Dr. Sarah Wootton

Meet Dr. Sarah Wootton

BSc, PhD

Keywords: Adeno-associated virus (AAV) vectors, gene therapy, lentiviral vectors, molecular virology, oncolytic virotherapy, oncolytic viruses, vectored immunoprophylaxis, viral pathogenesis, viral vectored vaccines.

Profile(s): University of Guelph Experts, Department of Pathobiology, Research Laboratory Page

Current Positions:

Associate Professor – Department of Pathobiology, University of Guelph, Ontario Veterinary College

Seeking Partnerships in the Areas of:

AAV gene therapy applications
Viral vector production and scale up
Gene therapy for monogenic lung diseases
Oncolytic viral therapy

Education and Employment Background:

B.Sc. Biochemistry, University of Guelph, Guelph, ON
Ph.D. Virology, Ontario Veterinary College, University of Guelph, Guelph, ON
Postdoctoral Training, Fred Hutchinson Cancer Research Center, Seattle, WA
Research Leave, National Microbiology Lab, PHAC, Winnipeg

Research Themes & Interests:

The overarching goal of research in Dr. Wootton’s lab is to engineer viral therapies to prevent, treat or cure illnesses including infectious diseases, cancer, monogenic disorders of the lung. One of her core research areas focuses on adeno-associated virus (AAV) vectors. Work in her lab centers on developing a robust platform for “Vectored Immunoprophylaxis” or VIP, in which AAV vectors are used to deliver broadly neutralizing monoclonal antibody (mAb) genes to mediate robust and prolonged protection from pathogens for which the human population has no pre-existing or vaccine-induced immunity and which pose a significant threat to public health, requiring rapid and cost effective countermeasures. With collaborators in the Special Pathogens Division at the National Microbiology Lab (NML), she has worked on developing a cocktail of AAV-mAbs to improve upon passive mAb transfer for Ebola virus, Marburg virus and now, SARS-CoV-2 treatment and prevention. They have also received funding to begin work to develop a broadly neutralizing mAb cocktail able to protect from all filovirus infections in a single formulation. Recently, Sarah has begun collaborating with James Crowe (Vanderbilt Vaccine Center) to reformulate their recently published Respiratory Syncytical virus mAb into AAV vectors and begun to explore AAV-VIP for the prevention of respiratory syncytial virus.

With regard to gene therapy, Dr. Wootton’s lab is collaborating with Dr. Bernard Thebaud’s group at OHRI to develop AAV gene replacement therapies for a variety of monogenic lung disease. In addition, her lab has developed AAV vectors expressing genome-editing nucleases (e.g. CRISPR) to mediate site-specific integration of functional copies of therapeutic genes or for targeted deletion of deleterious genes with an emphasis on monogenetic lung diseases including cystic fibrosis, alpha-1 antitrypsin deficiency and surfactant protein deficiencies. To facilitate lung gene delivery, her lab has developed novel AAV capsids and compact hybrid viral promoters with enhanced transduction and transgene expression in the lung. In collaboration with Drs Jim Petrik and Byram Bridle, her lab is also developing AAV vectors expressing anti-angiogenic proteins and immune checkpoint inhibitors for treating ovarian cancer and canine osteosarcoma.

Finally, her lab works on two animal-pathogen derived oncolytic viruses; Newcastle disease virus (NDV) and Parapox Orf virus (ORFV); and have engineered these viruses to express various immunomodulatory transgenes for improved oncolytic and immune stimulatory properties. Her lab has optimized production of high titer in vivo grade NDV and ORFV and has promising preclinical data showing tumor regression in a variety of mouse models of cancer and is now beginning to move into the cGMP production phase.

