- Laszlo T. Bito Associate Professor of Ophthalmology and Associate Professor of Pathology and Cell Biology
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 & 2016 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.
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.
Areas of Expertise
- Genetic Disorders
- Genetic Testing
- Pediatric Genetics
- Retinal Disorders
- Eye Genetics
- Clinical Genetics
- Adult Genetics
- Retina Disorder
- Retina Hole
- Retinal Bleeding
- Retina Degeneration
- Diabetic Retinopathy
- Retinal Vascular Disorders
- Vitreoretinal Disorder
- Unexplained Vision Loss
- Loss of Vision
- Marfan's Syndrome
- Macular Degeneration
- Retinal Disease
- Skin Pigmentation Disorder
- Columbia University College of Physicians and Surgeons
- Internship: New York Hospital Queens
- Residency: UCLA - Jules Stein Eye Institute
- Fellowship: Moorfields Eye Hospital, London
Education & Training
Edward S. Harkness Eye Institute635 West 165th Street
New York, NY 10032
- (212) 305-9535
- For new and current patient appointments, call:
- (212) 305-9535
- (212) 342-5293
Please contact the provider's office directly to verify that your particular insurance is accepted.
- Aetna [EPO, HMO, Medicare Managed Care, NY Signature, POS, PPO, Signature Administrators, Student Health]
- Amida Care [Special Needs Plan]
- Cigna [EPO, Great West, HMO, POS, PPO]
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- Empire Blue Cross Blue Shield [Blue Priority, EPO, HMO, Medicare (Mediblue), Medicare Managed Care, NYP Employee Plan, Pathway (Exchange), POS, PPO]
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This provider sees pediatric patients
This provider accepts new patients
Appointment Phone Number: (212) 305-9535
Edward S. Harkness Eye Institute Research Annex160 Fort Washington Avenue
5th Floor, Room 509B
New York, NY 10032
- (212) 342-1189
- (212) 305-4987
co-director, Basic Science Course in Ophthalmology, CUMC
co-director, Stem Cell, Graduate School of Arts & Sciences
American Soceity for Clinical Investigation;
NIH DPVS study section
Honors & Awards
- Named Lectureships
- 2006 Dr. Isaac Bekhor Lecturer, Doheny Eye Institute
- at University of Southern California (9/29)
- 2013 Dr. Paul Stringer Memorial Lectureship, McMaster University
- 2013 Dr. Bradley Straastma Lecturer, Resident Graduation, UCLA
- 2015 Dr. Joginder Nath Lecturer, West Virginia U. School of Medicine
- 2016 Lecturer, World Science Festival, CRISPR Technologies
- 1988 – 1989 Alpha Epsilon Delta, National Premedical Honor Society,
- Maryland Alpha (Historian)
- 1988 – 1989 Dean’s List, The Johns Hopkins University
- 1989 Graduate with Departmental Honor
- 1989 Recipient of Student Activities Award, The Johns Hopkins University
- 1989 – 1997 NIH-National Institute of General Medical Sciences Medical Scientist Training Program: MSTP fellowship PHS Grant # T32 GM 073667-14
- 1995 ARVO/National Eye Institute Travel Fellowship
- Grant for the 1995 ARVO meeting
- 1996 Dean’s Award for Excellence in Research, Graduate Sch of Arts & Sciences, Columbia U.
- Dr. Alfred Steiner Award for Best Medical Student Research, Columbia U.
- 1997 Best Overall Presentation at Eastern Student Research Forum sponsored by American Medical Association and the University of Miami
- 1997 Travel Grant, European Students’ Conference at the Charité in Berlin
- 1998 Edith McKane Award in Ophthalmology, College of Physicians and Surgeons, Columbia U.
- 1998 John Lattimer Award in Urology, College of Physicians and Surgeons, Columbia U.
