Bio

Bio


Dr. Mahajan is an Associate Professor and vitreoretinal surgeon and scientist in the Department of Ophthalmology at Stanford University. He directs the NIH-funded Omics Laboratory that uses high-throughput methods in genomics, proteomics, and phenomics to identify molecules involved in vitreoretinal disease.

His research team discovered the first gene to cause non syndromic uveitis and is now using protein crystallography to design therapeutic inhibitors for calpain-5. Mahajan and his team performed the first CRISPR gene editing therapy for eye disease in human stem cells. They have also created in vivo models for diabetic retinopathy and uveitis.

Using translational proteomics, Mahajan’s multidisciplinary team is developing new precision health approaches using molecular biomarkers to diagnose retinal disease, select personalized therapies, and decode the anatomic structures of the human eye.

Dr. Mahajan has trained numerous surgical fellows that now operate around the world. He has developed enhanced surgeries for complex cases of retinal detachment, macular hole, macular edema, diabetes, macular degeneration, proliferative vitreoretinopathy, optic maculopathy, uveitis, and others. He has identified safer approaches for vitreoretinal surgery in children and adults, and provides second opinions for complex cases. Dr. Mahajan is among only a handful of surgeons to perform human gene therapy for retinal disease. He has published new surgical biomarker studies that are the first to use personalized proteomics to precisely diagnose and treat otherwise problematic retinal diseases.

Dr. Mahajan earned his bachelor’s degree in Molecular and Cell Biology at the University of California, Berkeley. He then entered the Medical Scientist Training Program at the University of California, Irvine. Upon completion, he joined the residency program at the Jules Stein Eye Institute at the University of California, Los Angeles. At UCLA he completed post doctoral laboratory research as an EyeSTAR Fellow. He next specialized in vitreoretinal diseases and surgery at the University of Iowa’s Retina Fellowship Program and joined as faculty in 2008. He joined Stanford University in 2017.

Clinical Focus


  • Ophthalmology
  • VItreoretinal Disease and Surgery
  • Macular Degeneration
  • Retinal Detachment
  • Uveitis
  • Macular Hole
  • Epiretinal Membrane

Academic Appointments


Honors & Awards


  • Clinician Scientist Award, Doris Duke Charitable Foundation (2013)
  • Alumni Achievement Award, Fight for Sight (2017)

Professional Education


  • Fellowship:University of Iowa College of Medicine (2008) IA
  • Residency:University of California Los Angeles School of Medicine (2006) CA
  • Internship:University of California Los Angeles School of Medicine (2002) CA
  • Medical Education:University of California Irvine College of Medicine (2001) CA

Research & Scholarship

Current Research and Scholarly Interests


Our focus is the development of personalized medicine for eye diseases through translation of our discoveries in proteomics, genomics, and phenomics in humans, mice and tissue culture models.

My laboratory team is composed of scientists, surgeons, engineers, and students who are dedicated to curing blindness. We use high-throughput technologies (proteomics, genomics, phenomics) to identify candidate disease molecules. These are validated using biochemistry, tissue culture, and animal models. The findings are then directly translated into personalized medical therapies in humans. Major projects include: 1. Protein crystallography of Calpain-5 and its signaling mechanisms in the retina. 2. Proteomics of vitreoretinal disease. 3. Genome-wide knockout screen of mouse eye phenotypes. 4. CRISPR gene therapy for eye disease.

We identified CAPN5 as the first gene to cause uveitis. The gene encodes the calcium-activated cysteine protease. We are investigating the structure-function effects of mutations on its crystal structure and enzymatic activity, structure, function within photoreceptor cells, and activation of intracellular signaling pathways. We also conduct clinical and human genetic studies into the etiology and therapy of autoimmune eye disease.

Our unique access to human surgical eye tissues allowed us to map the human proteome in normal and diseased eyes with vitreoretinal conditions. We have identified major enzymatic pathways associated with diseases such as age-related macular degeneration, diabetic retinopathy, and autoimmunity. Specific molecules have been validated in mice and in cultured cells.

