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John Fraser Wright, Ph.D.

John Fraser Wright, Ph.D.

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Research Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine

Contact information
Abramson Research Center, 1216C
Children's Hospital of Philadelphia
3615 Civic Center Blvd
Philadelphia, PA 19104
Office: 267 426 5801
Fax: 267 426 0363
Education:
BS (Biochemistry Specialist, Physiology Major)
University of Toronto, Faculty of Arts and Sciences, 1983.
PhD (Biochemistry and Immunology)
University of Toronto, Faculty of Medicine, Department of Biochemistry, 1989.
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Description of Research Expertise

My primary research interests focus on the development and clinical translation of gene therapy vectors with the goal to find effective new treatments for serious human diseases. With basic training in biochemistry, immunology and virology, I have been engaged for over 20 years in the development of innovative virus-based investigational products. My lab has supported gene therapy at the preclinical and clinical trial stages for treatment of genetic diseases, including hemophilia B and Leber Congenital Amaurosis (LCA), and other debilitating diseases such as Parkinson's Disease, Acute Lymphoid Leukemia (ALL), AIDS and viral hepatitis (HCV). At the basic and translational research level, my team has established methodologies to generate, purify and characterize recombinant adeno-associated virus (AAV) and lentivirus -based gene transfer vectors at large scales i.e. sufficient to support studies in large animal models of disease, and for clinical trials. The lab has published widely, in specialized gene therapy journals describing innovations relating to gene therapy vector design and development, and in more general biomedical journals including Nature Medicine, New England Journal of Medicine, and Lancet as part of translational research teams performing human clinical trials. My lab is the designated NHLBI Gene Therapy Resource Program AAV Clinical Laboratory, supporting NIH researchers across the county. Having been directly involved in the development, my team supports one of the most advanced clinical gene therapy programs worldwide for a LCA2, a genetic form of blindness, that has achieved a number of firsts, including; first to safely administer a recombinant AAV vector expressing a therapeutic transgene (AAV-RPE65) to pediatric subjects for a non-lethal disease and first to re-administer therapeutic vector to the contra-lateral eye in humans, a program that is currently in advanced Phase III clinical trials. In other clinical gene therapy studies, working with colleagues at UCSF and the NIH, we have contributed to the development, production, characterization and certification for use in human clinical trials of AAV -based vectors expressing Aromatic Amino Acid Decarboxylase (AADC) and Glial cell Derived Neurotrophic Factor (GDNF) for Parkinson's Disease. A particular research interest is to address human immunological barriers that inhibit effective therapeutic gene transfer using viral vectors, and to develop and implement innovative strategies to overcome them and ultimately achieve better safety and efficacy for human gene therapy. As one example, we have recently innovated and contributed directly to the development and clinical implementation of a novel strategy to intercept pre-existing vector directed antibodies following systemic vector administration.

Description of Clinical Expertise

I established in 2004, and now direct a gene therapy Clinical Vector Core laboratory, part of the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia in order to help move cutting-edge, early-stage translational research being developed at CHOP, Penn, and the wider gene therapy community into the clinic by providing clinical grade gene therapy vectors suitable for human injection in clinical trials. Combining my scientific training and past basic research in biochemistry, immunology and virology with nine years experience in biopharma industry developing advanced investigational products for cancer, infectious and genetic diseases, this core facility meets the most rigorous standards to support gene therapy clinical research. The facility is staffed by highly experienced individuals with advanced training providing excellence in scientific knowledge, advanced bioengineering technology to establish and operate the scalable processes needed to support large scale human clinical trials, and most importantly compliance to the highest quality standards required to ensure safety in human clinical product development. My laboratory has developed and established the complex manufacturing processes, analytical characterization methods, and the overarching quality systems required to to ensure investigational product safety, identity, purity, potency, and consistency to ensure compliance with clinical research standards, and as required by national (FDA) and international regulatory agencies. Under my direction the Core team has innovated, developed and implemented state-of-the-art gene therapy vector technologies and capabilities; 2) written and maintain > 180 Standard Operating Procedures; 3) established and maintain a Biologics Master File with FDA/CBER; 4) prepared the critical Chemistry, Manufacturing and Controls (CMC) sections for seven U.S. Investigation New Drug (IND) applications and two E.U. Investigational Medicinal Product Dossier (IMPD) submissions; and 5) developed innovative pharmacy protocols to support gene therapy product administrations. The core facility and staff have enable dramatic progress in human gene therapy for Leber Congenital Amaurosis (LCA), Hemophilia B, Parkinson Disease, Acute Lympoid Leukemia (ALL), HIV infection, as well as several other promising programs in development. The overall goal of this Core facility is to maintain the highest achievable levels of gene therapy science, technology and compliance in order to develop safe and effective gene therapies, successfully address existing challenges in this field, further improve outcomes, advance clinical development and ultimately help bring to licensure important new medicines for serious human diseases.

