Description of Research Expertise

Research Interests
Dr. Wilson’s laboratory focuses on the development of gene transfer vectors and their application in the treatment of inherited and acquired diseases. Characterization of these novel viral isolates has yielded important insights into basic virology. More importantly, recombinant versions of these viruses have proven to be useful as improved gene transfer vehicles to a variety of targets such as the liver, cardiac and skeletal muscle, and the brain.

Key words: adeno-associated virus (AAV), gene therapy, gene transfer, gene editing, gene delivery, route of administration.

Description of Research
Dr. Wilson is an innovator and pioneer in the field of gene therapy. In a career spanning four decades, he has identified, isolated, and developed virus-based vectors for in vivo gene therapy. His laboratory is responsible for discovering a new family of endogenous adeno-associated viruses (AAV) that have become best-in-class for in vivo gene therapy vectors. His research efforts and novel technology have contributed to successful clinical programs of in vivo gene therapy for rare monogenic diseases developed by other companies, including Glybera® for familial lipoprotein lipase deficiency (AAV1), Luxturna® for RPE65-mediated retinal dystrophy (AAV2), and Zolgensma® for spinal muscular atrophy (AAV9). More recently, his laboratory demonstrated for the first time therapeutic in vivo genome editing in a large animal model, thus extending the therapeutic potential of the AAV platform.

During the early 2000s, Dr. Wilson found that AAV genomes are prevalent in primates; characterization of these novel capsids revealed an expanded family of viruses that have great therapeutic promise (1-3). For example, the rhesus isolate AAV8 has shown improved gene transfer to liver, muscle, and photoreceptors (1, 4) whereas the human isolate AAV9 is capable of crossing endothelial and blood-brain barriers that enable it to target the heart and central nervous system (5, 6). Recent work in Dr. Wilson’s laboratory has highlighted how specific AAV-protein interactions in endothelial cells enhance the ability of AAV to cross the blood-brain barrier (7); such work may prove instrumental in the development of new AAV-based therapies for genetic diseases which affect the central nervous system.

Dr. Wilson aims to expand gene therapy to also treat acquired diseases and other conditions, such as deploying AAV-based therapies to treat influenza (8) and central nervous system metastases located beyond the blood-brain barrier (9). Novel applications of the AAV platform include prophylaxis against subsequent organophosphate poisoning, potentially offering protection in biowarfare (10). Dr. Wilson is also pursuing in vivo genome editing. In a world-first, his laboratory recently demonstrated efficient and stable in vivo gene editing in liver cells in non-human primates that resulted in reduced levels of circulating PCSK9 and serum cholesterol; this work has important implications in the treatment of cardiovascular disease (11).

Translational research efforts are ongoing in his laboratory across a portfolio of lysosomal storage diseases, neurodegenerative diseases, infantile epilepsies, and liver metabolic diseases. A robust, discovery-oriented research program in virology, vector engineering, and gene editing complements the translational portfolio and informs the development of next generation vectors and therapies.

Recent Student Projects
1. Genome Editing for Central Nervous System Diseases
2. Vector Engineering: Altering Biodistribution of AAV9 via Targeted Mutagenesis
3. Isolation and Characterization of Novel AAV Natural Variants
4. Characterization of the Ly6a / PHP.B Interaction and Implications for Vector Engineering

Current Graduate Students:
Jacob Hoffman, PhD candidate
Alex Martino, PhD candidate
Kelly Martins, MD, PhD candidate
Kalyani Nambiar, PhD candidate

Open postdoctoral positions: www.med.upenn.edu/postdoc/

References
1. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, and Wilson JM. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A. 2002;99(18):11854-9.
2. Gao G, Alvira MR, Somanathan S, Lu Y, Vandenberghe LH, Rux JJ, et al. Adeno-associated viruses undergo substantial evolution in primates during natural infections. Proc Natl Acad Sci U S A. 2003;100(10):6081-6.
3. Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, et al. Clades of Adeno-associated viruses are widely disseminated in human tissues. J Virol. 2004;78(12):6381-8.
4. Vandenberghe LH, Bell P, Maguire AM, Cearley CN, Xiao R, Calcedo R, et al. Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey. Sci Transl Med. 2011;3(88):88ra54.
5. Bell CL, Vandenberghe LH, Bell P, Limberis MP, Gao GP, Van Vliet K, et al. The AAV9 receptor and its modification to improve in vivo lung gene transfer in mice. J Clin Invest. 2011;121(6):2427-35.
6. Bell CL, Gurda BL, Van Vliet K, Agbandje-McKenna M, and Wilson JM. Identification of the galactose binding domain of the adeno-associated virus serotype 9 capsid. J Virol. 2012;86(13):7326-33.
7. Hordeaux J, Yuan Y, Clark PM, Wang Q, Martino RA, Sims JJ, et al. The GPI-Linked Protein LY6A Drives AAV-PHP.B Transport across the Blood-Brain Barrier. Mol Ther. 2019;27(5):912-21.
8. Limberis MP, Adam VS, Wong G, Gren J, Kobasa D, Ross TM, et al. Intranasal antibody gene transfer in mice and ferrets elicits broad protection against pandemic influenza. Sci Transl Med. 2013;5(187):187ra72.
9. Rothwell WT, Bell P, Richman LK, Limberis MP, Tretiakova AP, Li M, et al. Intrathecal Viral Vector Delivery of Trastuzumab Prevents or Inhibits Tumor Growth of Human HER2-Positive Xenografts in Mice. Cancer Res. 2018;78(21):6171-82.
10. Gupta V, Cadieux CL, McMenamin D, Medina-Jaszek CA, Arif M, Ahonkhai O, et al. Adeno-associated virus-mediated expression of human butyrylcholinesterase to treat organophosphate poisoning. PLoS One. 2019;14(11):e0225188.
11. Wang L, Smith J, Breton C, Clark P, Zhang J, Ying L, et al. Meganuclease targeting of PCSK9 in macaque liver leads to stable reduction in serum cholesterol. Nat Biotechnol. 2018;36(8):717-25.

