Experimental gene therapy promises to protect brain against dementia and ALS
A new study led by scientists at the University of California San Diego School of Medicine reveals a promising experimental gene therapy. The approach seeks to safeguard the brain from damage and cognitive decline associated with TDP-43 proteinopathy, a form of neurodegeneration that is a major factor in frontotemporal dementia (FTD), Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). The research was detailed in the scientific journal Alzheimer’s & Dementia.
Although TDP-43 is not as well known to the general public, this protein is increasingly recognized by neuroscientists as a crucial factor in age-related brain diseases. Its abnormal accumulation is associated with ALS, also called Lou Gehrig’s disease, and FTD, which gained public attention following the diagnosis of actor Bruce Willis in 2023. More than half of Alzheimer’s cases also have the TDP-43 protein, and its presence is linked to faster cognitive decline, marked brain atrophy and a significant worsening of memory loss, highlighting the urgency of treatments targeting this condition.
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The innovative therapy uses a modified, harmless virus to deliver a beneficial gene, SynCav1, directly to brain cells. Unlike most gene therapies that require direct injections into brain or spinal cord tissue, this approach employs a virus capable of being administered systemically. It stimulates the production of caveolin-1, a neuroprotective protein that organizes crucial signaling pathways in the brain, focusing on strengthening neuronal resilience against the stress of disease and preserving brain function.
“While many therapies for neurodegenerative diseases focus on removing toxic proteins, neurons also lose the ability to deal with this stress,” explained Brian Head, professor of anesthesiology at UC San Diego School of Medicine. According to Head, the research results suggest that strengthening the resilience of neurons can be an effective therapeutic strategy, even in the presence of harmful proteins.
When testing the approach on rodents, the researchers observed important findings:
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- The therapy was able to overcome the blood-brain barrier, elevating the expression of caveolin-1 in neurons throughout the brain and spinal cord.
- In rats treated with SynCav1, there was preservation of learning, memory and fear extinction, a process that leads to a decrease in fear of a threatening stimulus after repeated exposures.
- SynCav1 treatment resulted in reduced levels of pathological TDP-43 in the cortex and hippocampus, areas of the brain associated with heightened cognitive function, voluntary movement, and social behavior.
- The therapy also brought intracellular benefits, such as the protection of mitochondria (energy-producing structures) and the conservation of lipid microdomains in the membrane, essential for communication between neuronal cells.
In addition to exploring a new avenue of treatment, the findings contribute to a better understanding of neurodegeneration at the cellular and molecular levels. This in-depth knowledge can enable scientists to identify and develop future therapeutic candidates.
“This study offers us a crucial new mechanistic clue about what actually happens in the brain during neurodegeneration,” said Shanshan Wang, co-corresponding author of the study and assistant professor of anesthesiology at UC San Diego School of Medicine. She highlighted that TDP-43 not only accumulates in inappropriate subcellular compartments, but also interferes with cellular processes vital for neuronal communication, and SynCav1 appears to help preserve this molecular machinery.
Although further investigation is still needed to refine the approach before its application in patients, the current results demonstrate the vast potential of SynCav1 as a neurocentric treatment candidate, with applicability in a variety of neurodegenerative diseases.
“It is particularly exciting to observe protection at multiple levels of behavior, synapses, axons, membrane signaling and mitochondrial structure,” added Brian Head. He concluded that this comprehensive neuroprotection is exactly what is sought in complex disorders like TDP-43-linked dementias, and the team is motivated to continue exploring its potential.
