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Dr. Wilson has worked in the field of gene therapy for the past 35 years.

He readily accepted the invitation to join our conference as he felt it was time to share the progress which has been made in the development of gene therapy, and to consider the possibility that this may become an effective treatment for patients with MSUD. Are we there yet? In Dr. Wilson’s words: “I leave it up to you to decide whether we’re just around the corner or not”. His goal was to update us on the progress of gene therapy across other disorders, specifically as it relates to treating liver metabolic diseases.

What is Gene Therapy?

All metabolic processes in our bodies start with a gene in the DNA. The gene makes messenger RNA (mRNA) and the mRNA makes a protein. DNA remains present for the life of the cell, but mRNA is only present when a protein needs to be made.

In MSUD, there is a defect in one or more of the 4 genes which produce the branched-chain alphaketo acid dehydrogenase complex (BCKDC) needed to metabolise the branched-chain amino acids. Due to the defective gene, the correct mRNA is not produced and therefore the incorrect protein is produced. This causes a block in metabolism and leads to the accumulation of toxic leucine.

The treatment for most metabolic diseases is to try to manipulate the accumulation of those metabolites with drugs or diet. This requires ongoing treatment and diet regimens that last a lifetime. Gene therapy aims to treat the disease at its root, in the gene. Dr. Wilson states that in MSUD “the normal version of the gene is the ultimate drug”. If we can insert a new form of this gene into the cell, to reside there permanently, we essentially correct the genetic defect.

What is the Challenge of Gene Therapy?

The normal version of the gene for BCKDC is known; the problem is getting it into the right cell. At the turn of this century it was discovered that packaging the DNA in the right way enables it to overcome the barrier of the cell membrane. Once through the cell membrane, the package containing DNA with the normal gene takes up residence in the cell, produces the correct protein, overcomes the block and diminishes the accumulation of leucine.

mRNA Therapy

Research has demonstrated that through mRNA therapy, the correct protein to overcome the metabolic defect can be produced. However, mRNA therapy is not permanent, and eventually the treatment is reversed.

Host Viruses

So how do we package DNA to get it into cells? Viruses. Viruses don’t have DNA of their own, making them a great package to shuttle the correct gene. Jean Bennett, an ophthalmologist, was the first to successfully use gene therapy through a vector system, improving retina sight for blind people with a specific genetic mutation. Despite the noted success, a good vector for the liver is still not available.

The problem with most host viruses is that they are too large to pass through the cell membrane. The advantage of the liver and what makes it a great organ for gene therapy over other organs is that the liver blood vessels have large pores in them. When a substance is injected into the blood it goes directly to the liver, not other organs such as the heart. With this in mind Dr. Wilson’s team treated mice with Hemophilia B, a genetic disease affecting the way the blood clots. This was successful, and they have since gone on to use this treatment in humans. This successful vector gene therapy in Hemophilia not only saves $300,000 per patient per year, more importantly, the patients do not require repeated infusions and are essentially cured of their disease. Many biopharmaceutical companies have since pursued gene therapy for Hemophilia using vectors.

Dr. Wilson says that what the researchers and the MSUD community need to look at now is whether this is a viable treatment for MSUD. The delivery vehicle, regulatory genes and treatment would be essentially the same as for hemophilia. The defective/ mutated gene would be swapped for the normal version of the gene.

Dr. Wilson notes that a patient who has been exposed to the virus that is used for the vector may have an immune response, causing the body to reject the virus and the treatment. Otherwise vector gene therapy has shown to be quite safe.

Genome Editing

An alternative to gene therapy is genome editing. Experimentation on Urea Cycle Disorder, another metabolic disorder, has shown that gene therapy may work with a mature liver but may not work in an infant whose liver is still growing. Since gene therapy introduces the new gene into the cell to fl oat in the cell, it doesn’t attach to the DNA. With an infant, as each cell divides and grows it will grow more of the new normal gene but also more of the old defective gene and eventually there will be more cells with the defective gene than the normal gene.

Genome Editing is different from gene therapy in that it not only delivers the normal gene to the cell but it actually goes in and corrects the mutation, which in turn corrects the mRNA, which produces a healthy protein. This would be the best approach for a newborn liver while gene therapy would theoretically work from 3 years of age and onwards.

Targeted Genome Editing

The challenge with genome editing is that each mutation requires a different drug. Researchers needed to find a way to use genome editing without being mutation specific. With this in mind, they successfully inserted the normal version of a gene into the chromosome of test mice. Unlike gene therapy where the gene is outside the chromosome, here the gene was actually inserted into the right place of the chromosome, so that it could function independent of the specific mutation. The survival and success rate of the mice was extremely high.

Orphan Disease Center

Going forward Dr. Wilson and his colleagues are using the positive data from the Hemophilia study, changing the gene, and leveraging the experience gained to multiple diseases. They have made the appropriate vectors for MSUD and will soon begin test runs in the mouse model. Dr. Wilson is quite confident that treatment in the mouse model will be successful and that human trials will follow.

Dr. Wilson closed by mentioning how humbling it is to see the commitment of physicians and caregivers, and the support that all provide to one another. He promised to continue to try his best, be transparent and keep the MSUD community informed. In his words: “I just hope to God it succeeds!”

Dr. Wilson’s research has been made possible by the University of Pennsylvania, Orphan Disease Center.



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