- 2000 Jules Stein Eye Institute Research Award
- 2000 RPB-Association of University Professors in Ophthalmology (AUPO) Resident Award
- 2001 – present Fight for Sight/Grant-In-Aid Review Panel Member
- 2003 Burroughs-Wellcome Fund Career Award in Biomedical Sciences
- 2003 RPB Association of University Professors in Ophthalmology Resident Award
- 2003 Nesburn Resident Award
- 2004 Dennis W. Jahnigen Award, American Geriatrics Society
- 2005 Becker-AUPO-RPB Award
- 2006 ARVO/Alcon Early Career Clinician Scientist Award
- 2007 Charles E. Culpeper Award
- 2008 Teacher Recognition Award, Columbia U.
- 2008 – 2009 Listed as one of “America’s Top Ophthalmologists” by Consumers’ Research Council of America http://consumersresearchcncl.org/Healthcare/Ophthalmologists/top_ophth.html
- 2009 Patients' Choice Award for 2008
- 2009 Elected to Macular Society
- 2010 Keynote Speaker, GTCbio 2nd Annual Ocular Diseases
- & Drug Discovery conferen. May 28, 2010
- 2012 Invited Lecturer, University of Geneva
- 2013, 14 Elected by his peers for inclusion in Best Doctors in America®
- 2013 ARVO Foundation Carl Camras Award
- 2014 Foundation Fighting Blindness Visionary Award
- Recipient and “Banking on a Cure” Honoree
- 2015 ARVO 2015 Annual Meeting Gene Editing Symposium
- Invited Lecturer in Denver, Colorado
- 2015 Elected to American Ophthalmological Society
- 2015 Invited Lecturer,Deutsche Ophthalmologische Gesellschaft DOG
- 2015 Plenary lecture, Rensselaer Center
- for Stem Cell Research (RCSCR) - Symposium
- 2015 Chair, Gene Editing/Rewriting the Genome Symposium
- American Society of Human Genetics Annual Meeting
- 2016 Elected to American Society for Clinical Investigation
- Calcium-mediated Neuronal Degeneration Mechanisms
- Light-induced Warburg Metabolism
- Genome Engineering in Patient-Specific Stem Cells
- Stem Cell and Gene Therapies
- Precision Genome Surgery
A SINGLE-MASKED, RANDOMISED, CONTROLLED, PARALLEL GROUP, PHASE 3 CLINICAL TRIAL OF RETINAL GENE THERAPY FOR CHOROIDEREMIA USING AN ADENO-ASSOCIATED VIRAL VECTOR (AAV2) ENCODING RAB ESCORT PROTEIN 1 (REP1) (P&S Industry Clinical Trial)
Feb 14 2017 - Feb 14 2022
THE JACKSON LABORATORY CENTER FOR PRECISION GENETICS: FROM NEW MODELS TO NOEL THERAPEUTICS (Federal Gov)
Aug 15 2015 - Jun 30 2020
MECHANISTIC STUDIES ON REGENERATIVE MEDICINE APPROACHES TO CHILDHOOD BLINDNESS (Federal Gov)
Apr 1 2016 - Mar 1 2020
GENOME ENGINEERING OF AMD RISK ALLELES IN PATIENT-SPECIFIC STEM CELLS (Private)
Dec 31 2016 - Dec 31 2018
Jan 1 2016 - Dec 31 2018
2013 RPB PHYSICIAN-SCIENTIST AWARD (Private)
Jul 1 2013 - Jun 30 2018
CHARACTERIZATIONS AND TREATMENT OF A MOUSE MODEL OF BUTTERFLY SHAPED PATTERNED DYSTROPHY (Private)
Jun 30 2015 - Jun 29 2018
DEFINING BARRIERS TO GENE THERAPY (Federal Gov)
Apr 1 2007 - Apr 30 2018
RPB MEDICAL STUDENT FELLOWSHIP (Private)
