now test a new therapeutic concept by combining gene therapy with the administration of ciliary neurotrophic factor (CNTF). Intravitreal CNTF causes transient dedifferentiation of photoreceptors, a process called deconstruction, whereby visual cells become immature with short outer segments, and decreased retinal function and gene expression that subsequently return to normal. Cone function was successfully rescued in all mutant dogs treated between 14 and 42 months of age with this strategy. CNTF-mediated deconstruction and regeneration of the photoreceptor outer segments prepares the mutant cones optimally for gene augmentation therapy.

Original languageEnglish
Pages (from-to)1131-1141
Number of pages11
JournalMolecular Therapy
Volume21
Issue number6
DOIs
StatePublished - Jun 1 2013

Fingerprint

Color Vision Defects
Ciliary Neurotrophic Factor
Dogs
Genetic Therapy
Retinal Photoreceptor Cell Outer Segment
Cyclic Nucleotide-Gated Cation Channels
Channelopathies
Dependovirus
Inborn Genetic Diseases
Regeneration
Complementary DNA
Gene Expression
Mutation
Genes
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Komáromy, A. M., Rowlan, J. S., Corr, A. T. P., Reinstein, S. L., Boye, S. L., Cooper, A. E., ... Aguirre, G. D. (2013). Transient photoreceptor deconstruction by CNTF enhances rAAV-Mediated cone functional rescue in late stage CNGB3-achromatopsia. Molecular Therapy, 21(6), 1131-1141. https://doi.org/10.1038/mt.2013.50

Transient photoreceptor deconstruction by CNTF enhances rAAV-Mediated cone functional rescue in late stage CNGB3-achromatopsia. / Komáromy, András M.; Rowlan, Jessica S.; Corr, Amanda T Parton; Reinstein, Shelby L.; Boye, Sanford L.; Cooper, Ann E.; Gonzalez, Amaliris; Levy, Britt; Wen, Rong; Hauswirth, William W.; Beltran, William A.; Aguirre, Gustavo D.

In: Molecular Therapy, Vol. 21, No. 6, 01.06.2013, p. 1131-1141.

Research output: Contribution to journalArticle

Komáromy, AM, Rowlan, JS, Corr, ATP, Reinstein, SL, Boye, SL, Cooper, AE, Gonzalez, A, Levy, B, Wen, R, Hauswirth, WW, Beltran, WA & Aguirre, GD 2013, 'Transient photoreceptor deconstruction by CNTF enhances rAAV-Mediated cone functional rescue in late stage CNGB3-achromatopsia', Molecular Therapy, vol. 21, no. 6, pp. 1131-1141. https://doi.org/10.1038/mt.2013.50
Komáromy, András M. ; Rowlan, Jessica S. ; Corr, Amanda T Parton ; Reinstein, Shelby L. ; Boye, Sanford L. ; Cooper, Ann E. ; Gonzalez, Amaliris ; Levy, Britt ; Wen, Rong ; Hauswirth, William W. ; Beltran, William A. ; Aguirre, Gustavo D. / Transient photoreceptor deconstruction by CNTF enhances rAAV-Mediated cone functional rescue in late stage CNGB3-achromatopsia. In: Molecular Therapy. 2013 ; Vol. 21, No. 6. pp. 1131-1141.
@article{754cdf0ab345442ca61dbc81425bfac6,
title = "Transient photoreceptor deconstruction by CNTF enhances rAAV-Mediated cone functional rescue in late stage CNGB3-achromatopsia",
abstract = "Achromatopsia is a genetic disorder of cones, and one of the most common forms is a channelopathy caused by mutations in the β-subunit, CNGB3, of the cone cyclic nucleotide-gated (CNG) channel. Recombinant adeno-associated virus of serotype 5 (rAAV5)-mediated gene transfer of human CNGB3 cDNA to mutant dog cones results in functional and structural rescue in dogs <0.5 years of age, but treatment is minimally effective in dogs >1 year. We now test a new therapeutic concept by combining gene therapy with the administration of ciliary neurotrophic factor (CNTF). Intravitreal CNTF causes transient dedifferentiation of photoreceptors, a process called deconstruction, whereby visual cells become immature with short outer segments, and decreased retinal function and gene expression that subsequently return to normal. Cone function was successfully rescued in all mutant dogs treated between 14 and 42 months of age with this strategy. CNTF-mediated deconstruction and regeneration of the photoreceptor outer segments prepares the mutant cones optimally for gene augmentation therapy.",
author = "Kom{\'a}romy, {Andr{\'a}s M.} and Rowlan, {Jessica S.} and Corr, {Amanda T Parton} and Reinstein, {Shelby L.} and Boye, {Sanford L.} and Cooper, {Ann E.} and Amaliris Gonzalez and Britt Levy and Rong Wen and Hauswirth, {William W.} and Beltran, {William A.} and Aguirre, {Gustavo D.}",
year = "2013",
month = "6",
day = "1",
doi = "10.1038/mt.2013.50",
language = "English",
volume = "21",
pages = "1131--1141",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Transient photoreceptor deconstruction by CNTF enhances rAAV-Mediated cone functional rescue in late stage CNGB3-achromatopsia

