BB-301 is a treatment for oculopharyngeal muscular dystrophy that Benitec Biopharma is developing.

It has been designated an orphan drug by both the European Medicines Agency and the U.S. Food and Drug Administration.

How BB-301 works

Oculopharyngeal muscular dystrophy, or OPMD, is a form of muscular dystrophy that primarily affects muscles in the eyelids and throat but can affect other face muscles and limbs. It usually occurs in people 40 to 50 years old.

OPMD is caused by a mutation of the PABPN1 gene. The abnormality causes the body to produce a faulty form of PABPN1 protein. Scientists think the abnormal protein clumps together in muscle cells, interfering with their function and leading to muscle degeneration. BB-301 silences the mutant gene and simultaneously replaces it with a healthy gene.

It silences the mutant gene by interfering with the process the gene uses to product abnormal PABPN1 protein. There are several steps in producing a protein from a gene. One is the production of a messenger molecule called an mRNA, which is essentially a copy of the portion of DNA encoding for a protein. The mRNA molecule travels from the cell’s nucleus, which contains DNA, to other structures in the cell that produce proteins.

BB-301’s therapeutic approach is called DNA-directed RNA interference or ddRNAi. It combines gene therapy with an RNA interference, or RNAi, strategy. Gene therapy involves using a virus that has been modified to render it harmless as a means of introducing genetic material into a cell. BB-301’s modified virus contains DNA that leads to the production of an RNAi molecule that binds to mutated PABPN1 mRNA. The binding prevents the gene from producing the abnormal PABPN1 protein — meaning that it has silenced, or shut off, the mutated gene.

The same virus used to introduce the DNA also contains a healthy copy of the PABPN1 gene. This allows the cell to produce the correct PABPN1 protein that is necessary for proper functioning and that does not generate clumps.

BB-301 in clinical trials

Experiments in mice with a mutation of the PABPN1 gene and symptoms that resemble OPMD suggest that BB-301 could be a promising treatment for the disease. Researchers found that when the mice were treated with BB-301, they produced less of the abnormal PABPN1 protein and started producing healthy protein instead. The team also saw fewer protein clumps in the mice’s muscle cells, and their muscle strength improved.

Benitec plans to start clinical trials of BB-301 by the end of 2018.

The orphan drug designation the therapy has received is aimed at helping pharmaceutical companies speed the clinical-trial and approval process of treatments for rare diseases.

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