Gene Therapy Could Boost Parkinson’s Disease Treatment

Degeneration of a neuron, conceptual illustration

Research led by Northwestern University shows that damage to mitochondria in the brain can cause late-onset Parkinson’s symptoms in mice and that it is possible to boost the effects of levodopa treatment in these animals using a form of gene therapy.

Mitochondria provide energy to cells around the body and the new research reveals that when these small organelles fail in the area of the brain linked to Parkinson’s disease, the dopamine-releasing neurons can no longer function properly and gradually die off.

“This is the first time there has been definitive evidence that injury to mitochondria in dopamine-releasing neurons is enough to cause a human-like parkinsonism in a mouse,” said lead study investigator James Surmeier, chair of neuroscience at Northwestern University Feinberg School of Medicine, in a press statement.

“Whether mitochondrial damage was a cause or consequence of the disease has long been debated. Now that this issue is resolved, we can focus our attention on developing therapies to preserve their function and slow the loss of these neurons.”

As described in the journal Nature, the team used intersectional genetics to disrupt mitochondrial function in the dopaminergic neurons of a mouse model. They found these mice developed the equivalent of late-onset Parkinson’s disease.

The mitochondrial dysfunction led to metabolic changes that allowed the neurons to survive but led to a gradual loss of dopaminergic function that first became noticeable in the nigrostriatal axons in the brain.

“This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism—which emerged only after the later loss of dopamine release in the substantia nigra,” write the authors. This link to the substantia nigra is something that was not previously clear.

Levodopa is a standard treatment for people with Parkinson’s disease to at least temporarily restore dopamine function, but it becomes less effective over time.

The researchers in this study tested a form of gene therapy on the mice with Parkinson’s symptoms to see if they could improve treatment options. They created an adeno-associated viral (AAV) vector to express the aromatic-l-amino acid decarboxylase (AADC) protein. AADC helps convert levodopa to dopamine in the body.

They found that the mice who were treated with this add-on therapy had a more beneficial effect from treatment with levodopa than those receiving levodopa alone.

Many biotech’s and big pharma have tried to develop new therapies for Parkinson’s disease and other similar neurodegenerative disorders in recent years, but few have succeeded in taking drugs or other therapies to the clinic. While this is an animal study and the results have yet to be validated in humans, the authors hope their findings will translate to benefits for patients with this debilitating condition.

“This new ‘human-like’ model may help us develop tests that would identify people who are on their way to being diagnosed with Parkinson’s disease in five or 10 years,” Surmeier said. “Doing so would allow us to get them started early on therapies that could alter disease progression.”

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