Pang J, Kiyosawa M, Seko Y, Yokota T, Harino S, Suzuki J. Clinicopathological report of retinitis pigmentosa with vitamin E deficiency caused by mutation of the alpha-tocopherol transfer protein gene. Jpn J Ophthalmol. 2001 Nov-Dec;45(6):672-6.
Yokota T, Uchihara T, Kumagai J, Shiojiri T, Pang JJ, Arita M, Arai H, Hayashi M, Kiyosawa M, Okeda R, Mizusawa H. A postmortem study of Friedreich-like ataxia with retinitis pigmentosa by mutation of alpha-tocopherol transfer protein gene. J Neurol Neurosurg Psychiatry, 2000;68:521-525.
Yokota T, Shiojiri T, Gotoda T, Arita M, Arai H, Ohga T, Kanda T, Suzuki J, Imai T, Matsumoto H, Harino S, Kiyosawa M, Mizusawa H, Inoue K. Friedreich-like ataxia with retinitis pigmentosa caused by the His101Gln mutation of the alpha-tocopherol transfer protein gene. Ann Neurol. 1997 Jun;41(6):826–832.
Recent years, more and more mutant genes that cause retinal diseases have been detected. At the same time, many naturally occurring mouse models of the human retinal diseases have also been found, which show similar changes as the human retinal diseases. Those together with the improved viral vector quality make more and more traditionally incurable retinal diseases becoming potential candidates for retinal gene therapy. Furthermore, viral vector-mediated therapeutic gene expression has successfully stopped or delayed the cancer cell growth, neuron degeneration, or neovascularization. Currently the common vehicle to deliver the therapeutic gene into target retinal cells is adeno-associated viral vector (AAV). Because of the immune privilege of subretinal space, subretinal injection of AAV vectors can efficiently target retinal pigment epithelium and photoreceptor cells, from which most of the retinal diseases originate. Different mouse models, especially naturally occurring mouse models of inherited retinal diseases including rd12 (Leber Congenital Amaurosis 2 models), rd10 (ArRP model), Cpfl5 (achromatopsia 2 model have been treated with AAV vector encoding therapeutic genes. AAV-mediated therapeutic gene expressions in targeted retinal cells of those models lead to obvious retinal rescues in many fields, including electrophysiology, morphology, biochemistry and behavior. Current ongoing phase I LCA2 clinical trial showed that up to 63,000 fold of visual sensitivity improvement was achieved following gene therapy. Conclusion: AAV-mediated gene therapy in mouse models of human retinal diseases and phase I gene therapy clinical trial on LCA2 showed that AAV-mediated therapeutic gene expression following subretinal injection can stop the retinal degeneration and restore the vision not only in congenital blind mice, but also in human patients, which show a hope for many currently incurable retinal diseases.
Jijing Pang, MD, PhD
Dr. Jijing Pang is a Research Associate Professor in the Department of Ophthalmology at the University of Florida. Dr. Pang received his MD in 1988 from China Medical University and became an attending physician in Ophthalmology with the 2nd Affiliated Hospital of CMU in 1993 before traveling to Japan for further training in research. In 1995, Dr. Pang became a PhD student of Professor Tokoro at Ophthalmology, Tokyo Medical and Dental University. As a result of his finding on blue light damage to RPE cells, Dr. Pang received his PhD in 1999.
During his PhD studies, Dr. Pang discovered a new type of Retinitis Pigmentosa due to vitamin E deficiency caused by an alpha-tocopherol transferase mutation. Oral administration of vitamin E stopped the progression of visual deterioration for the next 10 years. This experience led him to a postdoctoral position in Dr.Blanks’ lab at Oakland University in 1999.
Dr. Pang tested adenoviral and lentiviral vectors via subretinal injections to rescue the photoreceptor degeneration seen in rd1 mice. Although the technical difficulties make the subretinal injection-related damage obvious in the mouse, especially in young pups, it is this gene replacement technique that captured his interest and remains the focus of his research program as he becomes a mouse expert.
In 2002, Dr. Pang moved to the University of Florida with a well established mouse retinal surgery system. With rd12 mice, a model of LCA with Rpe65 mutation, he showed that AAV-mediated RPE65 expression lead to biochemical, structural, physioelectrical and behavioral rescues. Recently, Dr. Pang provided proof that delayed treatment at P90 can rescue the function and morphology of the remaining M-cones, which has important implications for the current ongoing LCA2 clinical trials.
After this concept-proving program, Dr. Pang expanded his retinal rescue program to many other mouse models of human retinal disease, for example, 1) the Cpfl5 mouse, a model of human achromatopsia with cnga3 mutations, 2) the Cpfl3 mouse, a model of human achromatopsia with a gnat2 mutations, 3) the rd10 mouse, a model of human retinitis pigmentosa with PDEmutations. Dr. Pang also collaborated with other researchers to rescue many other mouse models of human retinal degenerations, such as rd6, rd17, GC-1-/-, LART-/- and Ccl2/Cx3cr1 deficient mice and RCS rat. Currently, nanoparticles systems are also being tested to widen the application of AAV vectors in retinal gene therapy, which has led to NIH R21 grant funding. Dr. Pang’s recent work on rescue of mouse model of Achromatopsia has led to a grant funded by state of Florida as Co-PI.
Dr. Pang has published 28 refereed journal articles ralted with retinal gene therapy and made more than 30 presentations at national meetings in the past 5 years. He has also given more than 40 invited seminar presentations both nationally and internationally since 2003.
Dr. Pang was a 2005-2006 Burns Visiting Professor at University of Missouri-Columbia and a 2009-2010 Visiting Professor in Wenzhou Medical College. He received H. Talmage Dobbs Ophthalmic Research Award from Emory Eye Center in 2003. He is also a board member of OCAVER (Overseas Chinese Association for Vision and Eye Research).
Ji-jing Pang M. D., Ph. D.
Research Associate Professor
Department of Ophthalmology
College of Medicine, University of Florida
1600 SW Archer Road, Gainesville, FL 32610
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