DTx Pharma has discovered new molecules that could be treatment candidates for Charcot-Marie-Tooth disease (CMT) type 1A (CMT1A), reaching the second milestone of a study designed to find molecules that lower PMP22 levels.
CMT1A is the most common subtype of CMT type 1, accounting for about 60% of cases. CMT1A is caused by a duplication (extra copy) of the PMP22 gene, which provides instructions for making a protein called peripheral myelin protein 22 (PMP22). This protein is important for the formation of the myelin sheath — a wrapping around neurons that helps them send electrical signals more efficiently.
The extra copy causes the PMP22 protein to be produced in excess, which leads to defects in the myelin sheath and, ultimately, problems with neurons. Patients experience muscle weakness and atrophy, though most retain their ability to walk and have a normal life expectancy.
The DTx study seeks to produce therapeutics to treat CMT1A by targeting RNA to reduce the excess production of PMP22 protein.
The process of making a protein from a gene generally involves two steps. First, the gene is transcribed from DNA into messenger RNA, which is a copy of the gene that can be transported out of the nucleus, to where the cell’s protein-making machinery is located. Then, the messenger RNA is used as a template to make the corresponding protein.
The DTx study aims to produce RNA therapies that interfere with this process for PMP22, such as small interfering RNAs (siRNAs, also referred to as silencing RNAs). These small RNA molecules have a particular sequence that helps them bind to messenger RNA for specific genes. This leads the messenger RNA to be destroyed before more protein is produced. Ultimately, siRNA are a way to decrease the amount of a specific protein in cells.
DTx Pharma hit the first study milestone in April, after identifying a number of siRNAs able to lower PMP22 levels in cultured cells. Their technology also was found to be very successful in increasing the delivery of these silencing molecules to cells.
The second milestone was the production of a new set of siRNAs that strongly decreased the amount of PMP22 protein in cells cultured in laboratory, expanding the pool of candidate molecules.
The next step of the project is to test these candidate siRNAs in mouse models of CMT1A, and determine whether they can be delivered to the peripheral nervous system — the part of the nervous system that is damaged in CMT — in these animals.
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