A new study led by researchers at the University of California San Diego School of Medicine suggests that an experimental gene therapy could help protect the brain from the damage and cognitive decline linked to TDP-43-related proteinopathy, a type of neurodegeneration that is a major driver of frontotemporal dementia (FTD) and is also common in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). The study is published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association .
Though TDP-43 is not a household name, this protein is increasingly recognized among neuroscientists as one of the most important factors in age-related brain diseases. Abnormal TDP-43 accumulation has been linked to ALS — also known as Lou Gehrig's disease — and to FTD, which has drawn broader public attention in recent years following actor Bruce Willis's diagnosis in 2023. Researchers also estimate that TDP-43 is present in more than half of AD cases, and its presence has been associated with faster cognitive decline, greater brain atrophy and worsening memory loss.
The new therapy utilizes a modified, harmless virus to deliver a beneficial gene, called SynCav1, to brain cells. While most gene therapies targeting the brain and spinal cord heavily depend on direct tissue injections, this approach used a novel virus that can be delivered systemically to boost the production of caveolin-1, a neuroprotective protein that helps organize critical signaling pathways in the brain. Unlike many therapeutic approaches to treating neurodegeneration, which only focus on treating immediate damage, the new approach is designed to help vulnerable neurons better withstand disease-related stress and preserve brain function regardless of disease origin.
"Many therapies for neurodegenerative disease focus on removing toxic proteins, but neurons are also losing their ability to cope with that stress," said senior author Brian Head, PhD, senior author of the study who is a professor of anesthesiology at UC San Diego School of Medicine and research career scientist at the Veterans Affairs San Diego Healthcare System. "Our findings suggest that strengthening the neuron's resilience itself may be a powerful therapeutic strategy, even when toxic proteins are already present."
Testing the approach in mice, the researchers found:
- The therapy was able to cross the blood-brain barrier and boosted expression of caveolin 1 in neurons across the brain and spinal cord
- In mice who received the treatment, SynCav1 preserved learning, memory and fear extinction – the process by which a person or animal becomes less scared of a frightening stimulus after repeated exposures
- In mice who received the treatment, SynCav1 lowered levels of pathological TDP-43 in the cortex and hippocampus, regions of the brain associated with higher cognitive function, voluntary movement and social behavior
- The therapy also showed benefits inside the cell, including protecting energy-producing structures (mitochondria) and preserving subcellular structures that neuronal cells use to communicate with each other (membrane lipid rafts)
In addition to testing a treatment approach, the findings also help improve our overall understanding of neurodegeneration at the cellular and molecular level, which could help scientists discover further treatment candidates in the future.
"This study gives us an important new mechanistic clue as to what's really going on in the brain during neurodegeneration," said Shanshan Wang, MD, PhD, co-corresponding author of the study and assistant professor of anesthesiology at UC San Diego School of Medicine. "We found that TDP-43 is not only accumulating in the wrong subcellular compartments (i.e., membrane lipid rafts), but also disrupts cellular processes that are essential for neurons to communicate with one another. SynCav1 appears to help preserve this molecular machinery and subcellular localization."
While additional research is needed to refine the approach before it is available to patients, the findings demonstrate the potential of SynCav1 as a neuron-centric treatment candidate that could be applicable across many neurodegenerative diseases.
"What is especially exciting is that we saw protection across multiple levels — behavior, synapses, axons, membrane signaling and mitochondrial structure," Head added. "That kind of broad neuroprotection is exactly what is needed in complex disorders like TDP-43-related dementias, and we're excited to continue exploring its potential."
Additional co-authors on the study include: Dongsheng Wang, Vinh Ta, Hongxia Wang, Jerica Ju, Chun Wang, Christine Chehadeh, Albertina Torreblanca-Zanca, Yessenia Magaña and Michael J. Castle, all at UC San Diego.
The study was funded, in part, by the National Institutes of Health (grants UM1TR005449, K12TR005441, KL2TR001444) the U.S. Department of Veterans Affairs (BX003671, BX006318), Congressionally Directed Medical Research Programs (AL210059, AL230115) and the UC San Diego Gene Therapy Initiative (2039592).
Disclosure: Brian P. Head holds equity in and serves as a non-paid scientific advisory board member for Eikonoklastes Therapeutics LLC. Other authors reported no competing interests.
