ASOs Are An Effective Treatment Option for Pelizaeus-Merzbacher Disease, Researchers say

New research has identified and validated a novel treatment in mouse models for Pelizaeus-Merzbacher disease (PMD), a condition that targets the aberrant protein that results from a genetic mutation. The researchers achieved this feat by using a family of drugs known as antisense oligonucleotides (ASOs) to target the ribonucleic acid strands which formed toxic proteins that halted the production of the aberrant proteins. A study on this innovative treatment has provided promising results, as the study reported a significant reduction in PMD’s symptoms while simultaneously prolonging the patient’s lifespan.



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After the successful delivery of ASOs to myelin-producing cells, researchers then proposed the use of this method to treat other myelin disorders such as multiple sclerosis (MS). Paul Tesar the principal investigator of the published research stated “The pre-clinical results were profound. PMD mouse models that typically die within a few weeks of birth were able to live a full lifespan after treatment”. Tesar and colleagues have suggested that these favorable outcomes could open the door for the development of an effective treatment for PMD as well as potentially contributing as a treatment for other myelin diseases.

PMD, a Disease that Attacks the Young

Pelizaeus-Merzbacher disease is a rare genetic condition that primarily affects boys involves the nervous system, specifically the brain and spinal cord. Symptoms include jerky eye movements associated with abnormal head movements. Over time symptoms can worsen leading to severe muscle weakness, cognitive dysfunction, and difficulty walking. Most people with severe cases of the disease die in childhood as it is known to decrease life expectancy.

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The mechanism of the disease results from errors in a gene called proteolipid protein 1 (PLP1). PLP1 is a primary component of myelin, which insulates nerve fibers to allow for the transmission of electrical signals to its intended target. A defective PLP1 gene produces toxic proteins that attack and kill myelin-producing cells. This prevents the myelin sheath from conducting its regular function resulting in severe neurological damage. There is no treatment option for PMD that reduces symptom severity or extends lifespan. For the past decade, Tesar and colleague have spent their time investigating and developing therapeutic options for myelin disorders. Tesar and his team have found success in the commercial development and application of myelin-regenerating drugs for multiple sclerosis.

Researchers from Ionis Pharmaceuticals validate the Therapeutic Use of ASOs

In the current research, it was shown that suppressing mutant PLP1 and its toxic protein restored myelin-producing cells and reduced disease symptoms. The researchers validated PLP1 as the intended therapeutic target and recognized that mutations in the PLP1 gene produced a faulty RNA strand which created an aberrant protein.

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Researchers teamed with Ionis Pharmaceuticals, a leader in RNA-targeted therapies and pioneer of ASOs. ASO are short strings of chemically modified DNA that bind to a specific RNA target and block the production of its protein product. Although the use of ASOs is relatively new, the results seem promising. The FDA approved the first ASO drug for spinal muscular atrophy in 2016. The drug, Spinraza, was developed by Ionis Pharmaceuticals and commercialized by Biogen Inc. More ASO therapeutics are currently underway with hopes that it holds promise for the treatment of neurological disorders.

Tesar and colleagues will continue to pursue ongoing and planned experiments in the laboratory in hopes to develop ASO therapy for PMD. Researchers aim to answer more questions about how effective the treatment is, how long it lasts, the frequency of treatment, and whether it will be efficacious for all PMD patients regardless of disease severity.

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“While important research questions remain, I’m cautiously optimistic about the prospect for this method to move into clinical development and trials for PMD patients,” Tesar said. “I truly hope our work can make a difference for PMD patients and families.”


Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease




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