In partnership with the Sanger Institute, we are conducting a high-throughput phenotype screen in genetically modified mice. We have identified numerous genes that cause eye diseases in mice and their human correlates. The strategic integration of this genotype-phenotype platform provides excellent projects for mechanistic investigations.

Using mouse models of eye disease and human stem cells, we are exploring the application of CRISPR to treat blinding conditions.

The laboratory allows highly motivated individuals to be creative in an immersive, interactive environment intensely focused on the restoration of sight. Please contact us to learn more.

Teaching

Stanford Advisees


Publications

All Publications


  • CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa: A Brief Methodology. Methods in molecular biology (Clifton, N.J.) Wu, W. H., Tsai, Y. T., Justus, S., Cho, G. Y., Sengillo, J. D., Xu, Y., Cabral, T., Lin, C. S., Bassuk, A. G., Mahajan, V. B., Tsang, S. H. 2018; 1715: 191–205

    Abstract

    CRISPR/Cas9 genome engineering is currently the leading genome surgery technology in most genetics laboratories. Combined with other complementary techniques, it serves as a powerful tool for uncovering genotype-phenotype correlations. Here, we describe a simplified protocol that was used in our publication, CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa, providing an overview of each section of the experimental process.

    View details for DOI 10.1007/978-1-4939-7522-8_13

    View details for PubMedID 29188514

  • CRISPR-Cas Genome Surgery in Ophthalmology. Translational vision science & technology DiCarlo, J. E., Sengillo, J. D., Justus, S., Cabral, T., Tsang, S. H., Mahajan, V. B. 2017; 6 (3): 13-?

    Abstract

    Genetic disease affecting vision can significantly impact patient quality of life. Gene therapy seeks to slow the progression of these diseases by treating the underlying etiology at the level of the genome. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated systems (Cas) represent powerful tools for studying diseases through the creation of model organisms generated by targeted modification and by the correction of disease mutations for therapeutic purposes. CRISPR-Cas systems have been applied successfully to the visual sciences and study of ophthalmic disease - from the modification of zebrafish and mammalian models of eye development and disease, to the correction of pathogenic mutations in patient-derived stem cells. Recent advances in CRISPR-Cas delivery and optimization boast improved functionality that continues to enhance genome-engineering applications in the eye. This review provides a synopsis of the recent implementations of CRISPR-Cas tools in the field of ophthalmology.

    View details for DOI 10.1167/tvst.6.3.13

    View details for PubMedID 28573077

  • ACANTHAMOEBA ENDOPHTHALMITIS AFTER RECURRENT KERATITIS AND NODULAR SCLERITIS. Retinal cases & brief reports Mammo, Z., Almeida, D. R., Cunningham, M. A., Chin, E. K., Mahajan, V. B. 2017; 11 (2): 180-182

    Abstract

    To describe the clinical course of a patient with Acanthamoeba keratitis, who despite prompt treatment progressed to histopathology-confirmed Acanthamoeba retinitis and endophthalmitis.Case report.A healthy 30-year-old male wearing soft contact lens was diagnosed with Acanthamoeba keratitis and treated medically and surgically over the course of 1 year with presumed resolution of the infection. Yet, his infection recurred with documented spread to sclerokeratitis, and overwhelming endophthalmitis. Concerns about extra-ocular spread prompted a therapeutic enucleation with histopathologic evidence of Acanthamoeba organisms throughout the globe.This is a case of a severe recurrent Acanthamoeba infection presenting initially as keratitis, followed by sclerokeratitis and histolopathology-confirmed endophthalmitis. This case demonstrates that despite persistent medical and surgical intervention, eradication of organisms may not be possible.

    View details for DOI 10.1097/ICB.0000000000000323

    View details for PubMedID 27152698

  • Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO) PLOS ONE Cox, A. J., Darbro, B. W., Laxer, R. M., Velez, G., Bing, X., Finer, A. L., Erives, A., Mahajan, V. B., Bassuk, A. G., Ferguson, P. J. 2017; 12 (3)

    Abstract

    Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.

