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GEN Protocols Expert Exchanges: Critical ALS Biomarkers of Neuroinflammation & Oxidative Stress

Jun 24, 2022

Biomarkers are essential tools for the development of therapeutics, clinical trial design and patient stratification. Biomarkers also help evaluate the efficacy of therapeutic intervention on disease progression or relapse. Yet, biomarker driven patient stratification, a hallmark in oncology trials, has lagged in neurodegenerative diseases. 

In amyotrophic lateral sclerosis (ALS), a multifactorial, multisystem disease that involves the central nervous system and the peripheral immune system, malfunctions of the mitochondria induce oxidative stress and consequent cell damage. Oxidative stress (OS) also induces pro-inflammatory responses that provoke expression of acute phase proteins (APPs). 

In a recent phase I clinical trial sponsored in part by Coya Therapeutics, regulatory T lymphocyte (Treg) therapy was assessed for suppression of OS and APP responses in serum samples from ALS patients. ELISA assays showed that Treg therapy temporarily suppresses levels of lectin-type oxidized LDL receptor 1 (LOX-1) and oxidized low-density lipoprotein (ox-LDL), a commonly assessed serum marker for OS. The level of the biomarker subsequently increased during washout periods or upon stopping treatment. 

Treg therapy stabilized several inflammation-linked ALS biomarkers during treatment, but the levels rose when the treatment was suspended or stopped. These biomarkers included serum APPs, soluble CD14, lipopolysaccharide binding protein, and C reactive protein (CRP). 

In this GEN Protocols’ Expert Exchange, Stanley Appel, MD, and Adrian Hepner, MD, will talk about the opportunities and challenges involved in the measurement of biomarkers of mitochondrial dysfunction to monitor systemic oxidative stress and pro-inflammatory markers to monitor neuroinflammation, that could help monitor efficacies of evolving immunotherapies.

This Expert Exchange will focus on: 

  • ALS disease characteristics 
  • Inflammatory and oxidative stress in ALS
  • Regulatory T cell (Tregs) dysfunction as an underlying pathophysiological feature in ALS 
  • Biomarkers of systemic and neuro-inflammation and oxidative stress as potential indicators of disease progression, severity and treatment response in ALS
  • Therapeutic use of expanded Treg cells and Treg exosomes for ALS

Stanley Appel, MD, is the Peggy and Gary Edwards distinguished endowed chair for the treatment and research of ALS, co-director of the Houston Methodist Neurological Institute, chair of the department of neurology, Houston Methodist Hospital, professor of neurology at Weill Cornell Medical College, and a member of the Coya Scientific Advisory Board. He is also director of the MDA/ALSA ALS Research and Clinical Center at the Houston Methodist Neurological Institute. Dr. Appel's seminal research documented the intimate relationship of neurodegeneration and ALS progression with dysfunctional and decreased levels of Tregs. He is also renowned for his discovery of cryopreservation of Tregs demonstrating the ability to expand, freeze, and re-thaw Tregs, while maintaining viability and suppressive function. Dr. Appel is a member of numerous professional societies and committees and has authored 15 books and over 440 articles on topics such as ALS, neuromuscular disease, Alzheimer's Disease, and Parkinson's Disease.

Adrian Hepner, MD,  currently serves as chief medical officer at Coya Therapeutics. He previously served as chief medical officer at Pharnext and Eagle Pharmaceuticals. He has also held the positions of Vice President of Clinical Research at Avanir Pharmaceuticals, and Vice President of Clinical Research and Medical Affairs at BioDelivery Sciences International (BDSI). Prior to BDSI, Dr. Hepner was senior medical director at UCB BioSciences, Inc., and led global clinical research projects in Latin America for Teva Pharmaceuticals. Dr. Hepner has authored multiple publications, holds several patents and spent 17 years as a practicing physician specializing in neuropsychiatry.

 

Comments

Anser Azim Jul 25, 2022

Over hundreds of mutations in just SOD1 gene representing a small percentage of familial ALS shows how complicated this syndrome is , rightly mentioned by Prof Appel and Dr. Hepner! Very nice discussion! Axanopathy, protein folding, motor proteins, ubiquilinopathy and newly discovered some other familial genes are the leads! Woods are dark and deep and miles to go! I believe if we can address the blocked flow of information in upper or lower motor neurons that may solve the neuropathy and give some hope to the hopeless that includes patient and care giver at the same time! My 2 cents! We discovered the ALS2 gene some 22 years back in Teepu Siddique’s but the patient care hasn’t moved much!

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