Selected Publications

Breton, C, Clark, PM, Wang, LL, Greig, JA, Wilson, JM: ITR-Seq, a next-generation sequencing assay, identifies genome-wide DNA editing sites in vivo following adeno-associated viral vector-mediated genome editing bmc genomics 21 (1): 2020.

Somanathan, S, Calcedo, R, Wilson, JM: Adenovirus-Antibody Complexes Contributed to Lethal Systemic Inflammation in a Gene Therapy Trial molecular therapy 28 (3): 784-793,2020.

Wang, LL, Yang, Y, Breton, C, Bell, P, Li, MY, Zhang, J, Che, Y, Saveliev, A, He, ZN, White, J, Latshaw, C, Xu, CY, McMenamin, D, Yu, HW, Morizono, H, Batshaw, ML, Wilson, JM: A mutation-independent CRISPR-Cas9-mediated gene targeting approach to treat a murine model of ornithine transcarbamylase deficiency science advances 6 (7): 2020.

Hinderer, C, Katz, N, Dyer, C, Goode, T, Johansson, J, Bell, P, Richman, L, Buza, E, Wilson, JM: Translational Feasibility of Lumbar Puncture for Intrathecal AAV Administration molecular therapy-methods & clinical development 17 : 969-974,2020.

Wang, LL, Yang, Y, Breton, CA, White, J, Zhang, J, Che, Y, Saveliev, A, McMenamin, D, He, ZN, Latshaw, C, Li, MY, Wilson, JM: CRISPR/Cas9-mediated in vivo gene targeting corrects hemostasis in newborn and adult factor IX-knockout mice blood 133 (26): 2745-2752,2019.

Ashley, SN, Somanathan, S, Giles, AR, Wilson, JM: TLR9 signaling mediates adaptive immunity following systemic AAV gene therapy cellular immunology 346 : 2019.

Hordeaux, J, Hinderer, C, Buza, EL, Louboutin, JP, Jahan, T, Bell, P, Chichester, JA, Tarantal, AF, Wilson, JM: Safe and Sustained Expression of Human Iduronidase After Intrathecal Administration of Adeno-Associated Virus Serotype 9 in Infant Rhesus Monkeys human gene therapy 30 (8): 957-966,2019.

Hordeaux, J, Yuan, Y, Clark, PM, Wang, Q, Martino, RA, Sims, JJ, Bell, P, Raymond, A, Stanford, WL, Wilson, JM: The GPI-Linked Protein LY6A Drives AAV-PHP.B Transport across the Blood-Brain Barrier molecular therapy 27 (5): 912-921,2019.

Giles, AR, Sims, JJ, Turner, KB, Govindasamy, L, Alvira, MR, Lock, M, Wilson, JM: Deamidation of Amino Acids on the Surface of Adeno-Associated Virus Capsids Leads to Charge Heterogeneity and Altered Vector Function molecular therapy 26 (12): 2848-2862,2018.

Greig, JA, Nordin, JML, Smith, MK, Ashley, SN, Draper, C, Zhu, YQ, Bell, P, Buza, EL, Wilson, JM: A Gene Therapy Approach to Improve Copper Metabolism and Prevent Liver Damage in a Mouse Model of Wilson Disease human gene therapy clinical development 30 (1): 29-39,2019.

Gupta, V, Cadieux, CL, McMenamin, D, Medina-Jaszek, CA, Arif, M, Ahonkhai, O, Wielechowski, E, Taheri, M, Che, Y, Goode, T, Limberis, MP, Li, MY, Cerasoli, DM, Tretiakova, AP, Wilson, JM: Adeno-associated virus-mediated expression of human butyrylcholinesterase to treat organophosphate poisoning plos one 14 (11): 2019.

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Academic Contact Information

125 S. 31st Street,
Suite 1200 TRL
Philadelphia, PA 19104-3403
Phone: 215-573-9020