Selected Publications

Dong, B., Duan, X., Chow, H.T., Chen, L., Lu, H., Wu, W., Hauck, B., Wright, F., Kapranov, P., Xiao, W. : Proteomics analysis of co-purifying cellular proteins associated with rAAV vectors. PLOS ONE 9(2): e86453, February 2014.

Wu, T.-L., Hua L., Faust, S.M., Chi, E., Zhou, S., Wright, F., High, K.A., Ertl, H.C.J.: CD8+ T cell recognition of epitopes within the capsid of adeno-associated virus 8 -based gene transfer vectors depends on vectors’ genome. Molecular Therapy 22(1): 42-51, January 2014.

Ayuso, E., Blouin,V., Lock,M., Mcgorray, S., Alvira, M.R., Auricchio, A., Bosch, F., Bucher, S., Chtarto, A., Clark,K.R., Darmon, C., Doria, M., Flountain, W., Gao, G., Giacca, M., Kleinschmidt, J., Leon, X., Leuchs, B., Mizukami, H., Normand, Y., Ozawa, K., Sumaroka, M., Surosky, R., Tenenbaum, L., Van Linden, In., Weins, B., Wright, J.F., Zentilin, L. Zhang, X., Snyder,R.,A., Moullier, P. : Manufacture and characterization of a recombinant adeno-associated virust tyep 8 reference standard material. Human Gene Therapy Accepted for publication, 2014.

Doering, C., Brown, H., Wright, J.F., Zhou, S., Shields, J., Spencer, H.T., Lytle, A.: Bioengineered factor VIII enables long-term correction of murine hemophilia A following liver-directed adeno-associated viral vector delivery. Molecular Medicine - Methods and Clinical Development Accepted for publication, 2014.

Mingozzi, F., Anguela, X.M., Pavani, G., Chen, Y., Davidson, R.J., Hui, D.J., Yazicioglu, M., Elkouby, L., Hinderer, C.J., Faella, A., Howard, C., Tai, A., Podsakoff, G.M., Ragni, M.,C., Zhou, S., Basner-Tschakarnjan, E., Wright, J.F., High, K.A.: Overcoming pre-existing humoral immunity to AAV using capsid decoys. Science Translational Medicine 5(194): 194ra92, July 2013.

Testa, F., Maguire, A.M., Rossi, S, Pierce, E.A., Melillo, P., Marshall, K., Banfi, S., Surace, E.M., Sun, J., Acerra, C., Wright J.F., Wellman, J., High, K.A., Auricchio, A., Bennett, J., Simonelli, F.: Three year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital amaurosis Type 2. Ophthalmology 120(6): 1283-1291, June 2013.

Jin, S.Y., Xiao, J., Bao, J., Zhou, S., Wright, J.F., Zheng, X.L.: Adeno-associated virus-mediated expression of an ADAMTS13 variant prevents shigatoxin-induced thrombotic thrombocytopenic purpura. Blood 121(19): 3825-3829, May 2013.

Grupp, S.A., Kalos, M., Barrett, D., Aplenc, R., Porter, D.L., Rheingold, S.R., Teachey, D.T., Chew, A., Hauck, B., Wright, J.F., Milone, M.C., Levine, B., June, C.H. : Chimeric antigen receptor-modified T Cells for acute lymphoid leukemia. The New England Journal of Medicine 368(16): 1509-1518, April 2013.

Ciesielska, A., Hadaczek, P., Mittermeyer, G., Zhou, S., Wright, J.F., Bankiewicz, K.S., Forsayeth, J.: Cerebral infusion of AAV9 vector can elicit cell-mediated immune responses. Molecular Therapy 21(1): 158-166, January 2013.

Suhy, D., Kao, S.-C., Mao, T., Whiteley, L., Denise, H., Soubervielle, B., Burdick, A.D., Hayes, K., Wright J.F., Lavender, H., Roelvink, P., Kolykhalov, A., Brady, K., Moschos, S.A., Hauck, B., Zelenaia, O., Zhou, S., Scribner, C., High, K., Renison-Hall, S., Corbau, R.: Safe, long-term hepatic expression of anti-HCV shRNA in a non-human primate model. Molecular Therapy 20(9): 1737-1749, September 2012.

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Last updated: 10/03/2014
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