Dr. Phillip Laipis - 2001 Annual Meeting - Keynote Speaker

“Of Mice and Men---Long Term Reduction in Serum Phe Levels in a Mouse Model”

Gene Therapy is on its way!

A roomful of parents, children, young adults and professionals – all with the common bond of PKU – came together at the Conference Center at Rush Presbyterian St. Luke’s Medical Center in Chicago on a beautiful Saturday in November. Why? To attend the PKU Organization of Illinois Annual Meeting and to hear what Dr. Philip J. Laipis had to say about the progress of gene therapy research related to PKU.

J.C. , PKU Organization of Illinois Board Member, introduced Dr. Laipis to the anxious crowd. Jim told us how Dr. Laipis readily accepted the Organization’s invitation and did not hesitate for a moment about traveling from his home in Florida to Chicago even after the tragic events of September 11^th.

Dr. Laipis has been working on PKU since 1998 when he was approached by a patient with PKU. "We do not have a final cure yet," Laipis said, "but gene therapy is well on its way."

What is gene therapy? Gene therapy is the use of DNA and RNA molecules to provide a therapeutic function – like a drug. Gene therapy can be used to (a) replace a protein for diseases like hemophilia, cystic fibrosis and PKU; (b) make a substance that is missing and treat diseases like Parkinson’s diabetes, and assist with wound healing; and (c) destroy incorrect or foreign genes to prevent viral infections and dominant mutations. There are approximately 200 separate clinical trials going on in the United States at this time. While not specifically geared toward PKU, the results of many of these trials will be applicable to PKU.

Dr. Laipis began his talk by providing some basic genetic background about phenylketonuria and the PKU gene. He shared the theory that the PKU gene must have had some type of protective effect in the past - similar to how sickle cell and cystic fibrosis helped protect carriers against diseases such as malaria and cholera. Although the large number of mutations (typically 1 from the mother and 1 from the father) of the PKU gene makes it difficult to predict the effect of treatment and the severity of PKU in individuals, Dr. Laipis also reminded us that only 5-10% of normal enzyme activity is required to successfully treat PKU.

What are the rationales behind PKU gene therapy research? Dr. Laipis said what we were all thinking: Current treatment options for PKU work but they are not satisfactory. The nature of the PKU gene and condition is such that gene therapy will help most patients. An animal model, the PKU mouse, already exists and makes research easier. Another advantage to the PKU mouse is that PKU is expressed similarly to how it is expressed in humans. Female mice even exhibit maternal PKU syndrome. Although initial experiments showed transient results with treatment lasting only 10 days to 2 weeks, researchers were encouraged. "Because phenylalanine hydroxylase ("PAH") is small it was technically feasible to use it as a virus vector," Dr. Laipis told us. As we have heard before, having the right kind of vector to take the gene to the correct place in the body is a critical part of gene therapy treatment. In treating PKU the therapeutic gene must get to the liver.

With the PKU mouse already in existence, Dr. Laipis’ team began its work. Dr. Laipis is using a virus called the Adeno-Associated Virus (AAV). This is a small human virus which most of us have already been exposed to. It has not been shown to have any harmful effects in humans which means it is "non-pathogenic". AAV is being used to make virus vectors to help get the therapeutic gene to the liver in PKU mice. AAV is also currently being used in cystic fibrosis gene therapy research.

Dr. Laipis’ team began treating male mice with large doses of the AAV vectors. The results show that Phe levels were reduced quickly (within a week) to 6mg or less. The reduced levels lasted for 24 weeks at which time the experiment was ended. In some experiments the mice died of old age with a lasting expression of reduced phenylalanine levels. Dr. Laipis compared these results to male adults and shared that the results might last as long as 5 years. The experiments have shown no resulting damage to the mice to date. That’s all good news but the experiments were not without their difficulties. Dr. Laipis shared with us that in order to drop Phe levels into the therapeutic range his team had to use a lot more AAV than anticipated. This is very hard to do. Also, female mice did not respond when given the same dose as the male mice. The only way the female mice responded was to take out their ovaries and pump them up with testosterone. Certainly not acceptable for female humans! So, what now?

