RNA interference (RNAi) was developed as a tool for studying the function of genes. In recent years, RNAi has also been used as a gene therapy to treat genetic diseases, such as certain types of muscular dystrophy. Muscular dystrophy refers to a group of related genetic disorders characterized by muscle weakness and wasting.
What is RNAi?
Genes provide cells with information for making proteins, a process that goes through several steps. First, a temporary copy of the DNA is made. This is called messenger RNA (mRNA). This temporary copy is then used as a template by the cellular machinery that synthesizes protein.
RNAi is a method of silencing gene expression, or the synthesis of proteins from genes. Researchers use a small RNA piece that’s complementary to the mRNA of the gene that they wish to silence. The complementary sequences bind to each other, which signals the cellular machinery to break down the mRNA, thereby preventing the protein that it encodes for from being made.
How can RNAi be used to treat muscular dystrophy?
Many genetic diseases are caused by the production of mutant proteins, which are toxic to cells. By silencing mutated genes, the production of toxic proteins can be halted or reduced, potentially treating the disease, and slowing or reversing its progression. Not all muscular dystrophies are caused by abnormal protein accumulation, however, so this strategy may not be applicable to all forms of the disease.
RNAi for LGMD
LGMD (limb-girdle muscular dystrophy) is a group of related muscular dystrophies that cause progressive weakness in the muscles of the hips and shoulders. Patients can be broadly divided into two types of LGMD. Type 2 is inherited in an autosomal recessive pattern and is caused by the absence of a protein, so RNAi would not be an effective therapy. However, type 1 LGMD is caused by the production of abnormal proteins and may be amenable to treatment with RNAi therapy, possibly in combination with a gene therapy that promotes the production of the normal protein. This approach is currently in early stages of development.
RNAi for OPMD
BB-301 is an experimental RNAi therapy that is being investigated to treat a type of muscular dystrophy called OPMD (oculopharyngeal muscular dystrophy), which is characterized by weakness in the muscles of the eyelids and throat.
OPMD is caused by mutations in a gene called PABPN1. These mutations cause the PABPN1 protein to accumulate in muscle cells, resulting in cell death. BB-301 uses RNAi to prevent the production of the abnormal PABPN1 protein, and it also contains a normal copy of the gene. Therefore, the combined therapy is designed to silence the mutant gene and increase the production of normal PABPN1 protein in muscle cells.
Last updated: 07/15/2019
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