    View details for DOI 10.1371/journal.pone.0169687

    View details for Web of Science ID 000396318300002

    View details for PubMedID 28301468

    View details for PubMedCentralID PMC5354242

  • Retinal and choroidal angiogenesis: a review of new targets. International journal of retina and vitreous Cabral, T., Mello, L. G., Lima, L. H., Polido, J., Regatieri, C. V., Belfort, R., Mahajan, V. B. 2017; 3: 31

    Abstract

    Retinal and choroidal neovascularization are a major cause of significant visual impairment, worldwide. Understanding the various factors involved in the accompanying physiopathology is vital for development of novel treatments, and most important, for preserving patient vision. The intraocular use of anti-vascular endothelial growth factor therapeutics has improved management of the retinal and choroidal neovascularization but some patients do not respond, suggesting other vascular mediators may also contribute to ocular angiogenesis. Several recent studies examined possible new targets for future anti-angiogenic therapies. Potential targets of retinal and choroidal neovascularization therapy include members of the platelet-derived growth factor family, vascular endothelial growth factor sub-family, epidermal growth factor family, fibroblast growth factor family, transforming growth factor-β superfamily (TGF-β1, activins, follistatin and bone morphogenetic proteins), angiopoietin-like family, galectins family, integrin superfamily, as well as pigment epithelium derived factor, hepatocyte growth factor, angiopoietins, endothelins, hypoxia-inducible factors, insulin-like growth factors, cytokines, matrix metalloproteinases and their inhibitors and glycosylation proteins. This review highlights current antiangiogenic therapies under development, and discusses future retinal and choroidal pro- and anti-angiogenic targets as wells as the importance of developing of new drugs.

    View details for DOI 10.1186/s40942-017-0084-9

    View details for PubMedID 28835854

    View details for PubMedCentralID PMC5563895

  • Dissection of Human Retina and RPE-Choroid for Proteomic Analysis. Journal of visualized experiments : JoVE Cabral, T., Toral, M. A., Velez, G., DiCarlo, J. E., Gore, A. M., Mahajan, M., Tsang, S. H., Bassuk, A. G., Mahajan, V. B. 2017

    Abstract

    The human retina is composed of the sensory neuroretina and the underlying retinal pigmented epithelium (RPE), which is firmly complexed to the vascular choroid layer. Different regions of the retina are anatomically and molecularly distinct, facilitating unique functions and demonstrating differential susceptibility to disease. Proteomic analysis of each of these regions and layers can provide vital insights into the molecular process of many diseases, including Age-Related Macular Degeneration (AMD), diabetes mellitus, and glaucoma. However, separation of retinal regions and layers is essential before quantitative proteomic analysis can be accomplished. Here, we describe a method for dissection and collection of the foveal, macular, and peripheral retinal regions and underlying RPE-choroid complex, involving regional punch biopsies and manual removal of tissue layers from a human eye.One-dimensional SDS-PAGE as well as downstream proteomic analysis, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS), can be used to identify proteins in each dissected retinal layer, revealing molecular biomarkers for retinal disease.

    View details for DOI 10.3791/56203

    View details for PubMedID 29155757

  • CRISPR-mediated Ophthalmic Genome Surgery. Current ophthalmology reports Cho, G. Y., Abdulla, Y., Sengillo, J. D., Justus, S., Schaefer, K. A., Bassuk, A. G., Tsang, S. H., Mahajan, V. B. 2017; 5 (3): 199–206

    Abstract

    Clustered regularly interspaced short palindromic repeats (CRISPR) is a genome engineering system with great potential for clinical applications due to its versatility and programmability. This review highlights the development and use of CRISPR-mediated ophthalmic genome surgery in recent years.Diverse CRISPR techniques are in development to target a wide array of ophthalmic conditions, including inherited and acquired conditions. Preclinical disease modeling and recent successes in gene editing suggest potential efficacy of CRISPR as a therapeutic for inherited conditions. In particular, the treatment of Leber congenital amaurosis with CRISPR-mediated genome surgery is expected to reach clinical trials in the near future.Treatment options for inherited retinal dystrophies are currently limited. CRISPR-mediated genome surgery methods may be able to address this unmet need in the future.

