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I am the Director of the Center for Neurotherapeutics Discovery (CND) and a Professor of Neurology, Pediatrics, Neuroscience and Microbiology & Immunology at the University of Rochester Medical Center. The CND grew out of the Center for Neural Development and Disease (CNDD), which was renamed from i...
I am the Director of the Center for Neurotherapeutics Discovery (CND) and a Professor of Neurology, Pediatrics, Neuroscience and Microbiology & Immunology at the University of Rochester Medical Center. The CND grew out of the Center for Neural Development and Disease (CNDD), which was renamed from its original origin as the Center for Aging and Developmental Biology (CADB), started by the first Director, Howard J. Federoff. In 2007, Dr. Federoff left URMC and at his suggestion, I became the interim director of the CADB, until it was renamed the CNDD the following year to reflect our unswerving commitment to understand neurologic disease in the context of development. As we have evolved, it became apparent that our core strengths were reflected in our collective mission to not only understand development of the nervous system, but to create new therapies to fix disease at a molecular level. Thus, we have finally arrived at a collective identity known as the CND. I came to the URMC as a postdoctoral fellow in 1989, and stayed as a physician-scientist. While I started my career as a developmental neurobiologist and pediatric neurologist interested in how dopamine was affected during early brain injury, I shifted my research focus radically nearly 25 years ago in an attempt to repurpose already FDA-approved medicines for the treatment of neurologic disease associated with HIV-1 infection. Frustrated by the realization that our progress was incremental, I lead an interdisciplinary, international team to develop a new class of small molecule therapeutics that target mixed lineage kinases. Our efforts evolved to the point where we have secured three internationally prosecuted composition of matter and methods of use patents for these compounds, and we are more than halfway through investigational new drug-enabling studies for our development compound, URMC-099. These experiences have placed me at an intersection between preclinical laboratory efforts to understand relationships between immune effector cells in the central nervous system and synaptic repair during neuroinflammation, and the many steps necessary to bring small molecule technologies into existence as potential drugs. Thus, I feel privileged as the Director that the CND represents a unique opportunity for our investigators to ask questions about disease and answer them with new pathways to therapy.
Certified Specialties
Neurology with Special Qualification in Child Neurology
- American Board of Psychiatry & Neurology
Faculty Appointments
Professor
-
Department of Neurology, Child Neurology (SMD)
Professor
-
Department of Neuroscience (SMD) - Joint
Credentials
Residency & Fellowship
Fellowship, Neurology, Children's Hospital of Boston. 1988 - 1990
Fellowship, McLean Hospital. 1988 - 1990
Residency, Neurology, Children's Hospital of Boston. 1985 - 1988
Residency, Pediatrics, Children's Memorial Hospital. 1984 - 1985
Internship, Pediatrics, Children's Memorial Hospital. 1983 - 1984
Education
MD | Northwestern University Feinberg School of Medicine.1983
Awards
Herman and Gertrude Silver Award on Children, Youth and HIV.2019
Awardee of the Hilary Koprowski Prize in Neurovirology.2016
Inaugural Awardee of the Translational Research in NeuroVirology Lectureship.2015
Child Neurology Young Investigator Award.1990
Buswell Memorial Fellowship, University of Rochester.1990
First Prize, Wyeth-Ayerst Award or New Psychiatric Research, VIII World Congress of Psychiatry, Athens, Greece.1989
Sigma Xi, Thesis Research.1980
National Merit Scholar.1972
Research
Our lab's interests have been shaped by trying to understand how HIV-1 can disrupt normal cognitive functions by altering homeostasis between microglia and synaptic networks. Much like experience-driven synaptic plasticity, this has been and continues to be a work in progress influenced by our trai...