AU - Komáromy, András M.

AU - Rowlan, Jessica S.

AU - Corr, Amanda T Parton

AU - Reinstein, Shelby L.

AU - Boye, Sanford L.

AU - Cooper, Ann E.

AU - Gonzalez, Amaliris

AU - Levy, Britt

AU - Wen, Rong

AU - Hauswirth, William W.

AU - Beltran, William A.

AU - Aguirre, Gustavo D.

PY - 2013/6/1

Y1 - 2013/6/1

N2 - Achromatopsia is a genetic disorder of cones, and one of the most common forms is a channelopathy caused by mutations in the β-subunit, CNGB3, of the cone cyclic nucleotide-gated (CNG) channel. Recombinant adeno-associated virus of serotype 5 (rAAV5)-mediated gene transfer of human CNGB3 cDNA to mutant dog cones results in functional and structural rescue in dogs <0.5 years of age, but treatment is minimally effective in dogs >1 year. We now test a new therapeutic concept by combining gene therapy with the administration of ciliary neurotrophic factor (CNTF). Intravitreal CNTF causes transient dedifferentiation of photoreceptors, a process called deconstruction, whereby visual cells become immature with short outer segments, and decreased retinal function and gene expression that subsequently return to normal. Cone function was successfully rescued in all mutant dogs treated between 14 and 42 months of age with this strategy. CNTF-mediated deconstruction and regeneration of the photoreceptor outer segments prepares the mutant cones optimally for gene augmentation therapy.

AB - Achromatopsia is a genetic disorder of cones, and one of the most common forms is a channelopathy caused by mutations in the β-subunit, CNGB3, of the cone cyclic nucleotide-gated (CNG) channel. Recombinant adeno-associated virus of serotype 5 (rAAV5)-mediated gene transfer of human CNGB3 cDNA to mutant dog cones results in functional and structural rescue in dogs <0.5 years of age, but treatment is minimally effective in dogs >1 year. We now test a new therapeutic concept by combining gene therapy with the administration of ciliary neurotrophic factor (CNTF). Intravitreal CNTF causes transient dedifferentiation of photoreceptors, a process called deconstruction, whereby visual cells become immature with short outer segments, and decreased retinal function and gene expression that subsequently return to normal. Cone function was successfully rescued in all mutant dogs treated between 14 and 42 months of age with this strategy. CNTF-mediated deconstruction and regeneration of the photoreceptor outer segments prepares the mutant cones optimally for gene augmentation therapy.

UR - http://www.scopus.com/inward/record.url?scp=84878538674&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878538674&partnerID=8YFLogxK

U2 - 10.1038/mt.2013.50

DO - 10.1038/mt.2013.50

M3 - Article

VL - 21

SP - 1131

EP - 1141

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 6

ER -