Researcher’s Profile

Stephen H. Tsang, MD, PhD


Stephen H. Tsang, M.D, Ph.D. is an acclaimed clinical geneticist in the care of individuals with retinal degenerations, and is known worldwide for his pivotal research in reprogramming the metabolome as a therapeutic avenue.

Dr. Tsang graduated from Johns Hopkins University, where he began his medical genetics training under the tutelage of Professor Victor A. McKusick. He received his M.D.-Ph.D. degrees from the NIH-National Institute of General Medical Sciences Medical Scientist Training Program (MSTP) at Columbia University. Dr. Tsang then completed his residency at Jules Stein Eye Institute/UCLA, followed by studies with Professors Alan C. Bird and Graham E. Holder on improving the care of individuals with macular degenerations.

Dr. Tsang is a recognized pioneer in genome surgery in stem cells. Most recently, he has been invited to lecture at the genome surgery workshop during the annual Association for Research in Vision & Ophthalmology (ARVO) 2015, 16 & 18 Annual Meetings; and as a Moderator for Gene Editing/Rewriting the Genome: Moving from Association to Biology and Therapeutics session during the 65th American Society of Human Genetics (ASHG) Annual Meeting, and a lecturer at 2015 & 2016 CRISPR Revolution conferences at Cold Spring Harbor. 

In his New York State supported stem cell program (N09G-302), he is examining embryonic stem (ES) cells to model and replace diseased human retinal cells. His contributions were recognized by the 2005 Bernard Becker Association of University Professors in Ophthalmology's Research to Prevent Blindness Award. Dr. Tsang also participates in resident teaching and had been the Columbia ophthalmology basic science course director. He is a member of the American Society of Clinical Investigation.

Dr. Tsang is one of a handful of clinicians who can direct the full spectrum of bench-to-bedside research. PI’s research on cGMP-phosphodiesterase (PDE6) is a case in point. PDE6 defects lead to blindness in 72,000 people worldwide. PI generated the world’s first gene-targeted model of retinitis pigmentosa (a PDE6 mutant), and then used these mice to dissect the underlying pathophysiology. These studies led to novel and fundamental discoveries on PDE6 regulation of G-protein-coupled-receptor signaling and, eventually, preclinical testing in the same mice; of the different therapies tested, viral-gene therapy is slated for clinical trials. Many of his publications are in top rated general interest journals such as Science and Journal of Clinical Investigation, which attests to the broad impact that his work has had.


Research Statement: 

As a result of his groundbreaking metabolome reprogramming research, Dr. Tsang has earned a reputation as one of the world's foremost authority in therapeutics of neurodegenerative disoders. 

Dr Tsang's genome engineering laboratory is engaged in tackling neurodegenerative disorders by pursuing investigations in three areas, two of which include patient-specific mouse models: probing the role of phosphodiesterase (PDE) signaling in neurodegeneration, developing stem cell-based therapies for photoreceptor degeneration, and correlating the genotypes of various human retinal degenerations with the phenotypes revealed in live metabolic imaging (autofluorescence). We are also currently focused on genome engineering/CRISRP approaches to reprogamming metabolome in photoreceptor to promote cell survival, which may be broadly applicable to retinal degenerative diseases, regardless of the mutation. While light-adapted normal photoreceptors have a highly anabolic and aerobic (high lactate) metabolism similar to the Warburg effect observed in stem cells, dark-adapted photoreceptors have catabolism (low lactate), high-ATP metabolism similar to neurons. To translate this anabolic therapy to humans (who would rightly reject being maintained in darkness), our laboratory is developing  “genetic sunglasses” to promote a constant dark-adapted metabolic state in photoreceptor neurons while maintaining a normal light-dark circadian environment.

2008–2023 NIH-R01EY018213; PI: Stephen Tsang; Direct Costs: $250,000 per year

Defining Barriers to Gene Therapy

2015–2020 NIH-1R01EY024698; PI: Stephen Tsang; Direct Costs: $286,665 per year

Genome Surgery in Stem Cells

2016–2020 NIH 1R01EY026682; MPI ; Direct Costs: $318,599 per year

Regenerative Medicine Approaches to Childhood Blindness

2015-2017 R21AG050437; Direct Costs: $175,821 per year

Genome Surgery in patient specific stem cells

2014-2017 New York State C029572; PI: Stephen Tsang; Direct Costs: $300,00 per year

Comparative Effectiveness of Embryonic and Induced Pluripotent Stem Cell-based Therapies

Investigate the safety and efficacy of iPS-derived RPE grafts to restore vision in mouse models of both retinal damage and retinal degeneration.

2010–2016 Foundation Fighting Blindness Center C-NY05-0705-0312; co-PI: Stephen Tsang $70,00 per year

Electrophysiology and Imaging Module.