Jul 1 2016 - Jun 30 2017
COMPARATIVE EFFECTIVENESS OF EMBRYONIC AND INDUCED PLURIPOTENT STEM CELL-BASED THERAPIES (NY State Gov)
Jun 1 2014 - May 31 2017
CONSTRUCTION OF ENGINEERED PATIENT-SPECIFIC CELLULAR MODELS OF AMD (Private)
Apr 1 2015 - May 31 2016
BRINGING GENE SUPPLEMENTATION THERAPY FOR INHERITED PDE6A-AND DNGA3-ASSOCIATED RETINOPATHIES INTO CLINICAL PRACTICE (Private)
Feb 1 2015 - Jan 31 2016
2013 RPB MEDICAL STUDENT FELLOWSHIP (Private)
Jul 1 2013 - Dec 31 2015
NOVEL BIPARTITE VIRAL VECTORS COMBINING RNA INTERFENCES AND GENE SUPPLEMENTATION THERAPY FOR THE THE TREATMENT OF RETINITIS PIGMENTOSA (Private)
May 1 2014 - Apr 30 2015
SECONDSIGHT CP003001 (P&S Industry Clinical Trial)
Aug 3 2007 - Dec 31 2014
FUNCTIONAL ANALYSES OF EMBRYONIC STEM CELL DERIVED RETINAL C ELLS (NY State Gov)
Sep 1 2010 - Aug 31 2014
FUNCTIONAL ANALYSES OF EMBRYONIC STEM CELL DERIVED RETINAL CELLS (NY State Gov)
Sep 1 2010 - Aug 31 2014
EVALUATION OF DISEASE PROGRESSION IN RETINITIS PIGMENTOSA (Private)
Jun 30 2013 - Jun 29 2014
DISEASE PROGRESSION IN PDE6-DEFICIENT RETINITIS PIGMENTOSA PATIENTS (Private)
Jul 1 2013 - Nov 30 2013
ABSOLUTE FUNDUS AUTOFLUORESCENCE IN RETINAL DEGENERATIONS (Federal Gov)
Sep 1 2012 - Aug 31 2013
GENETIC AND ENVIRONMENTAL FACTORS IN AMD (Private)
Apr 1 2012 - Mar 31 2013
AMNION-DERIVED MULTIPOTENT PROGENITOR (AMP) AND AMNION-DERIVED CELLULAR CYTOKINE SOLUTION (ACCS) THERAPY FOR PROLIFERATIVE DIABETIC RETINOPATHY (Private)
Nov 7 2011 - Jan 11 2013
STEM CELLS IN PERSONALIZED, PREDICTIVE, AND TARGETED MEDICIN E FOR AMD (Private)
Dec 1 2011 - Nov 30 2012
PREVENTING VISUAL HANDICAP IN CHILDREN WITH TUBEROUS SCLEROS IS COMPLEX (Federal Gov)
Aug 28 2009 - Sep 27 2012
STEM CELL THERAPY FOR EARLY ONSET RETINAL DYSTROPHY IN AN AN IMAL MODEL (Private)
Aug 1 2007 - Jul 31 2012
STEM CELLS THERAPY FOR EARLY ONSET RETINAL DYSTROPHY IN AN A NMIAL MODEL (Private)
Aug 1 2007 - Jul 31 2012
MODELS OF STARGARDT MACULAR DEGENERATION STRATIFICATION AND PROGRESSION USING GENOTYPE, PHENOTYPE, AND STRUCTURE/FUNCTIO (Private)
Jun 30 2011 - Jun 29 2012
ABSOLUTE FUNDUS AUTOFLUORESCENCE IN RETINAL DEGENERATIONS (Federal Gov)
Sep 1 2010 - Mar 13 2012
ALCON BASIC SCIENCE COURSE (Private)
Jan 3 2011 - Aug 31 2011
NEURONAL FUNCTION RECOVERY AFTER DEGENERATION (Private)
Jul 1 2007 - Jun 30 2011
TRANSPLANTATION OF ES CELLS RESTORES VISUAL FUNCTION IN A RE TINITIS PIGMENTOSA MOUSE MODEL (Private)
Mar 1 2010 - Feb 28 2011
BASIC SCIENCE COURSE IN OPHTHALMOLOGY (Private)
Jan 2 2007 - Dec 31 2010
BASIC SCIENCE COURSE-- MACULA FOUNDATION (Private)
Dec 5 2008 - Jul 31 2010
ALCON BASIC SCIENCE COURSE (Private)
Feb 1 2008 - Jun 30 2010
PET STUDY OF TRANSCORNEAL ELECTRICAL STIMULATION IN SUBJECTS WITH RETINITIS PIGMENTOSA. (Federal Gov)
Feb 15 2009 - Jun 30 2009
2008–2018 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.
