Appel Lab

Peggy & Gary Edwards ALS Laboratory

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About the Lab

Research in Dr. Appel’s laboratory focuses on developing new insights into neurodegenerative diseases, with a primary emphasis on amyotrophic lateral sclerosis (ALS). The major goal is to develop therapeutics that suppress neuroinflammation and the immune/inflammatory alterations that drive neurodegenerative disease progression. In the mSOD1 mouse model of ALS, activated microglia, and T-cell lymphocytes drive disease progression. In vitro studies documented that motor neuron cytotoxicity is produced by pro-inflammatory M1 microglia, and neuroprotection is mediated by anti-inflammatory M2 microglia. The motor neuron injury that initiates the process can be reproduced in vitro with misfolded proteins (mSOD, TDP-43, and FUS) which activate microglia and promote an M1 phenotype that kills motor neurons. Neuroprotective cytokines IL-4 and IL10 released from M2 microglia/macrophages enhance motor neuron survival. In vitro Tregs not only suppress proliferation of Th1, but also suppress pro-inflammatory M1 microglia. These studies suggest that during early stages of disease, motor neurons are capable of intracellular repair abetted by surrounding glia enhanced and modulated by Tregs. However, with increasing injury within the motor neuron, misfolded proteins or their surrogates are released as danger signals and promote the pro-inflammatory M1 phenotype, diminishing protective Tregs and enhancing pro-inflammatory Th1 and Th17.

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. 

IMMUNE CELLS HOLD PROMISE IN SLOWING DOWN ALS

Patients with neurodegenerative diseases are in desperate need of transformative therapeutic options; harnessing the neuro-protective effects of Treg cell therapy shows great promise in unlocking a new treatment paradigm and will enable us to revolutionize care for patients with devastating neurodegenerative diseases.

T-Regulatory Cell Therapy Clinical Trial

T-Regulatory Cell Therapy Clinical Trial:
John’s Story

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
Inflammation is a significant component of neurodegenerative disorder including Alzheimer’s disease. From his research during residency through to his current role as assistant professor of neurology, Dr. Faridar has assessed inflammatory signaling cascades in neurodegenerative process. One of his major contributions in this area is studying the status of the adaptive immune system in Alzheimer’s disease and its role as a potential therapeutic target. Regulatory T cells (Tregs) play a neuroprotective role by suppressing microglia/macrophage-mediated inflammation and modulating adaptive immune reactions. Dr. Faridar and his team observed that Tregs of Alzheimer’s disease patients lose their ability to suppress inflammation. However, these dysfunctional Tregs might be a restorable therapeutic target. Based on this finding, Dr. Faridar and his team are conducting a phase I/IIa study to assess the safety and potential efficacy of an in vivo Treg expansion strategy in Alzheimer’s disease patients with promising preliminary findings.

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
Dr. Weihua Zhao is interested in the underlying mechanisms of neuroinflammation on motor neuron death and relevant therapeutic targets. Current research efforts aim to understand the roles of microglia/monocytes and T-cells on immune-mediated injury and repair in ALS. Dr. Zhao is investigating the neuroprotective potential of regulatory immune cells as new therapeutic options for ALS, and leads the cell therapy team on the manufacturing of expanded human Tregs in clinical trials. One focus is to integrate world-class technology and scientific application to clinical trial design and process development and improve Treg manufacture productivity and efficiency without compromising compliance standards of quality and Good Manufacturing Practices. Dr. Zhao also interests in exploring the synergistic effects of expanded Tregs with small molecule compounds on the main pro-inflammatory sources in ALS, which would help to determine future directions of clinical trials.

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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