Orphan diseases, including MSUD, are caused by a mutation in a gene. This mutated gene is unable to produce messenger RNA (mRNA), which carries the information from the gene needed to produce a protein.

Author(s): Dr. James Wilson

In gene therapy, a normal version of the gene is introduced into the cell. This is very difficult to do, and is usually accomplished by using a virus which will infect the cell and deliver the new gene. The virus is modified so that it cannot cause disease. The adeno-associated virus inserts its DNA into the nucleus of the cell where it can then make the healthy mRNA and the necessary protein. As it reproduces prolifically, the hope is that it will continue to make the required protein. This technique is now being used successfully in retinal disease, where the genes can easily be introduced into the appropriate cells in the eye.

Gene therapy for MSUD would require an introduction of the normal version of the BCKH gene into the liver. The blood vessels of the liver have large pores, and anything introduced into the blood will enter the liver.

Hemophilia, characterized by an absence of the gene which causes blood to clot, has been successfully treated by injecting the missing protein into the blood. This treatment must be repeated weekly as proteins don’t last. With gene therapy, the gene will be injected into the blood and taken up by the liver. In this way, adequate protein can be made for a long period of time.

A clinical trial for gene therapy is now under way for a urea cycle disorder called ornithine transcarbamylase deficiency (OTC). This is another metabolic liver disease controlled by diet and drugs.

Dr. Wilson’s lab is currently involved in a pilot gene therapy study using mice with intermediate MSUD (iMSUD mice). While reduced levels of BCAA have been observed, it is not yet known whether this will allow the mice to live (they currently die after a few weeks of life).

Messenger RNA (mRNA) therapy: This is an alternative technique to gene therapy in which mRNA is packaged and delivered to the liver using IV infusion. mRNA will make healthy protein, but will not be retained by the cell and will need to be reintroduced approximately every 2-4 weeks. However, this may be safer than gene therapy. As it bypasses the gene step, it provides activity within hours.

Genome editing: This technique aims to fix the mutation rather than adding a normal version of the gene. While this would be a permanent fix, it would require a different drug for each mutation. Dr. Wilson does not feel that this is viable for MSUD in the near future.

Future of Molecular Therapies for MSUD

UPenn is now evaluating the feasibility of gene therapy vs mRNA therapy for MSUD. Clinical trials are planned for July 2020.


The MSUD Family Support Group is currently funding several research projects and we are proactively looking for researchers interested in developing new treatments or finding a cure for MSUD. Significant funding is necessary if we are to accomplish this goal.
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