- 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
2014–2019 Global Phase III Trial of Collategene (AMG0001) Critical Limb Ischemia
2014-2017 Phase III Trial of AZD9291 versus Platinum-Based Doublet Chemotherapy Non-Small Cell Lung Cancer
2014–2017 ENDEAR Phase III Trial of ISIS-SMNRx Infantile-Onset Spinal Muscular Atrophy
2014–2016 SUMIT Phase III Trial of Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) Metastatic Uveal Melanoma
2014–2016 STARRS Phase II Trial of Selinexor (KPT-330) Squamous Cell Carcinoma
2014–2016 Phase II Trial of AZD9291Non-Small Cell Lung Cancer
2013–2018 Phase I/II Trial of ASP2215 Treatment-Refractory Acute myeloid Leukemia FLT3 Mutation
2013–2018 Study Title: A Phase 3 Open-Label, Multicenter, Randomized Study of ASP2215 versus Salvage Chemotherapy in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)
2013–2018 Phase III Trial of MK-8931m Amnestic Mild Cognitive Impairment in Alzheimer’s Disease
2013–2017 APOLLO Phase III Trial of Patisiran (ALN-TTR02)TTR-mediated Amyloidosis
2013–2015 Phase II Clinical Trial of Revusiran (ALN-TTRsc) TTR-mediated Cardiac Amyloidosis
2015-2018 Phase II Clinical Trial of AAV2-REP1 Choroideremia gene therapy
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.
Salchow, D.J., Gouras, P., Doi, K., Goff, S.P., Schwinger, E, Tsang S.H. (1999). A point mutation (W70A) in the rod PDE6γ gene desensitizing and delaying murine Rod photoreceptors. Invest Ophthal Vis Sci 40: 3262-3267.*
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.
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.
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 mutations in the mTOR modulator, TSC, and so likely holds the key to major questions regarding the function of mTOR in humans. A major phenotype of TSC is the development of non-malignant astrocytomas in the brain. Using a comprehensive battery of tests, we show the key feature controlling this phenotype is catenin delta-1 phosphorylation by mTOR signaling Our findings suggest malignant and benign astrocytomas differ in this phosphorylation event. The TSC astrocyte phenotype implies they are trapped in the mesenchyme to epithelium transition, and that mTOR tunes this reversible process.
10. Lijuan Zhang, Jianhai Du, Sally Justus, Chun-Wei Hsu, Luis Bonet-Ponce, Wen-Hsuan Wu, Yi-Ting Tsai , Wei-Pu Wu, Yading Jia, Jimmy K. Duong, Vinit B. Mahajan, Chyuan-Sheng Lin, Shuang Wang, James B. Hurley, STEPHEN H TSANG. Reprogramming Sirtuin 6 attenuates retinal degeneration Journal of Clinical Investigation. Nov 15, 2016, no citations yet.
Contribution: In healthy photoreceptors, glycolysis is balanced by gluconeogenesis; in degenerating rods, the rate of glycolysis is compromised. In our manuscript, we show that reprogramming rods into a state of perpetual glycolytic flux by knockdown of Sirtuin 6 (Sirt6), a transcriptional repressor, preserved the structure and function of diseased rod and cone photoreceptors in a preclinical model of RP. The vast heterogeneity of RP limits the applicability of gene editing strategies to ameliorating the disease, and developing a therapy that is not gene specific is highly desirable.
For a complete list of publications, please visit PubMed.gov