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Editor's Observations

The New England Connection for PKU and Allied Disorders held their 7th annual PKU & Metabolic Conference in Massachusetts for parents and professionals on March 20, 1999. Wayne and I attended and appreciated the presentations.

There are many similarities in PKU (phenylketonuria) and MSUD. One of the biggest differences in the past has been in dietary control. In the 60s and 70s, most clinics allowed those with PKU to go off diet when they were around six years old. Only a few clinics thought it necessary to maintain the diet for life.

Today it is evident that those with PKU, who stop the diet, gradually suffer the toxic effects of elevated levels of the amino acid, phenylalanine. These problems have only recently been recognized to be related to elevated levels in those who were early treated. Reports indicate lowered IQs, mood alterations, impulse control disorders, migraine headaches, lack of ability to concentrate, loss of short term memory, poor academic functioning, inability to hold a job, muscle weakness, tremor and poor social and personal relationships.

These problems vary in individuals with PKU. However, those who go back on diet or maintain the diet from infancy, find these conditions disappearing or greatly improved. There are adult persons with PKU with high IQs and in professional positions. Scott Merrill, an attorney at law, has PKU and was a master of ceremonies at this PKU meeting. He went back on diet as an adult and found his academic abilities improved.

Can we apply this observation to MSUD? I am hearing from adult persons with MSUD who are having some of these same problems. Although these adults were on diet since infancy, in the 70s and 80s it was not common practice to maintain leucine levels as low as recent evidence indicates best. Today improved treatment, including the addition of isoleucine and valine to daily diets, appears to help maintain lower and more controlled levels even in adults with MSUD.

The make up of individuals certainly plays an important part in the way high levels affect them. It is difficult to know for certain the cause and effect relationship of physical and mental problems to MSUD. Which effects are related to the time treatment began or to lack of dietary control or other causes? There are reports of headaches, sensitivities, body aches, tremors, social problems, inability to reason adequately, excessive talking, poor academic functioning, fatigue and weakness in muscles and joints. Some adults with MSUD may not experience any of these problems. As with PKU, some individuals may not recognize that their problem is similar to others with the same disorder.

At the PKU meeting there was a strong emphasis on maintaining diet for life. I would like to also encourage very strict dietary control for all those with MSUD regardless of age. Don't compromise future mental and physical health.

I am very interested in more documentation on the effects of MSUD on adults. I encourage those with MSUD and their parents to contact me. All information will be kept confidential.

Engineered Protein
Imagine adults with PKU going back on diet and facing the challenge of drinking the less-than-desirable tasting (to put it mildly ) medical formula for the major part of their diet. As with MSUD, those on the PKU diet keep wishing for more normal foods. The many new low protein products help but they cannot substitute for the medical formula which contains needed protein.

One person responding to this plea for a more normal diet is Dr. Bryan Hainline from the Department of Pediatric Metabolism and Genetics, Indiana Medical Center, Indianapolis, Indiana. He spoke on "Development of a New High Protein Phe-Free Diet Supplement" at the PKU Conference. (Phe is the abbreviation for phenylalanine, the amino acid involved in PKU and one of the essential amino acids found in all protein.) Following is a summary taken from this speech and an article on the same topic by Dr. Hainline in the PKU News (Vol. 10, No. 3, Winter '99 issue).

Dr. Hainline and his associates became interested in developing a phe-free protein which can be added to low protein foods. This would add a high quality protein to the diet in the form of foods that can be baked and heated and have the protein content of "normal" foods. Commercial companies could make high protein-low phe chips, breads, pastas, cookies, etc. By eating foods containing this new protein, persons with PKU could reduce the amount of formula they need because they would be getting some of their phe-free protein from these foods.

Using medical genetic techniques, they proposed to remove the phenylalanine from a corn protein called gamma zein found in the kernel of the corn. This protein contains 203 amino acids, two of which are phenylalanine. They have already modified the gene that codes for the production of gamma zein, allowing them to remove the two phenylalanine residues. Now they need to improve the nutritional content of the protein and produce the phe-free protein in a plant.

This naturally occurring gamma zein protein purified from corn does not have a distinctive flavor so is expected to take on the flavor of any food it is mixed with. Gamma zein is related to gluten, the protein in wheat that gives food baked with flour much of its structure. Therefore, it has an excellent chance of improving the texture of low protein foods. To be effective, large quantities of this protein would need to be eaten, so it is expected to be more useful for older persons with PKU. Other nutrients found in the formula would have to be supplied with vitamin/mineral supplements and additions of dietary fat and carbohydrates. The new foods could only be used under medical supervision.

If this research is successful in producing a phe-free protein, the underlying technology will be useful for designing similar proteins for other inborn errors of metabolism including MSUD. The projected time for this new protein to become available is five years according to Dr. Hainline. However, he recently told me that a lack of funding is hindering the research. He is currently looking for personnel to work in the laboratory. We can only hope the research in gene repair therapy discussed in the following article is successful so we may not need genetically changed protein for MSUD.

NOTE:
The Scott Foster Metabolic Research Fund has supported Dr. Hainline's research. It is the type of research for which the fund was established - research which can benefit a number of metabolic diseases including PKU and MSUD. However, much larger sums of money are needed to make an impact. To donate to The Scott Foster Metabolic Research Fund, send your donation to:

The Scott Foster Metabolic Research Fund
New England Connection for PKU and Allied Disorders
16 Angelina Lane
Mansfield, MA 02048
Phone: 508-261-1291

Update on Gene Repair Therapy
Dr. Blaese spoke on "Are We Getting Closer to Gene Therapy?" at the PKU Conference. (Michael Blaese, MD is Chief of Clinical Gene Therapy Branch, National Institute of Health and President of Kimeragen Molecular Pharmaceuticals.) In the Fall/Winter '98 MSUD Newsletter, we reported on the technology of gene repair therapy as explained by Dr. Blaese at Symposium '98.

Dr. Blaese explained the difference between this new gene repair therapy and the traditional gene therapy. Gene repair actually corrects the gene code by using a chimeric molecule (the chimeraplast) to harness the cell's normal DNA repair system to correct the gene.

Certain diseases cannot be corrected, only those with single cell mutations. Dr. Blaese gave a list of ten diseases that are targeted for this gene repair. MSUD and PKU are both on this list. However, the first disease scheduled for human trials is Crigler-Najjar - a very rare mutation in an enxyme required to properly metabolize and eliminate bilirubin. The bilirubin levels cause organ damage and the child often dies in the second year of life.

I asked Dr. Blaese for an update on the first human trials and his response follows.
"Progress is moving well toward our goal of beginning treatment for the Crigler-Najjar children before the end of this year. The clinical protocol is now being written and the documents needed for FDA review are being assembled. Last week we made our final determination of the exact structure and formulation for the chimeraplast that we will use for the Crigler trial, and we have now started to manufacture the larger amount of pharmaceutical grade material needed for the trial. We expect to submit our formal application to the FDA after all the required safety testing is complete in September and hope to begin treating three patients by November. However, we still have a lot of work to do before I am comfortable enough to actually begin treating the children. We do not want to begin prematurely or potentially cause harm, so it is possible that this preliminary schedule could be bumped back if issues come up that take more time to resolve.

Kimeragen was able to find some investors who provided funding for several months, and we are hopeful that additional money will become available so we can complete the initial trial - and demonstrate to the world that this unique therapy really does have the potential to change people's lives for the better. We are also looking for ways to obtain grants and contracts to support development of treatments for other orphan diseases, such as MSUD, and we are absolutely committed to finding a way to bring this treatment to those other conditions."

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