Gene therapy shows promise for early-onset Parkinson’s in lab study
Treatment protected key brain cells in mouse models of PRKN disease
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- Experimental gene therapy targets early-onset Parkinson’s linked to PRKN gene mutations.
- PRKN mutations are linked to dopamine neuron loss due to mitochondrial and lysosomal dysfunction.
- AAV9-PK041 gene therapy protected dopamine-producing brain cells in mouse models.
Scientists have developed an experimental gene therapy with the potential to treat early-onset Parkinson’s disease associated with PRKN gene mutations, according to a new preclinical study.
Delivery of the gene therapy carrying a functional version of the PRKN gene into the brains of two mouse models of Parkinson’s protected dopamine-producing nerve cells, the underlying cause of Parkinson’s.
The results support the therapeutic potential of targeted gene therapy for modifying disease course in PRKN-related Parkinson’s disease, with possible relevance to broader forms of the disease, the researchers wrote.
Study describes gene therapy approach in Parkinson’s models
The findings were described in the study, “In vitro and in vivo rescue of dopaminergic neurons in Parkinson’s disease models after Parkin gene therapy,” published in Nature Gene Therapy.
Parkinson’s disease is characterized by the progressive loss of dopaminergic neurons — brain cells that produce the signaling molecule dopamine. This disrupts normal neuronal communication, leading to the movement-related symptoms of the condition.
The disease most often develops later in life, with symptoms typically first appearing around age 60 or older. However, some cases occur earlier. PRKN-related Parkinson’s disease is a major genetic cause of juvenile forms of the disease (onset before age 20) and early-onset Parkinsonism (onset before about age 45).
One of the main genetic contributors to early forms of the disease is the PRKN (PARK2) gene. This gene carries instructions for parkin, an enzyme that helps maintain mitochondrial function (the cell’s energy producers) and helps cells remove damaged or unwanted proteins through cellular recycling processes involving lysosomes (the cell’s recycling centers).
Studies suggest that PRKN mutations and the resulting loss of functional parkin lead to mitochondrial defects and lysosomal dysfunction, which are thought to contribute to the death of dopaminergic neurons.
Gene replacement therapies primarily aim to provide cells with a functional version of a defective gene. Previous studies have shown that delivering PRKN to mouse models can reduce dopaminergic neuron loss, although results have varied across studies.
Researchers develop and test PRKN gene therapy in cells, mice
In this report, scientists at Takeda Pharmaceuticals developed and tested a new PRKN-replacement gene therapy in cells and two mouse models of Parkinson’s.
The team first identified several AAV9 (adeno-associated virus) gene therapy vectors that restored parkin protein production in dopaminergic neurons lacking the PRKN gene. Parkin was produced at levels similar to or higher than normal, helping correct defects in mitophagy, the process by which cells remove damaged mitochondria.
When tested in mice without the Prkn gene, three vectors produced human parkin protein in the midbrain. One candidate, AAV9-PK041, showed the strongest expression and most efficient delivery, and was selected for further testing.
In one widely used model, mice were exposed to the toxin 6-OHDA, which causes damage to dopaminergic neurons similar to what occurs in people with PRKN-related Parkinson’s. The gene therapy was injected into the substantia nigra, a brain region critical for movement, several weeks before toxin exposure.
AAV9-PK041 significantly protected dopaminergic neurons on the treated side of the brain compared with untreated animals. Most of these neurons produced the restored parkin protein, indicating successful delivery of the gene to the target cells. The protective effect was limited to the injected side, suggesting the therapy did not spread to the opposite side of the brain.
Second model suggests broader potential of gene therapy approach
Researchers also tested AAV9-PK041 in a second mouse model designed to mimic the progression of the more common, sporadic form of Parkinson’s. In this model, injections of misfolded alpha-synuclein protein trigger the buildup and spread of harmful protein clumps in the brain, similar to Lewy bodies seen in people with Parkinson’s. These changes are associated with inflammation and the gradual loss of dopaminergic neurons.
Mice that received the AAV9-PK041 treatment before the alpha-synuclein injections showed significant protection of dopaminergic neurons. The protective effect increased with higher doses, and at the highest dose, the number of surviving dopamine neurons was comparable to that seen in non-treated control animals.
“These findings highlight the therapeutic potential of AAV9-[PRKN] gene therapy for hereditary PRKN-[Parkinson’s disease], idiopathic [Parkinson’s disease], and related neurodegenerative conditions,” the team wrote.