    View details for DOI 10.1007/s40135-017-0144-1

    View details for PubMedID 28966884

    View details for PubMedCentralID PMC5613978

  • Gene Therapy Restores Mfrp and Corrects Axial Eye Length. Scientific reports Velez, G., Tsang, S. H., Tsai, Y. T., Hsu, C. W., Gore, A., Abdelhakim, A. H., Mahajan, M., Silverman, R. H., Sparrow, J. R., Bassuk, A. G., Mahajan, V. B. 2017; 7 (1): 16151

    Abstract

    Hyperopia (farsightedness) is a common and significant cause of visual impairment, and extreme hyperopia (nanophthalmos) is a consequence of loss-of-function MFRP mutations. MFRP deficiency causes abnormal eye growth along the visual axis and significant visual comorbidities, such as angle closure glaucoma, cystic macular edema, and exudative retinal detachment. The Mfrp rd6 /Mfrp rd6 mouse is used as a pre-clinical animal model of retinal degeneration, and we found it was also hyperopic. To test the effect of restoring Mfrp expression, we delivered a wild-type Mfrp to the retinal pigmented epithelium (RPE) of Mfrp rd6 /Mfrp rd6 mice via adeno-associated viral (AAV) gene therapy. Phenotypic rescue was evaluated using non-invasive, human clinical testing, including fundus auto-fluorescence, optical coherence tomography, electroretinography, and ultrasound. These analyses showed gene therapy restored retinal function and normalized axial length. Proteomic analysis of RPE tissue revealed rescue of specific proteins associated with eye growth and normal retinal and RPE function. The favorable response to gene therapy in Mfrp rd6 /Mfrp rd6 mice suggests hyperopia and associated refractive errors may be amenable to AAV gene therapy.

    View details for DOI 10.1038/s41598-017-16275-8

    View details for PubMedID 29170418

    View details for PubMedCentralID PMC5701072

  • Personalized proteomics in proliferative vitreoretinopathy implicate hematopoietic cell recruitment and mTOR as a therapeutic target. American journal of ophthalmology Roybal, C. N., Velez, G., Toral, M., Tsang, S. H., Bassuk, A. G., Mahajan, V. B. 2017

    Abstract

    To profile vitreous cytokine expression of proliferative vitreoretinopathy (PVR) patients DESIGN: Case-control study.Liquid biopsies were collected from two groups: control subjects (n=3) undergoing pars plana vitrectomy to remove an epiretinal membrane (ERM), and test subjects (n=7) with varying degrees of PVR. A high-throughput cytokine screen measured expression of 200 cytokines. Cytokine expression patterns were prospectively validated in separate cohorts of control patients and those with PVR-A, PVR-B, and PVR-C (n=10 for each group). Expression changes were evaluated by ANOVA (significant p-value <0.05), hierarchical cluster algorithm, and pathway analysis, to identify candidate pathways for prospective studies.In PVR vitreous, 29 cytokines were upregulated compared to controls. Early-PVR vitreous showed upregulation of T-cell markers, pro-fibrotic cytokines, and cytokines downstream of mTOR activation (IL-2, IL-6, and IL-13), whereas late PVR vitreous, cytokines driving monocyte responses and stem-cell recruitment (SDF-1) prevailed. Prospective validation confirmed the differential-expression of specific cytokines from PVR-A to C.Early PVR is characterized by activation of T-cells and mTOR signaling, whereas advanced-PVR is characterized by a chronic monocyte response. PVR might be treated by rational repositioning of existing drugs that target mTOR and IL-6. Our analysis demonstrates that successful therapeutic intervention will be highly dependent on the specific therapeutic target and the stage of PVR. This study provides insights into cytokines that will serve as biomarkers and therapeutic targets. These biomarkers will help design clinical trials that intervene at appropriate times.

