Experimental gene therapy could protect brain against Alzheimer’s and ALS – study
Gene therapy may help protect the brain from damage and cognitive decline linked to Alzheimer’s disease and ALS, an early study suggests.
The approach targets TDP-43, a harmful protein that plays a major role in frontotemporal dementia, a form of dementia that can affect behaviour and language, and is also found in many people with Alzheimer’s disease and ALS.
Researchers estimate TDP-43 is present in more than half of Alzheimer’s disease cases and say it has been linked to faster cognitive decline, greater brain atrophy, or shrinkage, and worsening memory loss.
The study, led by researchers at the University of California San Diego School of Medicine, tested the therapy in mice.
The experimental treatment uses a modified harmless virus to deliver a beneficial gene called SynCav1 to brain cells.
Rather than relying on direct tissue injections, the approach uses a virus that can be delivered through the body to boost production of caveolin-1, a neuroprotective protein that helps organise critical signalling pathways in the brain.
Instead of focusing only on immediate damage, the therapy is designed to help vulnerable neurons, the nerve cells that carry signals in the brain and nervous system, better withstand disease-related stress and preserve brain function.
Senior author Brian Head, professor of anaesthesiology at UC San Diego School of Medicine and research career scientist at the Veterans Affairs San Diego Healthcare System, said: “Many therapies for neurodegenerative disease focus on removing toxic proteins, but neurons are also losing their ability to cope with that stress.
“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, the protective layer that controls what enters the brain from the bloodstream, and boost caveolin-1 in neurons across the brain and spinal cord.
In mice given 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.
It also lowered levels of pathological TDP-43 in the cortex and hippocampus, regions of the brain associated with higher cognitive function, voluntary movement and social behaviour.
The therapy also showed benefits inside the cell, including protecting mitochondria, which produce energy for cells, and preserving membrane lipid rafts, subcellular structures that neurons use to communicate with each other.
Co-corresponding author Dr Shanshan Wang, assistant professor of anaesthesiology at UC San Diego School of Medicine, said the findings also offer clues about how neurodegeneration develops.
“This study gives us an important new mechanistic clue as to what’s really going on in the brain during neurodegeneration,” she said.
“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 localisation.”
The researchers said more work is needed before the approach can be made available to patients.
They said the findings demonstrate the potential of SynCav1 as a neuron-centred treatment candidate that could be applicable across many neurodegenerative diseases.
Head added: “What is especially exciting is that we saw protection across multiple levels, behaviour, synapses, axons, membrane signalling and mitochondrial structure.”
“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.”