Recent Research Focuses & Partnerships:

AAV vectored immunoprophylaxis for emerging and re-emerging infectious diseases
Engineering oncolytic Newcastle disease virus (NDV) and Parapox ORF virus (OrfV) to express immunomodulatory genes to enhance their oncolytic properties
Developing AAV vectors expressing site-specific nucleases (e.g. CRISPR, TALENs) to mediate integration of a functional gene and/or repair mutated genes for the treatment of Surfactant protein B deficienct, Cystic Fibrosis and Alpha-1 antitrypsin deficiency
Developing AAV vectors expressing anti-angiogenic proteins for treating ovarian cancer in collaboration with Dr. Jim Petrik.
Developing compact hybrid viral promoters with enhanced transgene expression in these tissues as well as identified novel adeno-associated virus capsids from veterinary species and uniquely engineered envelope glycoproteins for enhanced transduction in vivo for lung and liver disease therapy.

Select Publications:

PubMed Compilation: http://www.ncbi.nlm.nih.gov/pubmed?term=Wootton%20S[au]%20OR%20Wootton%20sk[au]%20AND%20virus%20NOT%20influenza%20NOT%20Wootton%20SH
Martin H. Kang, Laura P. van Lieshout^#, Liqun Xu^#, Jakob M. Domm^§, Arul Vadivel^§, Laurent Renesme, Christian Mühlfeld, Maria Hurskainen, Ivana Mizikova, Yanlong Pei, Sylvia P. Thomas, Claudia Milazzo, Chanele Cyr-Depauw, Jeffrey A Whitsett, Larry M Nogee, Sarah K. Wootton*, Bernard Thébaud*. A Novel Lung Tropic AAV Vector Dramatically Improves Survival and Surfactant Homeostasis in a Mouse Model of Inherited Surfactant B Deficiency. MS# NCOMMS-19-25908 Accepted at Nature Communications April 27, 2020.
Rosales Gerpe MC, van Lieshout LP, Domm JM, van Vloten JP, Datu J, Ingrao JC, Yu DL, de Jong Jd, Krell PJ, Moraes TJ, Bridle BW, Wootton SK. Optimized pre-clinical grade production of two novel lentiviral vector pseudotypes for lung gene delivery. Submitted to Human Gene Therapy Methods. 03/2020 https://doi.org/10.1089/hum.2019.211
van Vloten JP, Klafuric EM, Karimi K, McFadden G, Petrik JJ, Wootton SK, Bridle BW. Quantifying Antibody Responses Induced by Antigen-Agnostic Immunotherapies. Mol Ther Methods Clin Dev. 2019;14:189-196.
Yu DL†, Stegelmeier AA†, Chow N, Rghei AD, Matuszewska K, Lawler J, Bridle BW#, Petrik JJ#, Wootton SK#. AAV-Mediated Expression of 3TSR Inhibits Tumor and Metastatic Lesion Development and Extends Survival in a Murine Model of Epithelial Ovarian Carcinoma. Cancer Gene Ther. 2019 Jun 4. doi: 10.1038/s41417-019-0108-8
Lieshout LP, Domm JM, Wootton SK. AAV-Mediated Gene Delivery to the Lung. Methods in Molecular Biology. 2019;1950:361-372. doi: 10.1007/978-1-4939-9139-6_21
Matuszewska K, Santry LA, Au Yeung A, van Vloten JP, Lawler J, Major PP, Wootton SK, Bridle BW, Petrik JJ. Combining Vascular Normalization with an Oncolytic Virus Enhances Immunotherapy in Advanced Stage Ovarian Cancer. Clinical Cancer Research. 25(5):1624-1638. doi: 10.1158/1078-0432.
Commentary in Clinical Cancer Research entitled “Virus, Vessel, Victory: A Novel Approach to Tumor Killing” by Yonina Bykov and Dmitriy Zamarin
van Lieshout LP, Domm JM, Rindler T, Frost KL, Sorensen D, Booth SA, Bridges JP, Wootton SK. A novel triple mutant AAV6 capsid induces rapid and potent transgene expression in the muscle and respiratory tract of mice. Mol Ther Methods Clin Dev. 14;9:323-329, 2018.
van Lieshout LP, Soule G, Sorensen D, Frost KL, He S, Tierney K, Safronetz D, Booth SA, Kobinger GP, Qiu X, Wootton SK. Intramuscular AAV-mediated Expression of Monoclonal Antibodies Provides Complete Protection Against Ebola Virus Infection. Journal of Infectious Diseases. 5;217(6):916-925, 2018.