    View details for DOI 10.1016/j.ajo.2017.11.025

    View details for PubMedID 29246578

  • Limbal Trocar-Cannulas for Complex Vitrectomy Surgery. Retina (Philadelphia, Pa.) Mears, K. A., Mahajan, V. B. 2017

    View details for DOI 10.1097/IAE.0000000000001781

    View details for PubMedID 28737532

  • Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet (London, England) Russell, S., Bennett, J., Wellman, J. A., Chung, D. C., Yu, Z. F., Tillman, A., Wittes, J., Pappas, J., Elci, O., McCague, S., Cross, D., Marshall, K. A., Walshire, J., Kehoe, T. L., Reichert, H., Davis, M., Raffini, L., George, L. A., Hudson, F. P., Dingfield, L., Zhu, X., Haller, J. A., Sohn, E. H., Mahajan, V. B., Pfeifer, W., Weckmann, M., Johnson, C., Gewaily, D., Drack, A., Stone, E., Wachtel, K., Simonelli, F., Leroy, B. P., Wright, J. F., High, K. A., Maguire, A. M. 2017

    Abstract

    Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness.In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 10(11) vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete.Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity.Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable.Spark Therapeutics.

    View details for DOI 10.1016/S0140-6736(17)31868-8

    View details for PubMedID 28712537

  • Small-angle X-ray scattering of calpain-5 reveals a highly open conformation among calpains JOURNAL OF STRUCTURAL BIOLOGY Gakhar, L., Bassuk, A. G., Velez, G., Khan, S., Yang, J., Tsang, S. H., Mahajan, V. B. 2016; 196 (3): 309-318

    Abstract

    Calpain-5 is a calcium-activated protease expressed in the retina. Mutations in calpain-5 cause autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, OMIM#193235). The structure of calpain-5 has not been determined, thus hindering the investigation of its proteolytic targets and pathological role in ADNIV. Herein, we report models of the proteolytic core of calpain-5 (mini-calpain-5) containing two globular domains (termed DIIa-IIb) connected by a short, flexible linker, consistent with small-angle X-ray scattering (SAXS) data. Structural modeling in the absence of calcium suggests that mini-calpain-5 adopts a more open conformation when compared to previously determined structures of other calpain cores. This open conformation, achieved by a rotation of DIIa and DIIb with respect to each other, prevents formation of the active site and constrains the enzyme in an inactivated form. The relative domain rotation of 60-100° we found for mini-calpain-5 (a non-classical calpain) is significantly greater than the largest rotation previously observed for a classical calpain (i.e., 55.0° for mini-calpain-9). Together with our prediction that, in the full-length form, a long loop in DIIb (loop C1), a few residues downstream of the inter-domain linker, likely interacts with the shorter, acidic, inactivating loop on domain-III (DIII), these structural insights illuminate the complexity of calpain regulation. Moreover, our studies argue that pursuing higher resolution structural studies are necessary to understand the complex activity regulation prevalent in the calpain family and for the design of specific calpain inhibitors.

    View details for DOI 10.1016/j.jsb.2016.07.017

    View details for Web of Science ID 000389295000003

    View details for PubMedID 27474374

    View details for PubMedCentralID PMC5118095

  • Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration JOURNAL OF CLINICAL INVESTIGATION Zhang, L., Du, J., Justus, S., Hsu, C., Bonet-Ponce, L., Wu, W., Tsai, Y., Wu, W., Jia, Y., Duong, J. K., Mahajan, V. B., Lin, C., Wang, S., Hurley, J. B., Tsang, S. H. 2016; 126 (12): 4659-4673

    Abstract

    Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy-mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders.