Dr. Laipis’ team learned that we can reduce phenylalanine levels with an AAV vector but more work needs to be done with female mice. They believe that females may be more severely affected with PKU and that testosterone is somehow important in successful results in male mice. The research team is now looking at using a different enzyme or vector to improve results in female mice. They are also evaluating how to get more PAH into the female mice to improve results.

Dr. Laipis envisions a PKU gene therapy trial on humans within approximately 3-5 years. They will likely start with males as the researchers continue to work on improving results in females. These trials will cost money – approximately $100,000 per patient. He projects some results for PKU patients in the next 5-10 years.

But there is something we can do now. Dr. Laipis provided us with a survey he would like everyone to complete. The survey is looking to determine whether males with PKU are able to tolerate higher amounts of Phe over time than females. You can complete this survey online at http://www.medinfo.ufl.edu/cgi-bin/eval.cgi?pku . You will be prompted for a password. The password is guthrie. You can also register at this website to receive the results of the survey when it is complete. Your survey responses are anonymous and if you register to receive the results there is no link between the survey and your receipt of the results. You can also request a hard copy of the survey from the PKU Organization of Illinois.

Thank you Dr. Laipis for your enlightening talk and encouraging news about gene therapy and PKU.

Gene Therapy Q/A Session

After Dr. Philip J. Laipis, our keynote speaker finished his presentation, he joined our doctors, Dr. Paul Wong, Dr. George Hoganson and Dr. Barbara Burton for a question and answer session with our members. During this time, our members were able to get up-to-date information about their concerns regarding the current state and future potential of gene therapy.

Everyone is concerned about whether gene therapy is safe, especially following the tragic death of a patient undergoing gene therapy for a different condition last year. Dr. Laipis stated that based on his knowledge of the situation, he was aware of two potential problems with that particular patient. The first concerned whether the patient was in sufficiently good medical condition for the gene therapy trial. The way to address the concern in future trials is to have very strict guidelines regarding the health of any trial patients. The second concern involved the use of an adno-virus to introduce the gene therapy to the body. There can be an immune response to the adno-virus. Dr. Laipis stated that he is using an adno-associated virus in his gene therapy research and is able to avoid the immune response as a result.

Dr. Laipis indicated that although human trials related to PKU gene therapy will not occur for some time, based on current research, he believes that the trial patient most likely will be an adult male. Researchers would look for an adult to ensure that the patient had reached an appropriate maturation level for gene therapy. Current research involves PKU gene therapy in mice. Thus far, Dr. Laipis’ research is most relevant to about 60% of the PKU population. He is hoping to extend his gene therapy research trials in two ways: first, by identifying a mouse that mirrors the other 40% of the PKU population; and, second, by conducting gene therapy trials on a pregnant mouse. According to the doctors, in theory, if gene therapy could be used in utero, the best level of control of phe levels would be achieved and that in turn would mean that the potentially devastating affects on uncontrolled PKU would be avoided. In order for in utero therapy to work, however, researchers must identify an adno-associated virus or other vector for introducing the gene therapy to the body that would grow at the same rate as a fetus grows. It may be difficult to identify such a virus or vector. None of the doctors was aware of any gene therapy for any condition involving a pregnant female.

Dr. Laipis also would like to research ways to increase the amount of protein expressed during gene therapy so that side effects could be minimized. This research would involve modifying the vector used to introduce the gene therapy to a patient. Dr. Hoganson indicated that there has been some research conducted in Europe to improve enzyme activity functioning. Finally, Dr. Laipis hopes that future research will focus on ways to introduce gene therapy through muscles rather than through arteries because that will make more therapeutic choices available to patients. Currently, gene therapy in humans involves catheterization, a minor surgical procedure in which a tube is inserted into an artery.

