A team led by medical researchers at Case Western Reserve University has developed a potential treatment for Perizois-metzbach's disease (PMD). It is a fatal neurological disease caused by genetic mutations that prevent the body from producing myelin, which is a protective insulator around nerve cells.

Using the mouse neurological disorder model (https://www.creative-biolabs.com/drug-discovery/therapeutics/rodent-neur...), the researchers identified and verified a new therapeutic target—a toxic protein caused by genetic mutations. Next, they successfully used a series of drugs called ASOs (antisense oligonucleotides) against the ribonucleic acid (RNA) strands to prevent the production of abnormal proteins.

By demonstrating the effective delivery of ASOs to the production of myelin cells in the nervous system, the researchers pointed out the prospect of using this method to treat other myelin diseases that are caused by the dysfunction of these cells, including multiple sclerosis (MS). Their research was published online in the journal Nature on July 1, 2020.

This treatment reduces the hallmark symptoms of PMD and prolongs life span. The preclinical results are impressive that mouse models of PMD, which usually die within a few weeks of birth, can live a normal lifespan after treatment. The study opened the door to the development of the first treatment for PMD and new treatments for other myelin diseases.

Introduction to PMD

PMD is a rare genetic disease that involves the brain and spinal cord and mainly affects boys. The typical clinical manifestations are nystagmus, hypotonia, ataxia, and progressive motor dysfunction. During the development of PMD, most children can gradually progress initially, and then the mental motor development gradually regresses, and the motor dysfunction is more significant than the mental retardation. PMD is a kind of PLP1-related disease, a continuous spectrum of diseases from severe to mild. According to the clinical manifestations from severe to mild and the age of onset, they are divided into congenital PMD, classic PMD, transitional form, PLP1 null syndrome, complicated spastic paraplegia, and uncomplicated spastic paraplegia.

PMD is caused by a genetic error of proteolipid protein 1 (PLP1). Under normal circumstances, this gene produces protein lipoprotein (PLP), the main component of myelin, which wraps and isolates nerve fibers so that electrical signals can be transmitted normally in the nervous system. However, defects in the PLP1 gene can produce toxic proteins, which kill the cells that produce myelin, and prevent the normal development and function of the myelin, resulting in severe neurological dysfunction in PMD patients.

So far, there is no treatment that can relieve PMD symptoms or prolong life of patients.

Latest Research

In the current experimental phase, researchers have found that inhibiting mutations of PLP1 and its toxic protein can restore myelin-producing cells, produce functional myelin, reduce disease symptoms, and extend lifespan.

The successful clinical application of ASOs is relatively new, but recent progress seems promising. In 2016, the FDA approved the first ASO drug to treat spinal muscular atrophy, a neurological disease. The drug Spinraza was developed by Ionis and commercialized by Biogen Inc. More ASO therapies are under development and clinical trials, which are expected to solve many neurological diseases.
In this study, the mouse models play an indispensable part to achieve the results. It is of vital significance to evaluate a drug's effect during drug discovery and development stages. Various animal models have been developed to characterize the pharmacokinetics and pharmacodynamics of therapy. For the study of neurological diseases, commonly used neurological disorder models include rodent models and non-human primate (NHP) disease models.

* Rodent models of Central Nervous System (CNS) disorders are widely used to explore pathology and molecular mechanisms, identify potential biomarkers, and assess the therapeutic utility and estimate safety margins of new disease-specific drugs, which mainly cover chemically induced, surgical, genetically engineered, and spontaneous models.
* NHP models are generally applied for studying human brain function and neurological diseases, such as Parkinson’s disease (PD), middle cerebral artery occlusion, spinal cord injury, and cerebral infraction.

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