    View details for DOI 10.1172/JCI86905

    View details for Web of Science ID 000390131900025

    View details for PubMedID 27841758

    View details for PubMedCentralID PMC5127684

  • Management of Pediatric Aphakic Glaucoma With Vitrectomy and Tube Shunts JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS Elshatory, Y. M., Gauger, E. H., Kwon, Y. H., Alward, W. L., Boldt, H. C., Russell, S. R., Mahajan, V. B. 2016; 53 (6): 339-343

    Abstract

    To review the impact of vitrectomy and tube shunts on mean intraocular pressure (IOP) and number of glaucoma medications in pediatric aphakic glaucoma.A retrospective review of pediatric patients who underwent combined vitrectomy and glaucoma tube shunt surgery for aphakic glaucoma was conducted. Inclusion criteria were: age 18 years or younger, diagnosis of aphakic glaucoma, preoperative IOP data, and postoperative IOP data for at least 6 months. Mean IOP lowering at 1 year, number of glaucoma medications at 1 year, and surgical complications, including tube occlusion in the postoperative period, were noted.The mean ± standard deviation preoperative IOP was 33.9 ± 10.6 mm Hg (range: 18 to 57 mm Hg) with a mean of three topical IOP-lowering medications. A total of 5 (36%) Ahmed and 9 (64%) Baerveldt tube shunts were placed. One of the Baerveldt tube shunt procedures was combined with revision of a traumatically dislocated tube. The mean IOP at 12 months postoperatively was 16.6 ± 5.8 mm Hg (range: 6 to 28 mm Hg; P < .01, t = 3.74, df = 13) with a mean of 2.3 glaucoma medications. There were no cases of tube occlusion, corneal decompensation, endophthalmitis, or retinal detachment over the 12 months of follow-up.Combined vitrectomy and placement of a glaucoma tube shunt can be safe and effective in lowering IOP based on mean IOP values and number of glaucoma medications at 1 year. [J Pediatr Ophthalmol Strabismus. 2016;53(6):339-343.].

    View details for DOI 10.3928/01913913-20160818-01

    View details for Web of Science ID 000393050000005

    View details for PubMedID 27668871

  • COMBINED VITRECTOMY AND INTRAVITREAL DEXAMETHASONE (OZURDEX) SUSTAINED-RELEASE IMPLANT RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Zheng, A., Chin, E. K., Almeida, D. R., Tsang, S. H., Mahajan, V. B. 2016; 36 (11): 2087-2092

    Abstract

    To evaluate the safety and efficacy of combining intravitreal dexamethasone implantation (Ozurdex) with pars plana vitrectomy (PPV).A retrospective review was conducted on cases where Ozurdex injection was performed in the operating room in conjunction with pars plana vitrectomy. Our primary outcome measure was the presence of surgical complications in the perioperative and 3-month postoperative window. We also measured visual acuity, intraocular pressure (IOP), and macular edema at baseline, one, and 3 months after surgery.Fifteen eyes in 14 cases were reviewed. There were no complications intraoperatively or at 1-month postoperatively. Two patients (2 eyes) with prior retinal detachment developed proliferative vitreoretinopathy and redetachment at 3 months. Visual acuity improved in 7 of 15 eyes, and an average improvement of 2 lines was achieved for the entire cohort. There was no overall change in intraocular pressure although 1 patient developed an increase in intraocular pressure >5 mmHg. Five of 9 patients with baseline macular edema experienced improvement or resolution at 3 months.Intraoperative Ozurdex in combination with PPV may be safe and effective in treating macular edema caused by many different underlying diseases.

    View details for Web of Science ID 000387079800014

    View details for PubMedID 27148836

    View details for PubMedCentralID PMC5077653

  • Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors HUMAN MOLECULAR GENETICS Yang, J., Bassuk, A. G., Merl-Pham, J., Hsu, C., Colgan, D. F., Li, X., Au, K. S., Zhang, L., Smemo, S., Justus, S., Nagahama, Y., Grossbach, A. J., Howard, M. A., Kawasaki, H., Feldstein, N. A., Dobyns, W. B., Northrup, H., Hauck, S. M., Ueffing, M., Mahajan, V. B., Tsang, S. H. 2016; 25 (19): 4201-4210

