Appel Lab
Peggy & Gary Edwards ALS Laboratory
30934
97
About the Lab
Definitive evidence for the contribution of activated microglia to disease pathogenesis in the mouse model was produced by crossing the mSOD1 mouse with a PU.1 knockout mouse. Transplants with wild-type (a source of M2 anti-inflammatory microglia) bone marrow significantly prolonged life and disease duration compared to transplants with mSOD1 bone marrow ( a source of M1 pro-inflammatory microglia) thereby confirming the contribution of microglia to motor neuron viability and disease duration.
Studies with transgenic mice also established the importance of T lymphocytes in mediating disease duration and motor neuron viability; mSOD mice crossed with Rag2 KO or CD4 KO mice died significantly earlier than mSOD1 mice indicating that a T cell removed in Rag2KO or CD14 KO mice had been neuroprotective. The specific subpopulation of T cells that had been “lost” were regulatory T lymphocytes (Tregs), which was confirmed by transplanting Tregs, which rescued motor neurons and prolonged ALS mouse survival.
Regulatory T lymphocytes also modulate disease progression in ALS patients. Tregs numbers as well as suppressive functions are significantly decreased in ALS patients. This failure of Tregs to suppress T effector lymphocyte proliferation and pro-inflammatory myeloid cytokine secretion promotes neuroinflammation leading to enhanced burden and progression of disease. Isolation of Tregs from ALS patients and expansion ex vivo restores their neuroprotective anti-inflammatory function. Autologous infusions of these expanded Tregs formed the basis of a Phase 1 FDA-approved first-in-man clinical trial in ALS, which was safe and significantly slowed disease progression. A subsequent Phase 2A trial has just been completed, but enrollment and outcomes were compromised by COVID19. Nevertheless, in an open-label 6-month extension in 8 patients, safety and promising beneficial effects were noted. A large clinical study is planned for later his year utilizing this novel cell therapy to offer hope for ALS patients, addressing their unmet needs and enhancing their quality of life.
This game changing Treg platform has now been extended from ex vivo- expanded Tregs and autologous infusions, to include immunosuppressive exosomes derived from the GMP expansion process as well as biologics to enhance Treg expansion in vivo and suppress inflammation in Alzheimer Disease as well as ALS, with future application to other neurodegenerative diseases.
IMMUNE CELLS HOLD PROMISE IN SLOWING DOWN ALS
Our Research Team
Stanley H. Appel, MD, Lab Director
Dr. Appel is former chair of the Stanley H. Appel Department of Neurology. He is the director of the Ann Kimball & John W. Johnson Center for Cellular Therapeutics. Professor of Neurology at Weill Cornell Medical College, and the Peggy and Gary Edwards Distinguished Chair for the Treatment and Research of ALS at the Houston Methodist Research Institute. He was previously Chair of the Department of Neurology at Baylor College of Medicine as well as Chief of the Neurology division and the James B. Duke Professor of Medicine at Duke University Medical Center, North Carolina. Dr. Appel is a native of Massachusetts and received his Bachelor Degree at Harvard University and his Medical Degree from Columbia College of Physicians and Surgeons. He is Director of the MDA/ALSA ALS Research and Clinical Center at Houston Methodist Neurological Institute, and past Director of a National Institute of Aging Alzheimer’s Disease Research Center.
Research Interests
- Neurodegenerative diseases
- Alzheimer’s disease
- Parkinson’s disease
- Amyotrophic Lateral Sclerosis
- Neuromuscular disorders
David R. Beers, PhD, Neuroscientist
Dr. David Beers’ research interests include the underlying mechanisms of neuroinflammation that contributes to neuron death in Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases such as Alzheimer’s disease (AD), and their relevant neuroprotective therapeutic targets. Current research efforts aim to understand the roles of microglia/monocytes and T lymphocytes on immune-mediated injury and repair in ALS and AD. Dr. Beers is investigating the neuroprotective potential of regulatory T lymphocytes as new cellular therapeutic options for ALS patients. He is also interested in the pathology of various mutant proteins as well as abnormal peptides, and how they affect interactions among neurons, microglia, and T lymphocytes in neurodegenerative diseases. Dr. Beers is Chairman if the Houston Methodist Hospital Research Institute’s Institutional Animal Care and Use Committee (IACUC), and is dedicated to the ethical treatment of research animals and the proper training of all investigators using animals in their research at the Houston Methodist Hospital Research Institute. Dr. Beers is a member of several professional societies, and is the author of a number published books and many peer reviewed manuscripts on topics such as ALS.
Research Interests
- Amyotrophic lateral sclerosis (ALS)
- Alzheimer’s Disease
- Neuroprotection
- Neuroinflammation
- Neurotoxicity
Alireza Faridar, MD, Neurologist and Neuroscientist
Aaron D. Thome, PhD, Neuroscientist
Dr. Aaron Thome is a trained neuroimmunologist with a focus in neuroinflammation and neurodegenerative disease (Alzheimer’s disease, Parkinson’s disease, ALS). He trained at the Center for Neurodegeneration and Experimental Therapeutics at the University of Alabama at Birmingham followed by a postdoctoral fellowship under Stanley H. Appel, MD at the Houston Methodist Neurological Institute. He currently serves as an Assistant Research Professor of Neurology in the Stanley H. Appel Department of Neurology and Houston Methodist Research Institute. His current research involves elucidating the underlying inflammatory mechanisms (peripheral and central) in neurodegenerative diseases. His research utilizes clinical samples and pre-clinical models of disease to identify stage-specific immune changes in neurodegeneration with the goal of developing innovative immunomodulatory therapeutics for the treatment of neurodegenerative disease.
Research Interests
- Neuroinflammation
- Neurodegenerative disease
- Alzheimer’s disease
Weihua Zhao, MD, PhD, Neuroscientist
Research Interests
- Amyotrophic lateral sclerosis (ALS)
- Neuroprotection
- Neuroinflammation
- Neurotoxicity
Research Assistants
- Hui Xuan
- Jinghong Wang
- Shixiang Wen, BS
- Aiping Gao
- David Vo
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