Molecule Delivered in Small Fatty Vesicles May Be Potential Parkinson’s Therapy, Mouse Study Shows

Delivering an alpha-synuclein-targeting molecule, called ASO4, in tiny fatty vesicles reduced toxic alpha-synuclein clumps and dopaminergic neuron loss — two main hallmarks of Parkinson’s disease — and lessened motor impairments in a mouse model of the disease.

Results of the study add to previous findings suggesting that these vesicles, called exomes, may be a useful tool to deliver therapeutically relevant molecules to people with Parkinson’s and suggest that ASO4, delivered by exomes, may be a potential treatment for this condition.

More studies are needed to confirm the therapeutic potential of this approach and to optimize exomes to specifically deliver these molecules to target cells, such as dopaminergic neurons — nerve cells that produce a key chemical messenger called dopamine.

The study, “Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson’s disease,” was published in the journal Neurobiology of Disease.

Parkinson’s disease is characterized by the progressive degeneration and death of dopaminergic neurons and by the buildup of toxic alpha-synuclein protein aggregates (Lewy bodies) within brain cells, particularly dopaminergic neurons, likely contributing to their death.

As such, increasing efforts have focused on the development of ways to lower the levels of alpha-synuclein, and subsequently the accumulation of its toxic clumps, in the brain, as potential therapeutic approaches for Parkinson’s.

One of the most promising approaches is based on antisense oligonucleotides (ASOs), small messenger RNA- (mRNA)-targeting molecules designed to either suppress or correct the production of a particular protein. Of note, mRNA is the molecule generated from DNA and used as the template for protein production.

Since ASO molecules can hardly enter cells by themselves and are likely to be broken-down quickly inside cells, researchers have been working on several types of “carriers” to deliver them into cells.

Now, researchers at the Renmin Hospital of Wuhan University, in China, have provided evidence that exosomes, tiny fatty vesicles naturally produced by several cells (including neurons) may be optimal carriers of alpha-synuclein-targeting ASOs.

While their functions are not fully understood, exosomes are known to be involved in the transmission of large molecules. Importantly, these vesicles not only can easily enter cells by merging with cells’ membrane, but also evade cells’ natural degradation processes.

Researchers first screened for the most effective ASO targeting the mRNA of the SNCA gene — which contains the instructions to produce the alpha-synuclein protein — so as to prevent alpha-synuclein production.

After testing the best ASO candidates in alpha-synuclein-producing human cells grown in the lab, they identified ASO4 as the one that most effectively reduced alpha-synuclein levels, and in a dose-dependent way. In these experiments, an electric pulse was used to open temporary holes in the cells’ membrane to allow ASOs to enter.

Researchers then tested the delivery of ASO4 through exosomes to lab-grown nerve cells derived from a mouse model of Parkinson’s disease that produces A53T, a mutant form of alpha-synuclein known to form aggregates.

Data confirmed that ASO4-containing exosomes were highly effective at delivering ASO4 to nerve cells and protecting ASO4 from degradation. This approach also did not affect cells’ survival, highlighting its low toxicity.

When looking at the approach’s effectiveness, the team found that ASO4-containing exosomes significantly dropped alpha-synuclein protein levels — by nearly 80% — and reduced the formation of toxic clumps.

The team then evaluated the effects of administering ASO4-containing exosomes directly into the brain fluid of the Parkinson’s mouse model, three times a week for six weeks.

Results showed that treated mice had a significant decrease in alpha-synuclein protein levels (by 32.9%) and a reduction in alpha-synuclein clumps, compared with untreated mice. Notably, ASO4-containing exosomes also lessened dopaminergic neuron degeneration and loss and significantly improved the mice’s motor function.

“These data suggest that ASO delivered by exosomes can efficiently decrease the level of α-syn [alpha-synuclein] and thereby reduce the [disease-associated] process caused by [overproduced] α-syn, reversing the motor deficiencies in PD [Parkinson’s disease] mouse models,” the researchers wrote.

As such, “exosome-mediated delivery of ASOs is a promising therapeutic approach for patients with PD,” they added.

They also noted that since, in theory, it may be possible to modify exosomes to specifically target dopaminergic neurons, future studies should focus on the development of such optimized exosomes.