Our lab's interests have been shaped by trying to understand how HIV-1 can disrupt normal cognitive functions by altering homeostasis between microglia and synaptic networks. Much like experience-driven synaptic plasticity, this has been and continues to be a work in progress influenced by our trainees' interests, the experimental approaches they have formulated to help us understand how innate immunity can both shape and repair the central nervous system (CNS), and the novel results that they have produced. Our laboratory has no single technique that has influenced our approach to understanding how the virus can disrupt normal synaptic transmission, although we favor methods that allow us to visualize our data, preferably in real time. Because my training as a molecular neuropharmacologist has emphasized understanding how signaling pathways can be disrupted during disease and whether these pathways can be restored to a new homeostatic relationship between the immune system and vulnerable synaptic networks, we have focused on kinase signaling that controls neuroinflammation. Our efforts to both understand how HIV-1 infection in the CNS disrupts this type of kinase signaling and create small molecule inhibitors of the mixed lineage kinases (MLKs) so that we could test this as a therapeutic approach to HIV-1 associated neurocognitive disorders (HAND), led us to the current point of successfully developing a new class of drugs that inhibit MLKs in macrophages/microglia and neurons to restore homeostasis. This has been extraordinarily serendipitous for us, because we have realized that loss of homeostasis between an end organ target cell, whether it is a neuron, cardiomyocyte or hepatocyte can be restored, with disease-modifying outcomes in HAND, MS (using an EAE model employed by Dr. Matt Bellizzi in our lab), post-operative cognitive dysfunction (POCD; in collaboration with Dr. Niccolo Terrando at Duke University), Alzheimer's disease (with Dr. Gendelman at UNMC and Drs. Todd Krauss and Brad Nilsson at UR), non-alcoholic steatohepatitis (NASH; in collaboration with Dr. Samar Ibrahim at Mayo Clinic) and ischemia-reperfusion injuries (MI; in collaboration with Dr. Burns Blaxall at the Cincinnati Children's Hospital). Lastly, and perhaps most importantly to our lab's core mission, in work we have done with Dr. Howard Gendelman (UNMC) and Drs. Maggirwar and Dewhurst here at URMC, we have discovered that the combination of nanoformulated antiretroviral therapy (nanoART, developed by Dr. Gendelman) for HIV-1 and our lead compound for inhibition of MLKs, URMC-099, can reverse HIV-1 blockade of autophagy in persistently infected macrophages, allowing nanoART to effectively eliminate HIV-1 without inflammation and bystander cellular damage. This has led to additional approaches to new therapies both for HAND and eradication of persistent HIV-1 infection. For trainees at the pre- and postdoctoral level, we are currently investigating the role of the transcription factor, Mafb, using a combination of optogenetic and CRISPR/Cas9 techniques, in regulating a neuroinflammatory response during HIV-1 infection of the CNS; the role of soluble intercellular adhesion molecule type 5 (sICAM-5) as a biomarker for synaptodendritic damage during HAND; dysregulation of complement signaling during HAND and MS; and therapeutic strategies to repair hippocampal and cortical synaptic injury during MS that remain resistant to current immunomodulatory therapies. Additional projects related to our collaborations with other investigators described above are also ongoing.
Patents
MLK Inhibitors and Methods of Use
Issue date: October 24, 2017
Patent #: 2,744,498
Country: Canada
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
MLK Inhibitors and Methods of Use
Issue date: November 04, 2015
Patent #: 2379561
Country: Europe
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
MLK Inhibitors and Methods of Use
Issue date: May 13, 2016
Patent #: 5930278
Country: Japan
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
Substituted Pyrrolo [2,3-B] Pyridines as MLK Inhibitors
Issue date: November 04, 2014
Patent #: 8,877,772
Country: United States
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
MLK Inhibitors and Methods of Use
Issue date: February 11, 2015
Patent #: ZL200980152665.1
Country: China, People's Republic of
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
MLK Inhibitors and Methods of Use
Issue date: July 23, 2015
Patent #: 2009324894
Country: Australia
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
Bicyclic Heteroaryl Kinase Inhibitors and Methods of Use
Issue date: March 30, 2017
Patent #: 2011258465
Country: Australia
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Satheesh Babu Ravula, Torsten Wiemann
Bicyclic Heteroaryl Kinase Inhibitors and Methods of Use
Issue date: August 28, 2018
Patent #: 2,800,176
Country: Canada
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Satheesh Babu Ravula, Torsten Wiemann
Bicyclic Heteroaryl Kinase Inhibitors and Methods of Use
Issue date: February 03, 2015
Patent #: 603644
Country: New Zealand
