Advertisement
Precision metabolome reprogramming for imprecision therapeutics in retinitis pigmentosa
Salvatore Marco Caruso,1,6 Joseph Ryu,1 Peter M.J. Quinn,1 and Stephen H. Tsang1,2,3,4,5,6,7,8
1Jonas Children’s Vision Care and Bernard and Shirlee Brown Glaucoma Research Laboratory,
2Columbia Stem Cell Initiative,
3Department of Ophthalmology,
4Department of Pathology,
5Department of Cell Biology,
6Department of Biomedical Engineering, and
7Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
8Edward S. Harkness Eye Institute, New York–Presbyterian Hospital, New York, New York, USA.
Address correspondence to: Stephen H. Tsang, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, 635 West 165th Street, Box 212, New York, New York 10032, USA. Phone: 212.342.1189; Email: sht2@columbia.edu.
Authorship note: SMC and JR contributed equally to this work.
Find articles by Caruso, S. in: JCI | PubMed | Google Scholar
1Jonas Children’s Vision Care and Bernard and Shirlee Brown Glaucoma Research Laboratory,
2Columbia Stem Cell Initiative,
3Department of Ophthalmology,
4Department of Pathology,
5Department of Cell Biology,
6Department of Biomedical Engineering, and
7Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
8Edward S. Harkness Eye Institute, New York–Presbyterian Hospital, New York, New York, USA.
Address correspondence to: Stephen H. Tsang, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, 635 West 165th Street, Box 212, New York, New York 10032, USA. Phone: 212.342.1189; Email: sht2@columbia.edu.
Authorship note: SMC and JR contributed equally to this work.
Find articles by Ryu, J. in: JCI | PubMed | Google Scholar
1Jonas Children’s Vision Care and Bernard and Shirlee Brown Glaucoma Research Laboratory,
2Columbia Stem Cell Initiative,
3Department of Ophthalmology,
4Department of Pathology,
5Department of Cell Biology,
6Department of Biomedical Engineering, and
7Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
8Edward S. Harkness Eye Institute, New York–Presbyterian Hospital, New York, New York, USA.
Address correspondence to: Stephen H. Tsang, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, 635 West 165th Street, Box 212, New York, New York 10032, USA. Phone: 212.342.1189; Email: sht2@columbia.edu.
Authorship note: SMC and JR contributed equally to this work.
Find articles by
Quinn, P.
in:
JCI
|
PubMed
|
Google Scholar
|
1Jonas Children’s Vision Care and Bernard and Shirlee Brown Glaucoma Research Laboratory,
2Columbia Stem Cell Initiative,
3Department of Ophthalmology,
4Department of Pathology,
5Department of Cell Biology,
6Department of Biomedical Engineering, and
7Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
8Edward S. Harkness Eye Institute, New York–Presbyterian Hospital, New York, New York, USA.
Address correspondence to: Stephen H. Tsang, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, 635 West 165th Street, Box 212, New York, New York 10032, USA. Phone: 212.342.1189; Email: sht2@columbia.edu.
Authorship note: SMC and JR contributed equally to this work.
Find articles by
Tsang, S.
in:
JCI
|
PubMed
|
Google Scholar
|
Published July 13, 2020 - More info
J Clin Invest. 2020;130(8):3971–3973. https://doi.org/10.1172/JCI139239.
© 2020 American Society for Clinical Investigation
Related article:
Abstract
Retinitis pigmentosa (RP) is a genetically heterogenous group of eye diseases in which initial degeneration of rods triggers secondary degeneration of cones, leading to significant loss of daylight, color, and high-acuity vision. Gene complementation with adeno-associated viral (AAV) vectors is one strategy to treat RP. Its implementation faces substantial challenges, however; for example, the tremendous number of loci with causal mutations. Gene therapy targeting secondary cone degeneration is an alternative approach that could provide a much-needed generic treatment for many patients with RP. Here, we show that microglia are required for the upregulation of potentially neurotoxic inflammatory factors during cone degeneration in RP, creating conditions that might contribute to cone dysfunction and death. To ameliorate the effects of such factors, we used AAV vectors to express isoforms of the antiinflammatory cytokine transforming growth factor beta (TGF-β). AAV-mediated delivery of TGF-β1 rescued degenerating cones in 3 mouse models of RP carrying different pathogenic mutations. Treatment with TGF-β1 protected vision, as measured by 2 behavioral assays, and could be pharmacologically disrupted by either depleting microglia or blocking the TGF-β receptors. Our results suggest that TGF-β1 may be broadly beneficial for patients with cone degeneration, and potentially other forms of neurodegeneration, through a pathway dependent upon microglia.
Authors
Sean K. Wang, Yunlu Xue, Constance L. Cepko
-
Future directions in precision reprogramming
Cell type–specific metabolic reprogramming can rejuvenate aerobic glycolytic balance within the eye and rescue vision. Importantly, Wang and colleagues elegantly validate the therapeutic feasibility of using AAVs (7). AAVs have become the most widely used vector in FDA trials due to their low immunogenicity and cytotoxicity, and the ability of their serotype to be engineered for cell type–specific targeting (1). As such, they represent the ideal gene delivery vehicle to mediate metabolomic reprogramming in microglia as well as other retinal cells. As proposed by the Hurley hypothesis, different retinal cells are metabolically coupled (12), and thus how these dynamics are disrupted in dystrophic retinas may pose another critical direction for cone preservation (Table 1).
Recently, the photoreceptors and retinal pigmented epithelial cells have been identified as other cell types that suffer from dysregulation of glycolytic and oxidative phase-shifting during RP progression. In healthy retinas, rods take up glucose from the retinal pigmented epithelium (RPE) and convert it to lactate via aerobic glycolysis, even in the presence of oxygen. Much like microglia, young RPE prefers an oxidative metabolic state and uses the generated lactate as a substrate for oxidative phosphorylation and a suppressor for RPE-specific glucose consumption. In contrast, in PDE6 dystrophies, the lactate production decreases as rods die, stagnating NAD+ consumption in the RPE. The resultant accumulation of NAD+ stimulates glycolysis in the RPE, which depletes all the available glucose from the choriocapillaris as an energy source. As the delicate mutualism between oxidative and glycolytic tissue processes fails, cones begin to die from malnutrition (5). These findings suggest that boosting aerobic glycolysis in dystrophic photoreceptors might counter photoreceptor death from RP-induced metabolic imbalance. Clinicians can apply the AAV vector delivery implemented by Wang et al. to drive diseased photoreceptors toward enhancing aerobic glycolysis (Table 1). Genetically ablating inhibitors of aerobic glycolysis, either Tsc1 (13) or Sirt6 (14), increase the number of photoreceptors in RP retinas (13–15). SIRT6 is a master promoter of aerobic glycolysis via the rate-limiting enzymes for glycolysis and GLUT1-mediated glucose transport. Future studies directed toward precision metabolome reprogramming may substantially advance the development of a gene agnostic therapy for neurodegenerative disorders.
Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)