Osaka University scientists have built short fragments of DNA that can stop the production of abnormal alpha-synuclein protein in the brain — which may advance the development of new therapies for the control and prevention of Parkinson’s disease.
“Although there are drugs that treat the symptoms associated with PD [Parkinson’s disease], there is no fundamental treatment to control the onset and progression of the disease,” Takuya Uehara, PhD, the study’s lead author, said in a press release.
It is believed that gene therapy could someday be used to treat or halt Parkinson’s. Potential therapeutic targets include genes associated with the disorder, such as the SNCA gene — the gene that codes for the alpha-synuclein protein. Mutations in SNCA lead to the production and accumulation of an abnormal, and harmful, form of the alpha-synuclein protein within brain cells of people with Parkinson’s. As the disease progresses, neuronal toxic protein buildup increases, eventually leading to cellular death. That, in turn, leads to the onset of disease-related motor and non-motor symptoms.
“The antisense oligonucleotide (ASO) is a potential gene therapy for targeting the SNCA gene. ASO-based therapies have already been approved for neuromuscular diseases including spinal muscular atrophy (SMA) [Spinraza] and Duchenne muscular dystrophy [Exondys 51],” the researchers said.
Japanese researchers now looked for ways to prevent the production of toxic alpha-synuclein, hoping to eliminate Parkinson’s molecular trigger. To do so, they designed 50 small fragments of DNA that mirrored parts of the coding sequence of the SNCA gene messenger RNA (mRNA).
All genetic information contained within genes (DNA) is ultimately translated into proteins. However, several complex steps exist before a protein can be produced: DNA is first transformed into mRNA, and eventually, into a protein.
The man-made DNA fragments, also known as amido-bridged nucleic acid-modified antisense oligonucleotides (AmNA-ASO), were stabilized with resilient cyclic amide structures (hence the term “amido-bridged”). Amide are compounds that confer structural rigidity.
In total, these 50 molecules covered around 80.7% of SNCA’s mRNA. In doing so, engineered molecules were able to bind to their matching natural mRNA sequence, disabling it from being translated into a protein.
Using human embryonic kidney cells that naturally produce alpha-synuclein, scientists observed that several of these engineered molecules reduced SNCA mRNA levels. One of the constructs, specifically number 19, significantly decreased SNCA mRNA levels to 24.5% of the normal alpha-synuclein levels, “suggesting that AmNA-ASO [number] 19 is highly potent for targeting SNCA mRNA in human cultured cells,” the researchers said.
Importantly, this particular ASO was efficiently delivered into the brains of mice using an intracerebroventricular (a fluid-filled interconnected brain cavity) injection, without the aid of additional chemical carriers. The ASO was then mainly taken up by neurons and neuronal support cells.
Further testing, using a Parkinson’s mouse model that had disease-characteristic motor impairment, revealed AmNA-ASO number 19 successfully reduced alpha-synuclein protein levels, and significantly eased symptom severity 27 days after administration.
The researchers concluded that reducing alpha-synuclein mRNA and corresponding protein levels via gene therapy seems to enhance Parkinson’s-related motor manifestations in mice. This highlighted AmNA-ASO’s potential as a novel therapy for this neurodegenerative disorder.
The ASO Spinraza (nusinersen) was approved by the U.S. Food and Drug Administration (FDA) in December 2016 for treating spinal muscular atrophy. The FDA granted accelerated approval to Exondys 51 (eteplirsen) in September 2016, making it the first drug approved to treat Duchenne muscular dystrophy.