Lab Members: 
Chun Wei Hsu, MS, Lentiviral Research Assistant
Richard Davis, PhD, Associate Research Scientist
Katherine J. Wert, PhD Student
Susanne Koch, PhD, Postdoctoral Fellow
Wen-Hsuan Wu, AAV, CRISPR Research Assistant
Iris Yao Li, MD, Reprogramming Fellow
Yi-Ting Tsai, PhD student (Metabolic Biology)
Jin Yang, MD, SILAC Fellow
Lijuan Zhang, MD, Metabolomics Research Fellow
Tharikarn Sujirakul, MD, Ion Torrent Fellow
Deniz Erol, Research Assistant

H-index 42

Gene therapy and genome surgery in the retina. DiCarlo JE, Mahajan VB, Tsang SH.  Journal of Clinical Investigation.  2018 Jun 1;128(6):2177-2188.

Tsang S.H., Gouras P., Yamashita C.K., Fisher J., Farber D.B., and Goff SP (1996). Retinal Degeneration in Mice Lacking the γ subunit of cGMP phosphodiesterase. Science 272: 1026-1029.

Tsang S.H., Burns, M. E., Calvert, P. D., Gouras, P., Baylor, D. A., Goff, S. P., and Arshavsky, V. Y. (1998). Role of the Target Enzyme in Deactivation of Photoreceptor G Protein in Vivo. Science. 282, 117-21.

Tsang S.H., Woodruff, M. L., Chen, C. K., Yamashita, C. Y., Cilluffo, M. C., Rao, A. L., Farber, D. B., and Fain, G. L. (2006). Modulation of phosphodiesterase6 turnoff during background illumination in mouse rod photoreceptors J Neurosci 26, 4472-4480.

Wert KJ, Mahajan VB, Zhang L, Yan Y, Li Y, Tosi J, Hsu CW, Nagasaki T, Janisch KM, Grant MB, Mahajan M, Bassuk AG, Tsang SH. Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy. Signal Transduct Target Ther. 2016;1. pii: 16005. Epub 2016 Apr 22. PubMed PMID: 27195131; PubMed Central PMCID: PMC4868361.

Petersen-Jones S.M., Occelli L.M., Winkler P.A., Lee W., Sparrow J.R., Tsukikawa M., Boye S.L., Chiodo V., Capasso J.E., Becirovic E., Schön C., Seeliger M.W., Levin A.V., Michalakis S., Hauswirth W.W., Tsang S.H. (2018). Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach. Journal of Clinical Investigation. 128(1):190-206. doi:10.1172/JCI95161.

1. Li, Y, Tsai, YT, Hsu, CW, Erol, D, Yang, J, Wu, WH, Davis, Richard, Egli, Dieter, TSANG, STEPHEN H. Long-term safety and efficacy of human induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa. Molecular Medicine18: 1312-1319. Cited 55 times.                                                      

Contribution: This high-impact study used a preclinical model for retinitis pigmentosa (RP) to provide the first evidence for human iPS-cell-mediated recovery of visual function. Therefore, this research provided critical feasibility data for therapies using autologous iPS-cell transplantation to treat retinal degenerations in humans. This study is also one of the first to provide strong in vivo preclinical evidence that this potential cell therapy does not induce tumor formation. This discovery was featured in numerous news outlets – including a Medscape Medical News article (1/7/13), and in two Columbia University Medical Center press releases (10/1/12 and 12/20/12).

2. Wert, K.J., Sancho-Pelluz, J., Davis, R.J., Nishina, P.M., and TSANG, S.H. Gene Therapy Provides Long-term Visual Function in a Pre-clinical Model of Retinitis Pigmentosa. (2013) Human Molecular Genetics. 22:558-567. Cited 18 times.

Contribution: This manuscript is unique in the field of gene therapy in that it demonstrates stable, sustained rescue – both functional and structural. These strong feasibility data provide a solid foundation for moving forward with gene-therapy in patients with a specific genetic form of retinitis pigmentosa (RP). In fact, we are currently recruiting patients for our upcoming gene-therapy trial, “Bringing Gene Supplementation Therapy for PDE6-associated Retinopathies into Clinical Practice” (funded by Tistou and Charlotte Kerstan Foundation).

3. Li Y, Wu W-H, Hsu C-W, Nguyen H-V, Tsai Y-T, Nagasaki T, Maumenee IH, Yannuzzi LA, Hoang QV, Hua H, Egli D, TSANG, S.H. Gene therapy in patient-specific stem cell lines and a preclinical model of retinitis pigmentosa with membrane frizzled-related protein (MFRP) defects. (2014) Molecular Therapy. 2014 Sep;22(9):1688-97. Cited 15 times.

Contribution: This is the first demonstration that patient-specific induced pluripotent stem (iPS) cells can be used to model a disease phenotype, and study its etiology. This is also the first report of human iPS-derived cells being successfully used as a recipient for viral gene therapy.

4. Yang J, Li Y, Chan L, Tsai YT, Wu WH, Nguyen HV, Hsu CW, Li X, Brown LM, Egli D, Sparrow JR, TSANG, S.H. (2014) Validation of genome-wide association study (GWAS)-identified disease risk alleles with patient-specific stem cell lines. Human Molecular Genetics. Jan 31. PMID: 24497574.  Cited 27 times.

