Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration
No treatment is available for nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1)-associated retinal degeneration, an inherited disease that leads to severe vision loss early in life. Although the causative gene, NMNAT1, plays an essential role in nuclear nicotinamide adenine dinucleotide (NA...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050120301522 |
| _version_ | 1818018634531864576 |
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| author | Scott H. Greenwald Emily E. Brown Michael J. Scandura Erin Hennessey Raymond Farmer Basil S. Pawlyk Ru Xiao Luk H. Vandenberghe Eric A. Pierce |
| author_facet | Scott H. Greenwald Emily E. Brown Michael J. Scandura Erin Hennessey Raymond Farmer Basil S. Pawlyk Ru Xiao Luk H. Vandenberghe Eric A. Pierce |
| author_sort | Scott H. Greenwald |
| collection | DOAJ |
| description | No treatment is available for nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1)-associated retinal degeneration, an inherited disease that leads to severe vision loss early in life. Although the causative gene, NMNAT1, plays an essential role in nuclear nicotinamide adenine dinucleotide (NAD)+ metabolism in tissues throughout the body, NMNAT1-associated disease is isolated to the retina. Since this condition is recessive, supplementing the retina with a normal copy of NMNAT1 should protect vulnerable cells from disease progression. We tested this hypothesis in a mouse model that harbors the p.Val9Met mutation in Nmnat1 and consequently develops a retinal degenerative phenotype that recapitulates key features of the human disease. Gene augmentation therapy, delivered by subretinal injection of adeno-associated virus (AAV) carrying a normal human copy of NMNAT1, rescued retinal structure and function. Due to the early-onset profile of the phenotype, a rapidly activating self-complementary AAV was required to initiate transgene expression during the narrow therapeutic window. These data represent the first proof of concept for a therapy to treat patients with NMNAT1-associated disease. |
| first_indexed | 2024-04-14T07:42:10Z |
| format | Article |
| id | doaj.art-5d02e3397cf744a298ba15f2fe1d0c82 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-14T07:42:10Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-5d02e3397cf744a298ba15f2fe1d0c822022-12-22T02:05:27ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-09-0118582594Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal DegenerationScott H. Greenwald0Emily E. Brown1Michael J. Scandura2Erin Hennessey3Raymond Farmer4Basil S. Pawlyk5Ru Xiao6Luk H. Vandenberghe7Eric A. Pierce8Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USAOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USAOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USAOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USAOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USAOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USAOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA; Ocular Genomics Institute, Grousebeck Gene Therapy Center, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USAOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA; Ocular Genomics Institute, Grousebeck Gene Therapy Center, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USAOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA; Corresponding author: Eric A. Pierce, Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.No treatment is available for nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1)-associated retinal degeneration, an inherited disease that leads to severe vision loss early in life. Although the causative gene, NMNAT1, plays an essential role in nuclear nicotinamide adenine dinucleotide (NAD)+ metabolism in tissues throughout the body, NMNAT1-associated disease is isolated to the retina. Since this condition is recessive, supplementing the retina with a normal copy of NMNAT1 should protect vulnerable cells from disease progression. We tested this hypothesis in a mouse model that harbors the p.Val9Met mutation in Nmnat1 and consequently develops a retinal degenerative phenotype that recapitulates key features of the human disease. Gene augmentation therapy, delivered by subretinal injection of adeno-associated virus (AAV) carrying a normal human copy of NMNAT1, rescued retinal structure and function. Due to the early-onset profile of the phenotype, a rapidly activating self-complementary AAV was required to initiate transgene expression during the narrow therapeutic window. These data represent the first proof of concept for a therapy to treat patients with NMNAT1-associated disease.http://www.sciencedirect.com/science/article/pii/S2329050120301522NMNAT1Leber congenital amaurosisLCA9gene therapyAAVNAD+ |
| spellingShingle | Scott H. Greenwald Emily E. Brown Michael J. Scandura Erin Hennessey Raymond Farmer Basil S. Pawlyk Ru Xiao Luk H. Vandenberghe Eric A. Pierce Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration Molecular Therapy: Methods & Clinical Development NMNAT1 Leber congenital amaurosis LCA9 gene therapy AAV NAD+ |
| title | Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration |
| title_full | Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration |
| title_fullStr | Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration |
| title_full_unstemmed | Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration |
| title_short | Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration |
| title_sort | gene therapy preserves retinal structure and function in a mouse model of nmnat1 associated retinal degeneration |
| topic | NMNAT1 Leber congenital amaurosis LCA9 gene therapy AAV NAD+ |
| url | http://www.sciencedirect.com/science/article/pii/S2329050120301522 |
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