    Abstract

    Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumours in the brain. Since TSC effectors are largely unknown in the human brain, TSC patient cortical tubers were used to uncover hyperphosphorylation unique to TSC primary astrocytes, the cell type affected in the brain. We found abnormal hyperphosphorylation of catenin delta-1 S268, which was reversible by mTOR-specific inhibitors. In contrast, in three metastatic astrocytoma cell lines, S268 was under phosphorylated, suggesting S268 phosphorylation controls metastasis. TSC astrocytes appeared epithelial (i.e. tightly adherent, less motile, and epithelial (E)-cadherin positive), whereas wild-type astrocytes were mesenchymal (i.e. E-cadherin negative and highly motile). Despite their epithelial phenotype, TSC astrocytes outgrew contact inhibition, and monolayers sporadically generated tuberous foci, a phenotype blocked by the mTOR inhibitor, Torin1. Also, mTOR-regulated phosphokinase C epsilon (PKCe) activity induced phosphorylation of catenin delta-1 S268, which in turn mediated cell-cell adhesion in astrocytes. The mTOR-dependent, epithelial phenotype of TSC astrocytes suggests TSC1/2 and mTOR tune the phosphorylation level of catenin delta-1 by controlling PKCe activity, thereby regulating the mesenchymal-epithelial-transition (MET). Thus, some forms of TSC could be treated with PKCe inhibitors, while metastasis of astrocytomas might be blocked by PKCe stimulators.

    View details for DOI 10.1093/hmg/ddw253

    View details for Web of Science ID 000395807800005

    View details for PubMedID 27516388

    View details for PubMedCentralID PMC5291196

  • BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE HUMAN MOLECULAR GENETICS Moshfegh, Y., Velez, G., Li, Y., Bassuk, A. G., Mahajan, V. B., Tsang, S. H. 2016; 25 (13): 2672-2680

    Abstract

    Bestrophin1 (BEST1) is expressed in human retinal pigment epithelium (RPE) and mutations in the BEST1 gene commonly cause retinal dysfunction and macular degeneration. BEST1 is presumed to assemble into a calcium-activated chloride channel and be involved in chloride transport but there is no direct evidence in live human RPE cells to support this idea. To test whether BEST1 functions as a chloride channel in living tissue, BEST1-mutant RPE (R218H, L234P, A243T) were generated from patient-derived induced pluripotent stem cells and compared with wild-type RPE in a retinal environment, using a biosensor that visualizes calcium-induced chloride ion flux in the cell. Calcium stimulation elicited chloride ion export in normal RPE but not in RPE derived from three patients with BEST1 mutations. These data, along with three-dimensional modeling, provide evidence that BEST1 assembles into a key calcium-sensing chloride channel in human RPE.

    View details for DOI 10.1093/hmg/ddw126

    View details for Web of Science ID 000393064400005

    View details for PubMedID 27193166

    View details for PubMedCentralID PMC5181636

  • Complication of Autologous Stem Cell Transplantation in Retinitis Pigmentosa JAMA OPHTHALMOLOGY Boudreault, K., Justus, S., Lee, W., Mahajan, V. B., Tsang, S. H. 2016; 134 (6): 711-712
  • Response to Sandford et al.: PRICKLE2 Variants in Epilepsy: A Call for Precision Medicine AMERICAN JOURNAL OF HUMAN GENETICS Mahajan, V. B., Bassuk, A. G. 2016; 98 (3): 590-591

    View details for DOI 10.1016/j.ajhg.2016.02.002

    View details for Web of Science ID 000372383100022

    View details for PubMedID 26942292

    View details for PubMedCentralID PMC4800048

  • Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy. Signal transduction and targeted therapy Wert, K. J., Mahajan, V. B., Zhang, L., Yan, Y., Li, Y., Tosi, J., Hsu, C. W., Nagasaki, T., Janisch, K. M., Grant, M. B., Mahajan, M., Bassuk, A. G., Tsang, S. H. 2016; 1