Contribution: In vitro models for age-related diseases are invariably based on immortal cells, which are inherently unsuitable for modeling diseases of aging. In this study, we developed a novel human stem-cell-based model for age-related macular degeneration (AMD), an ocular disease with high incidence. We then used these cells to determine the function of two important, but poorly understood AMD risk factors. This is the first demonstration that patient-specific induced pluripotent stem (iPS) cells can be used to model a late onset disease phenotype, and study its etiology.

5. Koch SF, Tsai YT, Duong JK, Wu WH, Hsu CW, Wu WP, Bonet-Ponce L, Lin CS, TSANG SH. (2) Halting progressive neurodegeneration in advanced retinitis pigmentosa. 2015. Journal of Clinical Investigation. 2015 Sep;125(9):3704-13. doi: 10.1172/JCI82462. Epub 2015 Aug 24. PMID:26301813. Cited 5 times.

Koch SF, Duong JK, Hsu CW, Tsai YT, Lin CS, Wahl-Schott CA, Tsang SH. Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa. Proc Natl Acad Sci U S A. 2017 May 16;114(20):5259-5264.

Contribution: Recent follow-up studies to the human RPE65 gene therapy trials demonstrated that the interventions failed to halt or even slow photoreceptor degeneration. As a means to explain this treatment failure, it was suggested that the diseased photoreceptors had reached a “point-of-no-return.” In this report, we tested this hypothesis in an RP mouse model, using a novel driver to deliver therapy to all rod photoreceptors at early, mid, and late disease stages. In these optimally treated retinas, not only was function rescued, but photoreceptor degeneration was also halted. Critically, we demonstrated significant sustained rescue, even at the late disease stage.

6. Wu WH, Tsai YT, Justus S, Lee TT, Zhang L, Lin CS, Bassuk AG, Mahajan VB, TSANG SH. CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa. Molecular Therapy 2016 Aug;24(8):1388-94. doi: 10.1038/mt.2016.107. Epub 2016 May 20. PMID:27203441. New publication (May 20), no citations yet.

Contribution: In the current era of next-generation sequencing, copious genetic variants are identified. This report illustrates how CRISPR can be used to validate sequence variants, distinguish between their pathogenicity, and elucidate disease pathophysiology. We applied CRISPR/Cas9 to resolve a century-long debate on the molecular origins of the Pde6brd1/Pde6brd1 (Rd1) mouse., Rd1 mice express two mutations – a murine leukemia virus (Xmv-28) insertion and a nonsense mutation (C to A transversion) in codon 347 – that still remain controversial. We sought to determine whether one or both of these mutations engenders the fast-progressing retinal deterioration typical of Rd1 mice.

7. Moshfegh Y, Velez G, Li Y, Bassuk AG, Mahajan VB, TSANG SH. BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE. Hum Mol Genet. 2016 May 18. pii: ddw126. PMID: 27193166. New publication (May 18), no citations yet.

Contribution: Mutations in the BEST1 gene are clearly linked to eye disease in human RPE, including Best vitelliform macular dystrophy. The mechanism linking mutations in the gene to eye pathology is unknown, and the question of whether BEST1 is a bona fide chloride channel has been remaining in the field.  In this report we show that BEST1 encodes a predicted transmembrane anion channel that is calcium-activated and highly permeable to chloride ions. We have taken advantage of iPSC-RPE cell modeling of BEST1 disease, and developed a new approach for directly measuring chloride currents in live patient RPE with a biosensor.

8. Zhang L, Justus S, Xu Y, Pluchenik T, Hsu CW, Yang J, Duong JK, Lin CS, Jia Y, Bassuk AG, Mahajan VB, TSANG SH. Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa. Hum Mol Genet. 2016 Aug 11. pii: ddw256. PMID: 27516389. New publication (Aug 11), no citations yet.

Contribution: In RP, outer segment (OS) gets shortening which triggers photoreceptor death is mainly due to the imbalance between anabolic and catabolic processes. OS is shed and regenerated daily, but in disease photoreceptors, the rate of shedding exceeds the rate of renewal, leading to significantly shorter OS, excessive anabolic demands and subsequent death. Augmenting anabolism could theoretically fuel protein and lipid synthesis, thus encouraging OS regenesis.  Ablation of Tsc1, a transcriptional inhibitor of the mTOR pathway, preserved the structure and function of diseased rod and cone photoreceptors in a preclinical model of RP.

9. Yang J, Bassuk AG, Merl-Pham J, Hsu CW, Colgan DF, Li X, Au KS, Zhang L, Smemo S, Justus S, Nagahama Y, Grossbach AJ, Howard MA 3rd, Kawasaki H, Feldstein NA, Dobyns WB, Northrup H, Hauck SM, Ueffing M, Mahajan VB, TSANG SH. Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors. Hum Mol Genet. 2016 Aug 11. pii: ddw253. PMID:27516388. New publication (Aug 11), no citations yet.

Contribution: The tuberosclerosis complex (TSC) syndrome is due to mut