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Satheesh Babu Ravula, Torsten Wiemann
Bicyclic Heteroaryl Kinase Inhibitors and Methods of Use
Issue date: September 30, 2014
Patent #: 8,846,909
Country: United States
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Satheesh Babu Ravula, Torsten Wiemann
Bicyclic Heteroaryl Kinase Inhibitors and Methods of Use
Issue date: February 10, 2016
Patent #: ZL201180036376.2
Country: China, People's Republic of
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Satheesh Babu Ravula, Torsten Wiemann
Bicyclic Heteroaryl Kinase Inhibitors and Methods of Use
Issue date: February 10, 2017
Patent #: 6086326
Country: Japan
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Satheesh Babu Ravula, Torsten Wiemann
MLK Inhibitors and Methods of Use
Issue date: June 30, 2015
Patent #: 614904
Country: New Zealand
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
Mixed Lineage Kinase Inhibitors and Method of Treatments
Issue date: June 21, 2016
Patent #: 9,370,515
Country: United States
Inventors: Harris A Gelbard, Val S Goodfellow, Thong X Nguyen, Satheesh Babu Ravula
Substituted Pyrrolo [2,3-B] Pyridines as MLK Inhibitors
Issue date: November 10, 2015
Patent #: 9,181,247
Country: United States
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
MLK Inhibitors and Methods of Use
Issue date: January 22, 2016
Patent #: 5873544
Country: Japan
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
Mixed Lineage Kinase Inhibitors for HIV/AIDS Therapies
Issue date: August 10, 2018
Patent #: ZL201380060736.1
Country: China, People's Republic of
Inventors: Stephen Dewhurst, Harris A Gelbard, Howard E Gendelman
Mixed Lineage Kinase Inhibitors for HIV/AIDS Therapies
Issue date: January 09, 2019
Patent #: 2925319
Country: Europe
Inventors: Stephen Dewhurst, Harris A Gelbard, Howard E Gendelman
Mixed Lineage Kinase Inhibitors for HIV/AIDS Therapies
Issue date: November 26, 2019
Patent #: 10,485,800
Country: United States
Inventors: Stephen Dewhurst, Harris A Gelbard, Howard E Gendelman
MLK Inhibitors and Methods of Use
Issue date: November 04, 2015
Patent #: FR2379561
Country: France
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
MLK Inhibitors and Methods of Use
Issue date: November 04, 2015
Patent #: DE2379561
Country: Germany
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
MLK Inhibitors and Methods of Use
Issue date: November 04, 2015
Patent #: IT2379561
Country: Italy
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
MLK Inhibitors and Methods of Use
Issue date: November 04, 2015
Patent #: ES2379561
Country: Spain
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
MLK Inhibitors and Methods of Use
Issue date: November 04, 2015
Patent #: GB2379561
Country: United Kingdom
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
Substituted Pyrrolo [2,3-b] Pyridines as MLK Inhibitors
Issue date: November 14, 2017
Patent #: 9,814,704
Country: United States
Inventors: Stephen Dewhurst, Harris A Gelbard, Val S Goodfellow, Colin J Loweth, Torsten Wiemann
Mixed Lineage Kinase Inhibitors for HIV/AIDS Therapies
Issue date: January 09, 2019
Patent #: FR2925319
Country: France
Inventors: Stephen Dewhurst, Harris A Gelbard, Howard E Gendelman
Mixed Lineage Kinase Inhibitors for HIV/AIDS Therapies
Issue date: January 09, 2019
Patent #: 602013049719.2
Country: Germany
Inventors: Stephen Dewhurst, Harris A Gelbard, Howard E Gendelman
Mixed Lineage Kinase Inhibitors for HIV/AIDS Therapies
Issue date: January 09, 2019
Patent #: GB2925319
Country: United Kingdom
Inventors: Stephen Dewhurst, Harris A Gelbard, Howard E Gendelman
Birbeck GL, Mwenechanya M, Ume-Ezeoke I, Mathews M, Bositis CM, Kalungwana L, Bearden D, Elafros M, Gelbard HA, Theodore WH, Koralnik IJ, Okulicz JF, Johnson BA, Musonda N, Siddiqi OK, Potchen MJ, Sikazwe I
Epilepsia open.. 2024 April 9 (2):750-757. Epub 02/17/2024.
Bearden DR, Mwanza-Kabaghe S, Bositis CM, Dallah I, Johnson BA, Siddiqi OK, Elafros MA, Gelbard HA, Okulicz JF, Kalungwana L, Musonda N, Theodore WH, Mwenechanya M, Mathews M, Sikazwe IT, Birbeck GL
Journal of acquired immune deficiency syndromes : JAIDS.. 2024 March 195 (3):291-296. Epub 1900 01 01.
Navis A, Dallah I, Mabeta C, Musukuma K, Siddiqi OK, Bositis CM, Koralnik IJ, Gelbard HA, Theodore WH, Okulicz JF, Johnson BA, Sikazwe I, Bearden DR, Birbeck GL
Epilepsia.. 2020 December 61 (12):2705-2711. Epub 10/21/2020.
Nguyen L, Laboissonniere LA, Guo S, Pilotto F, Scheidegger O, Oestmann A, Hammond JW, Li H, Hyysalo A, Peltola R, Pattamatta A, Zu T, Voutilainen MH, Gelbard HA, Saxena S, Ranum LPW
Neuron.. 2020 November 25108 (4):784-796.e3. Epub 10/05/2020.
Kasischke KA, Lambert EM, Panepento B, Sun A, Gelbard HA, Burgess RW, Foster TH, Nedergaard M
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.. 2011 January 31 (1):68-81. Epub 09/22/2010.
Tong N, Perry SW, Zhang Q, James HJ, Guo H, Brooks A, Bal H, Kinnear SA, Fine S, Epstein LG, Dairaghi D, Schall TJ, Gendelman HE, Dewhurst S, Sharer LR, Gelbard HA
The Journal of immunology : official journal of the American Association of Immunologists.. 2000 February 1164 (3):1333-9. Epub 1900 01 01.
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