About our work
The major goal of the Ocular Gene Therapy Core (OGTC) is to develop adeno-associated virus (AAV)-based gene therapeutics for inherited and acquired ocular diseases. We also provide expertise and cutting edge design options of AAV vectors to collaborating research groups interested in bringing AAV vector-based gene therapeutics to the clinic.
AAV vector is one of the most efficient gene delivery tools for modifying retinal cells. Gene therapy clinical trials using AAV vectors have been conducted for treatment of several inherited retinal diseases (IRD) and have shown promising results in patients with Leber congenital amaurosis type 2 (LCA2), choroideremia and Leber's hereditary optic neuropathy (LHON). To date, over 250 genes have been identified as disease-causing genes for IRD, and a majority of these diseases could be targets of gene therapy. We have been focusing our efforts on developing therapies for the diseases affecting relatively large patient populations or with severe symptoms.
Gene replacement therapy for X-Linked Retinitis Pigmentosa (XLRP)
Mutations in Retinitis Pigmentosa GTPase Regulator (RPGR) and Retinitis Pigmentosa 2 (RP2) genes account for the majority of XLRP. RPGR mutations are one of the most frequent causes of total RP cases. We have conducted long-term efficacy and preliminary safety studies of gene replacement therapy in Rpgr and Rp2 gene knock-out mouse models (Wu et al., Hum Mol Genet, 2015; Mookherjee, et al., Hum Mol Genet, 2015), which have paved the way for further clinical development. NEI is prosecuting patent on this technology.
Mechanism-based gene therapy for LCA due to CEP290 mutations
Mutations in CEP290 gene are the most common cause of LCA. Gene replacement for CEP290-LCA is difficult to achieve, since a full-length CEP290 coding sequence is too large to be delivered by an AAV vector. We are currently seeking mechanism-based gene therapy for the disease, based on the existing knowledge of CEP290 protein structure and its interactome.
CRISPR/Cas9 mediated genome editing in postmitotic retinal neurons
We have established an AAV-based photoreceptor-specific CRISPR/Cas9 genome editing system. As precise gene correction or modification relies on homology-directed repair which is unfavorable in postmitotic photoreceptors, our initial effort will be focused on gene disruption mediated by non-homologous end joining. This may lead to novel therapies for retinal degeneration caused by gain-of-function or dominant mutations.
Gene replacement therapy for X-linked Juvenile Retinoschisis (XLRS)
We have been actively engaged in the pre-clinical and clinical development of gene therapy for X-linked Juvenile Retinoschisis (XLRS) led by Dr. Paul Sieving (NEI Director). We helped to design and develop the human retinoschisin AAV vector, which is currently being tested in phase I clinical trials of XLRS at NEI. NEI is also prosecuting patent on this technology.
Yu W, Mookherjee S, Chaitankar V, Hiriyanna S, Kim JW, Brooks M, Ataeijannati Y, Sun X, Dong L, Li T, Swaroop A, Wu Z. Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice. Nat. Commun. 2017; 8: 14716
Somasundaram P, Wyrick GR, Fernandez DC, Ghahari A, Pinhal CM, Simmonds-Richardson M, Rupp AC, Cui L, Wu Z, Brown RL, Badea TC, Robinson PR, Hattar S. C-terminal phosphorylation regulates the kinetics of a subset of melanopsin-mediated behaviors in mice. Proc Natl Acad Sci U S A. 2017; 114(10):2741-2746
Keenan WT, Rupp AC, Ross RA, Somasundaram P, Hiriyanna S, Wu Z, Badea TC, Robinson PR, Lowell BB, Hattar SS. A visual circuit uses complementary mechanisms to support transient and sustained pupil constriction. Elife. 2016; pii: e15392
Zeng Y, Petralia RS, Vijayasarathy C, Wu Z, Hiriyanna S, Song H, Wang YX, Sieving PA, Bush RA. Retinal structure and gene therapy outcome in retinoschisin-deficient mice assessed by spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2016; 57(9): OCT277-87
Sun X, Park JH, Gumerson J, Wu Z, Swaroop A, Qian H, Roll-Mecak A, Li T. Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TLL5 mutation. Proc Natl Acad Sci U S A. 2016; 113 (21): E2925-34
Song H, Vijayasarathy C, Zeng Y, Marangoni D, Bush RA, Wu Z, Sieving PA. NADPH oxidase contributes to photoreceptor degeneration in constitutively active RAC1 mice. Invest Ophthalmol Vis Sci. 2016; 57(6): 2864-75
Bush RA, Zeng Y, Colosi P, Kjellstrom S, Hiriyanna S, Vijayasarathy C, Santos M, Li J, Wu Z, Sieving PA. Preclinical dose-escalation study of intravitreal AAV-RS1 gene therapy in a mouse model of X-linked retinoschisis: Dose-dependent expression and improved retinal structure and function. Hum Gene Ther. 2016; 27(5): 376-89
Hanke-Gogokhia C, Wu Z, Gerstner CD, Frederick JM, Zhang H, Baehr W. Arf-like protein 3 (ARL3) regulates protein trafficking and ciliogenesis in mouse photoreceptors. J Biol Chem. 2016; 291(13): 7142-55
Díaz-Lezama N, Wu Z, Adán-Castro E, Arnold E, Vázquez-Membrillo M, Arredondo-Zamarripa D, Ledesma-Colunga MG, Moreno-Carranza B, Martinez de la Escalera G, Colosi P, Clapp C. Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1. Lab Invest. 2016; 96(3): 283-95
Mookherjee S, Hiriyanna S, Kaneshiro K, Li L, Li Y, Li W, Qian H, Li T, Khanna H, Colosi P, Swaroop A, Wu Z. Long-term rescue of cone photoreceptor degeneration in retinitis pigmentosa 2 (RP2) knockout mice by gene replacement therapy. Hum Mol Genet. 2015; 24(22):6446-58
Shen F, Mao L, Zhu W, Lawton MT, Pechan P, Colosi P, Wu Z, Scaria A, Su H. Inhibition of pathological brain angiogenesis through systemic delivery of AAV vector expressing soluble FLT1. Gene Ther. 2015; 22(11): 893-900
Ou J, Vijayasarathy C, Ziccardi L, Chen S, Zeng Y, Marangoni D, Pope JG, Bush RA, Wu Z, Li W, Sieving PA. Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer. J Clin Invest. 2015; 125(7): 2891-903
Wu Z, Hiriyanna S, Qian H, Mookherjee S, Campos MM, Gao C, Fariss R, Sieving PA, Li T, Colosi P, Swaroop A. A long-term efficacy study of gene replacement therapy for RPGR-associated retinal degeneration. Hum Mol Genet. 2015; 24(14): 3956-70 12
Monahan PE, Sun J, Gui T, Hu G, Hannah WB, Wichlan DG, Wu Z, Grieger JC, Li C, Suwanmanee T, Stafford DW, Booth CJ, Samulski JJ, Kafri T, McPhee SW, Samulski RJ. Employing a gain-of-function factor IX variant R338L to advance the efficacy and safety of hemophilia B human gene therapy: Preclinical evaluation supporting an ongoing AAV clinical trial. Hum Gene Ther. 2015; 26(2): 69-81
Marangoni D, Wu Z, Wiley HE, Zeiss CJ, Vijayasarathy C, Zeng Y, Hiriyanna S, Bush RA, Wei LL, Colosi P, Sieving PA. Preclinical safety evaluation of a recombinant AAV8 vector for X-linked retinoschisis after intravitreal administration in rabbits. Hum Gene Ther Clin Dev. 2014; 25(4): 202-11