Findings show bone marrow transplantation may be a novel treatment approach
Orange, Calif. — The immune system, along with the body’s central nervous system, may play a fundamental role in amyotrophic lateral sclerosis (ALS), suggesting that bone marrow transplants may be an effective new treatment for the neurodegenerative disease, according to a research study led by Albert LaSpada, MD, PhD, a distinguished professor of pathology, neurology and biological chemistry at the UCI School of Medicine.
The study, titled “Clonally expanded CD8 T-cells characterize amyotrophic lateral sclerosis-4,” recently published in the journal Nature, was a collaboration between LaSpada and microbiologists Laura Campisi, PhD, and Ivan Marazzi, PhD, with the Icahn School of Medicine at Mount Sinai in New York City.
The team found immune and nervous system dysfunctions in both animal models and patients with ALS4, a slowly progressive juvenile form of ALS that is caused by mutations in the protein-coding gene senataxin.
“This is the first study to implicate altered cell-mediated immune system function in ALS and raises the prospect of abnormal cell mediated immunity as a contributing factor in not only ALS4, but also in other forms of the disease, including sporadic ALS, which accounts for 90% of all cases,” said LaSpada, a corresponding author on the study.
ALS is a neuromuscular disorder that is characterized by the progressive death of motor neurons, which severely impairs a person’s ability to move their arms and legs, speak, swallow and, eventually, breathe. There is no treatment or cure. Previous research has focused on neurons, but more recent studies, have shown evidence of interaction between the central nervous and immune systems.
The UC Irvine-Mount Sinai team’s most important discovery was that cell-mediated immunity, which does not involve antibodies, is altered in ALS4, based on the presence of expanded CD8 T cells. These cells contribute to the degeneration of motor neurons in ALS4. Further research showed that replacing bone marrow in ALS4 mice with the bone marrow cells of normal control mice was an effective treatment.
“The therapeutic benefit conferred by bone marrow transplantation in ALS4 mice can now be considered as a treatment for human patients,” LaSpada said. “Furthermore, although ALS4 is a rare familial inherited form of ALS, it shares the same cardinal histopathological findings observed in sporadic ALS and most other familial forms. Hence, if future research implicates an aberrant CD8 T-cell response in sporadic ALS, then bone marrow transplantation could be a novel treatment approach for many ALS patients in the future,” .
Considering the potential therapeutic opportunities suggested by these findings, LaSpada recommends reevaluating cell-mediated immunity in sporadic ALS patients to determine if altered T-cell function is a feature of their disease process.
This study was supported by the National Institutes of Health; Burroughs Wellcome Fund; and the Chan Zuckerberg Initiative Neurodegeneration Challenge Network.
About Albert R. LaSpada, MD, PhD — Founder and director of the UCI Institute for Neurotherapeutics and a fellowship trained specialist in clinical genetics and neurogenetics, LaSpada’s research focuses upon neurodegenerative disease, specifically investigating the molecular events that underlie neurodegeneration and neuron cell death in ALS, Huntington’s Parkinson’s and Alzheimer’s diseases. His research has uncovered evidence for transcription dysregulation, perturbed bioenergetics and altered protein quality control as contributing factors to neuron dysfunction. His research in reproducing molecular pathology in mice and in neurons, astrocytes, microglia and skeletal muscle cells derived from human patient stem cells has been instrumental in developing therapies to treat these disorders.
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