Drs. Hoganson, Burton and Wong indicated that there also had been some research on a special amino acid mixture to prevent the uptake of phenylalanine to the brain. In addition, research on the PAL pill continues. The PAL pill would be taken with a meal and would act to break down phe to constituents that are not harmful to the body. While this appears to be a promising avenue of treatment, because of the complexities of the human body, the doctors indicated that the PAL pill might have drawbacks. First, it may not buffer increases in amino acid levels associated with stress, illness or other medical conditions. Second, it may block the uptake of other amino acids that are important for long-term health. Also, the PAL pill may not be appropriate for use in maternal PKU patients because the patients may not be able to achieve the required level of phe control necessary to ameliorate or avoid negative effects on the fetuses.

All in all, the doctors are encouraged by the level of research and the variety. Based on current research, it appears that there will not be a single fix for PKU, but instead a number of treatment options from diet to gene therapy may be used throughout a patient’s life to achieve the appropriate phe levels necessary for sound growth and development and a healthy life.

Illinois Department of Public Health (IDPH) News

We were very please to have Karen Burget of the Illinois Department of Public Health join us at our annual meeting. She gave us updates on activities that are occurring in the department related to PKU.

- Legislation has been drafted for insurance coverage for PKU medical formula. This bill would require insurance companies to cover the cost of the medical formula. It has been forwarded back to committee status. The IDPH currently spends approximately $1 million dollars a year on PKU medical formulas for us. This averages $40 a can, and if the bill passes, then it could result in both a savings for the state as well as possibilities for additional PKU medical products.

- New products are available from IDPH by working through the clinic dieticians. They will not be listed on the paper order forms.

- Expanded Newborn Screening. The state currently performs newborn screening for 6 disorders, including PKU. Over the past year, the state has put 4 new machines in place to perform newborn screening tests utilizing a technique called Tandem Mass Spectrometry. This method makes it possible to perform newborn screening on many additional disorders at a reasonable cost. Beginning early in 2002, Illinois will screen for an additional 22 disorders, bringing the total to 28. The cost of the newborn screening test will increase from the current $32 to $47. The turnaround time is expected to be the same as it is currently. Prior to the expanded newborn screening becoming effective, families may work with their doctor and request that this screening be done by having a blood sample sent to either Baylor University Medical Center or NeoGen Screening.

- The IDPH is updating it's website and it will be ready by the first of the year. This can be found at www.idph.state.il.us

Phenylalanine Free Protein Update

The staff of the Pediatric Metabolism Research Laboratory at the J. W. Riley Hospital for Children thanks the PKU Organization of Illinois for their kind financial support. Our research has continued to make slow but steady progress in the development of a phenylalanine free protein that can be used as part of the PKU diet. We are preparing two papers to submit to scientific journals in plant science, which will describe the successful replacement of the phenylalanine residues by tyrosine. We have submitted a grant to the National Institutes of Health which requests funding for the development of a model plant that will express the mutant protein for the first time. We have also begun discussions with a horticulture scientist from Purdue University with the aim for expressing one or more forms of the phenylalanine free gamma zein in a crop such as potato. A more detailed report will follow in a later edition of this newsletter.

Bryan E. Hainline, MD, Ph.D.

Mustapha Benmoussa, Ph.D.

2001 Family Camp

The following PKU Family Camp summary was written by a mother (K.S.) from Michigan. She wrote it to the PKU Listserv the day after the end of camp. We got her permission to reprint it here, and felt that it described this year’s camp much better than any of us could have done.

Good Morning Everyone,

I wanted to take a moment to share with you another great year at the
Illinois PKU camp!! Once again my son, his good buddy and her
mom and I arrived at the camp first thing Saturday morning. We were so
happy to see the familiar faces from last year and to also see some new faces
of families we were looking forward to getting to know.

Soon after we settled into our cabins we headed off for a hike through the
woods to the cafeteria that offered a wonderful spaghetti lunch with a PKU
line and a "regular" food line. They had Italian ice for dessert and the
kids all thought that was great. Right after lunch we headed back to the
camp ground only to find this HUGE castle moonwalk just waiting for excited
children to fill it with laughter and fun.....and before you knew it the fun
had begun!! The moonwalk was up all day so the kids could come and go as
they pleased to get the most of the action!!

