AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models

Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1(st) or 2(nd) decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as th...

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Published inPloS one Vol. 8; no. 5; p. e61396
Main Authors Vasireddy, Vidyullatha, Mills, Jason A., Gaddameedi, Rajashekhar, Basner-Tschakarjan, Etiena, Kohnke, Monika, Black, Aaron D., Alexandrov, Krill, Zhou, Shangzhen, Maguire, Albert M., Chung, Daniel C., Mac, Helen, Sullivan, Lisa, Gadue, Paul, Bennicelli, Jeannette L., French, Deborah L., Bennett, Jean
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 07.05.2013
Public Library of Science (PLoS)
Subjects
Adaptor Proteins, Signal Transducing - genetics
Animal models
Animals
Augmentation
Biology
Blindness
Cell Line
Choroideremia - genetics
Choroideremia - therapy
Degeneration
Dependovirus - genetics
Enzymatic activity
Female
Gene therapy
Genes
Genetic Therapy - adverse effects
Genetic Therapy - methods
Humans
Lymphoblasts
Male
Medicine
Mice
Mutation
Nyctalopia
Patients
Peripheral vision
Physicians
Plasmids - genetics
Pluripotency
Precision Medicine
Protein transport
Protein Transport - genetics
rab GTP-Binding Proteins - metabolism
Recovery of function
Retina
Retinal degeneration
Safety
Stem cells
Toxicity
Viruses
United States > US
Pennsylvania
Online AccessGet full text

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Abstract Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1(st) or 2(nd) decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.
AbstractList Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1st or 2nd decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.
Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1.sup.st or 2.sup.nd decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.
Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1 st or 2 nd decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.
Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1(st) or 2(nd) decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1(st) or 2(nd) decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.
Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1(st) or 2(nd) decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.
Audience Academic
Author Basner-Tschakarjan, Etiena
Chung, Daniel C.
Bennicelli, Jeannette L.
Mills, Jason A.
Sullivan, Lisa
Zhou, Shangzhen
Gadue, Paul
Vasireddy, Vidyullatha
Black, Aaron D.
Maguire, Albert M.
Gaddameedi, Rajashekhar
French, Deborah L.
Kohnke, Monika
Mac, Helen
Bennett, Jean
Alexandrov, Krill
AuthorAffiliation 4 Department of Anatomic Pathology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
3 Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia
2 Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
University of Florida, United States of America
1 F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
5 Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
AuthorAffiliation_xml – name: 1 F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
– name: 3 Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia
– name: University of Florida, United States of America
– name: 2 Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
– name: 4 Department of Anatomic Pathology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
– name: 5 Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/23667438$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright COPYRIGHT 2013 Public Library of Science
2013 Vasireddy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2013 Vasireddy et al 2013 Vasireddy et al
Copyright_xml – notice: COPYRIGHT 2013 Public Library of Science
– notice: 2013 Vasireddy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
– notice: 2013 Vasireddy et al 2013 Vasireddy et al
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DocumentTitleAlternate AAV-Mediated Gene Therapy for Choroideremia
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Conceived and designed the experiments: VV JAM RG EBT MK JLB DLF JB. Performed the experiments: VV JAM RG EBT ADB AMM DCC HM LS PG JLB JB SZ. Analyzed the data: VV JAM RG EBT ADB HM LS PG JLB DLF JB. Contributed reagents/materials/analysis tools: MK KA AMM JLB DLF JB SZ SZ. Wrote the paper: VV JB.
Competing Interests: JB and AMM are co-inventors of a patent for a method to treat or slow the development of blindness, but both waived any financial interest in this technology in 2002. JB serves on a scientific advisory board for Avalanche Technologies and is a co-founder of GenSight. The authors have a patent pending relating to material pertinent to this article. This patent, provisional patent 61/486608, “Proviral plasmids for production of recombinant adeno-associated virus,” describes the proviral plasmid, pAAV2.CBAe.hCHM, used to generate the experimental vector (AAV2.hCHM) used in this study. The pAAV2.CBAe.hCHM construct will also be used to generate a clinical vector to be used in human clinical trials. There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors and in compliance with US FDA regulations.
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Snippet Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1(st) or 2(nd) decade of life causing nyctalopia and loss of peripheral...
Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1.sup.st or 2.sup.nd decade of life causing nyctalopia and loss of...
Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1st or 2nd decade of life causing nyctalopia and loss of peripheral vision....
Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1 st or 2 nd decade of life causing nyctalopia and loss of peripheral...
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StartPage e61396
SubjectTerms Adaptor Proteins, Signal Transducing - genetics
Animal models
Animals
Augmentation
Biology
Blindness
Cell Line
Choroideremia - genetics
Choroideremia - therapy
Degeneration
Dependovirus - genetics
Enzymatic activity
Female
Gene therapy
Genes
Genetic Therapy - adverse effects
Genetic Therapy - methods
Humans
Lymphoblasts
Male
Medicine
Mice
Mutation
Nyctalopia
Patients
Peripheral vision
Physicians
Plasmids - genetics
Pluripotency
Precision Medicine
Protein transport
Protein Transport - genetics
rab GTP-Binding Proteins - metabolism
Recovery of function
Retina
Retinal degeneration
Safety
Stem cells
Toxicity
Viruses
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Title AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models
URI https://www.ncbi.nlm.nih.gov/pubmed/23667438
https://www.proquest.com/docview/1350972544
https://www.proquest.com/docview/1350895244
https://pubmed.ncbi.nlm.nih.gov/PMC3646845
https://doaj.org/article/5013639fa82b45b9b6483d086bbfb112
http://dx.doi.org/10.1371/journal.pone.0061396
Volume 8
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