Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept

Astra Dinculescu, Jackie Estreicher, Juan C. Zenteno, Tomas S. Aleman, Sharon B. Schwartz, Wei Chieh Huang, Alejandro J. Roman, Alexander Sumaroka, Qiuhong Li, Wen-Tao Deng, Seok-Hong Min, Vince A. Chiodo, Andy Neeley, Xuan Liu, Xinhua Shu, Margarita Matias-Florentino, Beatriz Buentello-Volante, Sanford L. Boye, Artur V. Cideciyan, William W. HauswirthSamuel G. Jacobson

Research output: Contribution to journalArticle

Abstract

Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken ß-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.
Original languageEnglish
Pages (from-to)367-376
Number of pages10
JournalHuman Gene Therapy
Volume23
Issue number4
Early online date26 Jan 2012
DOIs
Publication statusPublished - Apr 2012

Fingerprint

Retinitis Pigmentosa
Genetic Therapy
Phenotype
Mutation
Membranes
Retinal Degeneration
Genes
Retinal Cone Photoreceptor Cells
Retinal Rod Photoreceptor Cells
Electroretinography
Vertebrate Photoreceptor Cells
Retinal Pigment Epithelium
Capsid
Microvilli
Tyrosine
Retina
Actins
Chickens
Histology
FRZB protein

Keywords

  • MFRP mutations
  • RP
  • gene-based therapy
  • retinal degeneration

Cite this

Dinculescu, A., Estreicher, J., Zenteno, J. C., Aleman, T. S., Schwartz, S. B., Huang, W. C., ... Jacobson, S. G. (2012). Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept. Human Gene Therapy, 23(4), 367-376. https://doi.org/10.1089/hum.2011.169
Dinculescu, Astra ; Estreicher, Jackie ; Zenteno, Juan C. ; Aleman, Tomas S. ; Schwartz, Sharon B. ; Huang, Wei Chieh ; Roman, Alejandro J. ; Sumaroka, Alexander ; Li, Qiuhong ; Deng, Wen-Tao ; Min, Seok-Hong ; Chiodo, Vince A. ; Neeley, Andy ; Liu, Xuan ; Shu, Xinhua ; Matias-Florentino, Margarita ; Buentello-Volante, Beatriz ; Boye, Sanford L. ; Cideciyan, Artur V. ; Hauswirth, William W. ; Jacobson, Samuel G. / Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept. In: Human Gene Therapy. 2012 ; Vol. 23, No. 4. pp. 367-376.
@article{e4e5c0e5a59f4ef39ee2a40cbb56b0b7,
title = "Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept",
abstract = "Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken {\ss}-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.",
keywords = "MFRP mutations, RP, gene-based therapy, retinal degeneration",
author = "Astra Dinculescu and Jackie Estreicher and Zenteno, {Juan C.} and Aleman, {Tomas S.} and Schwartz, {Sharon B.} and Huang, {Wei Chieh} and Roman, {Alejandro J.} and Alexander Sumaroka and Qiuhong Li and Wen-Tao Deng and Seok-Hong Min and Chiodo, {Vince A.} and Andy Neeley and Xuan Liu and Xinhua Shu and Margarita Matias-Florentino and Beatriz Buentello-Volante and Boye, {Sanford L.} and Cideciyan, {Artur V.} and Hauswirth, {William W.} and Jacobson, {Samuel G.}",
note = "Acceptance date from webpage which is reached through Other Link - DOI link doesn't have the information - EL 25-10-19",
year = "2012",
month = "4",
doi = "10.1089/hum.2011.169",
language = "English",
volume = "23",
pages = "367--376",
journal = "Human Gene Therapy",
issn = "1043-0342",
publisher = "Mary Ann Liebert",
number = "4",

}

Dinculescu, A, Estreicher, J, Zenteno, JC, Aleman, TS, Schwartz, SB, Huang, WC, Roman, AJ, Sumaroka, A, Li, Q, Deng, W-T, Min, S-H, Chiodo, VA, Neeley, A, Liu, X, Shu, X, Matias-Florentino, M, Buentello-Volante, B, Boye, SL, Cideciyan, AV, Hauswirth, WW & Jacobson, SG 2012, 'Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept', Human Gene Therapy, vol. 23, no. 4, pp. 367-376. https://doi.org/10.1089/hum.2011.169

Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept. / Dinculescu, Astra ; Estreicher, Jackie ; Zenteno, Juan C.; Aleman, Tomas S.; Schwartz, Sharon B.; Huang, Wei Chieh ; Roman, Alejandro J.; Sumaroka, Alexander; Li, Qiuhong ; Deng, Wen-Tao ; Min, Seok-Hong ; Chiodo, Vince A.; Neeley, Andy ; Liu, Xuan ; Shu, Xinhua; Matias-Florentino, Margarita ; Buentello-Volante, Beatriz ; Boye, Sanford L.; Cideciyan, Artur V.; Hauswirth, William W.; Jacobson, Samuel G.

In: Human Gene Therapy, Vol. 23, No. 4, 04.2012, p. 367-376.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept

AU - Dinculescu, Astra

AU - Estreicher, Jackie

AU - Zenteno, Juan C.

AU - Aleman, Tomas S.

AU - Schwartz, Sharon B.

AU - Huang, Wei Chieh

AU - Roman, Alejandro J.

AU - Sumaroka, Alexander

AU - Li, Qiuhong

AU - Deng, Wen-Tao

AU - Min, Seok-Hong

AU - Chiodo, Vince A.

AU - Neeley, Andy

AU - Liu, Xuan

AU - Shu, Xinhua

AU - Matias-Florentino, Margarita

AU - Buentello-Volante, Beatriz

AU - Boye, Sanford L.

AU - Cideciyan, Artur V.

AU - Hauswirth, William W.

AU - Jacobson, Samuel G.

N1 - Acceptance date from webpage which is reached through Other Link - DOI link doesn't have the information - EL 25-10-19

PY - 2012/4

Y1 - 2012/4

N2 - Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken ß-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.

AB - Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken ß-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.

KW - MFRP mutations

KW - RP

KW - gene-based therapy

KW - retinal degeneration

UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327606/

U2 - 10.1089/hum.2011.169

DO - 10.1089/hum.2011.169

M3 - Article

VL - 23

SP - 367

EP - 376

JO - Human Gene Therapy

JF - Human Gene Therapy

SN - 1043-0342

IS - 4

ER -