In the early afternoon everyone gathered at the indoor pool to splash, laugh
and just have some good ol' pool fun. This was great for the kids to get
reacquainted with one another and to have the opportunity to make some new
friends. After swimming everyone headed to the main building for crafts and
hayrides. The crafts were just as creative as last year.....snow globes for
Christmas and chalk board turkeys for Thanksgiving. And craft-making fun
was not just had by the kids but by the adults as well!! Everyone took
turns taking the hayrides and that was a great time to relax and enjoy the
beautiful day we had been blessed with. Another nice gesture was the fact
that a table was set up constantly with an unbelievable variety of PKU foods.
Some foods the kids were familiar with and munched away at them and others
were items they had never seen before. This gave them the chance to try some
new foods and to have the comfort of snacking while still complying with the
diet.

Dinner time arrived before you knew it!! Mini low-pro pizza shells had been
made so the kids had a blast making their own personalized pizza's just the
way they like them. After dinner the campfire was roaring bright and warm
and everyone sat around enjoying cotton candy made right before their eyes
and roasted marshmallows. But the fun wasn't over yet.....whew....can you
believe it!! Just as the stars were coming out we took a short walk over to
the rec center where there was dancing, games and fun had by all. It was a
perfect time to let everyone just let loose and burn off whatever energy they
had left....and for us adults I know at that point it wasn't
much...HA!!....the kids on the other hand were going strong!! After a
completely fun-filled day bedtime had finally arrived. The weather was
really perfect and provided a very comfortable night for sleeping.

First thing the next morning we were presented with yet another great spread
of low-protein and regular foods. The kids could have anything for breakfast
they wanted!! After breakfast we were off for more fun and games. This
time the kids were put into different groups and able to work together as a
team. They all seemed to really like that. They had hoola-hoop
contest....water balloon toss....t-shirt relay....water bucket relay and
tug-of-war. The morning ended with everyone being a winner and prizes for
all the kids to enjoy.

The weekend was a great hit!! Everything was so organized and ran so
smoothly. There was never a dull moment or any confusion. I can't thank the
parent board from Illinois enough for all their hard work and caring efforts
that went into making this another great year!!

As we were pulling out of camp after saying our good-byes it was amazing that
yet another year had gone by....time goes so quickly. But it was exciting to
know that next year we will be back and we can't wait to see what adventures
will be in waiting for us!!

To the Illinois parent group and everyone who helped to make this a weekend
of memories we will never forget....a heartfelt thank you!!

2001 Northern Illinois Picnic

It’s Raining, It’s Pouring, the Old Man . . .

Sure wasn’t doing any swimmin’, but those who attended the Northern Illinois Picnic still had a good time. On August 18^th, a small group of families gathered at a neighborhood swim club in Naperville for the Northern Illinois Picnic. Attendance was smaller than anticipated because of a torrential downpour that lasted nearly all day. But the rainy weather didn’t stop the show; instead, we gathered indoors and ate lots of great PKU foods. While the adults were visiting with one another, the kids played some games (modified for indoors). We had different sizes of beach balls that were "door prizes" for the kids. Since we couldn’t toss them around in the water, we blew them up and played with them in the clubhouse. The kids each took turns rolling around on the super duper sized beach ball and later played a modified game of volleyball with the smaller beach balls. The volleyball game ended in a tie – mainly because it was difficult to tell when either team won a point due to the absence of a net! When there was a break in the rain and it looked like we would be able to go into the pool, flashes of lightening appeared in the sky. So, we played outside for a bit (but stayed away from the water). We came back indoors when the rain returned and R. C. led the kids in another round of fun games! We sent everyone home with some leftovers and some PKU products that we had for sampling. All in all, despite the rain, we had a fun time. But, for next year, we decided to stop foolin’ with Mother Nature and plan the pool party as an indoor, winter event for the Schaumburg Waterworks.

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Last modified: January 09, 2004