AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

eLife

Helian Feng¹  Parimal Rana²  Yunlu Xue³  Constance L Cepko⁴  Sean K Wang⁴  David M Wu⁵  Emma R West⁶  Christin M Hong⁶ 

[1]Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, United States

[2]Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States

[3]Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States

[4]Department of Ophthalmology, Harvard Medical School, Boston, United States

[5]Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States

[6]Department of Ophthalmology, Harvard Medical School, Boston, United States

[7]Howard Hughs Medical Institute, Chevy Chase, United States

[8]Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States

[9]Department of Ophthalmology, Harvard Medical School, Boston, United States

[10]Retina Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, United States

[11]Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States

[12]Howard Hughs Medical Institute, Chevy Chase, United States

关键词: retina;    neurodegeneration;    gene therapy;    cone photoreceptor;    retinal metabolism;    mitochondria;    Mouse;   

DOI  :  10.7554/eLife.66240

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Retinitis pigmentosa (RP) is an inherited retinal disease affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high-acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a disease gene-agnostic therapy, we screened 20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb) and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

【 授权许可】

CC BY