    Abstract

    Diabetic retinopathy (DR) affects approximately one-third of diabetic patients and, if left untreated, progresses to proliferative DR (PDR) with associated vitreous hemorrhage, retinal detachment, iris neovascularization, glaucoma and irreversible blindness. In vitreous samples of human patients with PDR, we found elevated levels of hypoxia inducible factor 1 alpha (HIF1α). HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases. To recreate the human PDR phenotype for a preclinical animal model, we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein, a protein that targets HIF1α for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1α and developed severe, irreversible ischemic retinopathy that has features of human PDR. Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders. In addition, this model system can be used to manipulate the modulation of the hypoxia signaling pathways, for the treatment of non-ocular ischemic and inflammatory disorders.

    View details for PubMedID 27195131

    View details for PubMedCentralID PMC4868361

  • Secondary glaucoma in CAPN5-associated neovascular inflammatory vitreoretinopathy. Clinical ophthalmology (Auckland, N.Z.) Cham, A., Bansal, M., Banda, H. K., Kwon, Y., Tlucek, P. S., Bassuk, A. G., Tsang, S. H., Sobol, W. M., Folk, J. C., Yeh, S., Mahajan, V. B. 2016; 10: 1187-1197

    Abstract

    The objective of this study was to review the treatment outcomes of patients with secondary glaucoma in cases of autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a hereditary autoimmune uveitis due to mutations in CAPN5.A retrospective, observational case series was assembled from ADNIV patients with secondary glaucoma. The main outcome measures were intraocular pressure (IOP), visual acuity, use of antiglaucoma medications, ocular surgeries, and adverse outcomes. Perimetry and optic disk optical coherence tomography (OCT) were also analyzed.Nine eyes of five ADNIV patients with secondary glaucoma were reviewed. Each received a fluocinolone acetonide (FA) implant for the management of posterior uveitis. Following implantation, no eyes developed neovascular glaucoma. Five eyes (in patients 1, 2, and 5) required Ahmed glaucoma valve surgery for the management of steroid-responsive glaucoma. Patient 2 also developed angle closure with iris bombe and underwent laser peripheral iridotomy. Patient 4 had both hypotony and elevated IOP that required periodic antiglaucoma medication in the FA-implanted eye. Patient 3 did not develop steroid-response glaucoma in either eye. Optic disk examinations were obscured by fibrosis and better assessed with OCT.ADNIV patients show combined mechanism secondary glaucoma best assessed by OCT of the optic disk. The FA implants have reduced uveitic and neovascular glaucoma. Nevertheless, IOP management remains complex due to steroid-response glaucoma, angle closure glaucoma, and hypotony.

    View details for DOI 10.2147/OPTH.S103324

    View details for PubMedID 27390515

    View details for PubMedCentralID PMC4930228

  • Mutations in Prickle Orthologs Cause Seizures in Flies, Mice, and Humans AMERICAN JOURNAL OF HUMAN GENETICS Tao, H., Manak, J. R., Sowers, L., Mei, X., Kiyonari, H., Abe, T., Dandaleh, N. S., Yang, T., Wu, S., Chen, S., Fox, M. H., Gurnett, C., Montine, T., Bird, T., Shaffer, L. G., Rosenfeld, J. A., McConne, J., Madan-Khetarpal, S., Berry-Kravis, E., Griesbach, H., Saneto, R. P., Scott, M. P., Antic, D., Reed, J., Boland, R., Ehaideb, S. N., El-Shanti, H., Mahajan, V. B., Ferguson, P. J., Axelrod, J. D., Lehesjoki, A., Fritzsch, B., Slusarski, D. C., Wemmie, J., Ueno, N., Bassuk, A. G. 2011; 88 (2): 138-149

    Abstract

    Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution.

    View details for DOI 10.1016/j.ajhg.2010.12.012

    View details for Web of Science ID 000287684100002

    View details for PubMedID 21276947

    View details for PubMedCentralID PMC3035715