First Treatment for Genetic Disorder-- In-Depth Doctor’s Interview

Ivanhoe Broadcast News Interview with

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Eric Crombez, M.D., Assistant Professor and Biochemical Geneticist<o:p></o:p>

<st1:place w:st="on"><st1:PlaceName w:st="on">David</st1:PlaceName> <st1:PlaceName w:st="on">Geffen</st1:PlaceName> <st1:PlaceType w:st="on">School</st1:PlaceType></st1:place> of Medicine at UCLA<o:p></o:p>

Las <st1:place w:st="on"><st1:City w:st="on">Angeles</st1:City>, <st1:country-region w:st="on">C.A.</st1:country-region></st1:place><o:p></o:p>

TOPIC: First Treatment for Genetic Disorder<o:p></o:p>

Date of Interview: April 18, 2007<o:p></o:p>

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Can you explain for us what Hunters Syndrome is?<o:p></o:p>

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Hunter Syndrome is a type of lysosomal storage disorder. Patients with this disorder are missing an enzyme that is meant to break down waste products, and it builds up in the lysosome, eventually causing cell death and then tissue and organ damage.<o:p></o:p>

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How common is Hunters Syndrome?<o:p></o:p>

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This is not a very common disorder. The incidence for this lysosomal disorder, and storage disorders as a group, runs between one and forty thousand, all the way up to one in a million. This is one of the more common lysosomal storage disorders, probably closer to 1/132,000 to 1/165,000 in males.<o:p></o:p>

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What are some of the early symptoms of this disease?<o:p></o:p>

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Children with the classic form of the disease have early-on coarsening of the facial features. The best way to describe this is that their skin starts to look older than their age. This is due to a buildup of material in the skin and connected tissue. Early on, they can have problems with hernias because their connective tissue is weaker and they have liver enlargement because of storage material. Also a slowly progressive stiffening of the joints occurs and can cause problems with movement and range of motion.<o:p></o:p>

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How serious can this condition be?<o:p></o:p>

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This condition is slowly progressive, and does become life threatening. In the classic form of the disease, we really would like to identify these children before their first birthday so we can get them started on treatment to get the best response possible. Without treatment, very few of these children will make it past their tenth birthday.<o:p></o:p>

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How difficult was it in the past for Doctors to be looking at a disease there is no treatment for?<o:p></o:p>

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That is one of the hard things about genetics. Up until recently, it really was a research field. It was the type of disease that we were able to diagnose; we could give the prognosis, supportive treatments were available, and that helps the quality of life. <o:p></o:p>

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We really weren’t able to treat many of these disorders. That’s why I went into the specialty because with biochemical genetics, we have a lot of treatments coming down the line, and I really wanted to be able to treat genetic disorders and not just be a researcher.<o:p></o:p>

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How do you detect it? How do the parents know if their kids have it?<o:p></o:p>

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It can be very difficult early on and the difficulty falls really on the primary care provider. They really need to start looking at a clustering of very common signs and symptoms which can be easy to miss. They tend to have recurrent ear infections, hernias, noisy breathing because of all of the congestion, and this can be very common and easy to miss in the pediatric population. They do start to have stiffening, which is always abnormal in children. They do eventually have coarse facial features where it becomes obvious, but again, we want to diagnose those symptoms as soon as possible so we can start treatment, and have the best chance and the best outcome. Once they’re referred to us, we can do enzymatic or gene testing to confirm the diagnosis<o:p></o:p>

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What is gene testing?<o:p></o:p>

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It is a blood test to measure the activity of the enzyme. These patients will essentially have below 5% of activity. <st1:City w:st="on"><st1:place w:st="on">Normal</st1:place></st1:City> is very close to 100, and we can then look at the gene for changes and mutations.<o:p></o:p>

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What do you use to treat this disease?<o:p></o:p>

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It’s always been supportive care; if they need respiratory support we can do that and help them with their recurrent ear infections. They need a lot of antibiotics, tubes in their ears, physical therapy to maintain their range of motion as long as possible, and those types of supportive things can help their quality of life. However, that never reverses or stops the progression; it just helps the quality of life.<o:p></o:p>

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How does the new therapy Elaprase work?<o:p></o:p>

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Elaprase is a new therapy for Hunters Syndrome that just became FDA approved this summer. It is an enzyme replacement therapy and we now have a group of therapies for lysosomal storage disorders. This is just one of the newest ones that became available, and while the technology is very difficult and took some time to work out; really it’s a very simple idea. We are simply growing large amounts of the enzyme and then infusing it back into the patient. It does require an IV infusion, so they need to receive this in an infusion center. This is a lifelong infusion treatment at this point. This treatment is once a week where some of the other treatments are once every two weeks, which sounds very straight forward, but does become a burden for the families, because it is a half a day in clinic for us, where the kids are missing school and parents do need to miss work. Hopefully, once we establish this treatment as safe, we can move it into the home so they don’t have to miss as much school and work.<o:p></o:p>

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With this treatment, are you just stopping the progression of the disease, or is it actually helping?<o:p></o:p>

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It depends on how early you are diagnosed, how early you start treatment, and then how severe it is. It is a spectrum of science and symptoms, some people are more mildly affected and they’re going to respond better. With this specific disorder, we are trying to mostly stop the progression of the disease. We do see some improvement in symptoms like the big liver and problems with the connective tissue. The bones are more difficult, because they don’t have a very good blood supply, so it’s difficult to get the enzyme there. If we get them early, we can stop them from occurring all together. At this point, we can’t reverse all the damage to the skeletal system, but it is an improvement so we’ll see what happens two years from now. We don’t really know how much improvement to expect from some of the signs and symptoms. Some of them we actually do see improvement, the technology is available, to do the newborn screening for these disorders. No state has started to do newborn screening fir these disorders yet, but that will be something that will come down the line Those kids will be identified prior to any onset of symptoms and you know, possibly started on treatment very early.<o:p></o:p>

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Once they start on this drug, what is their prognosis from that point? How is it different?<o:p></o:p>

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The prognosis is going to change, but we don’t have a lot of experience with this medication. Were not so sure how much this prognosis is going to change, but patients are living longer, we’ve already seen that, we’ve seen much fewer hospitalizations. A lot of times, these patients are hospitalized with minor colds, just because they do not have the reserve to support themselves, so we are improving the quality of life, we are keeping them out of the hospital, and their life expectancy will increase quite a bit.<o:p></o:p>

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Is there any way to know how long these patients will live?<o:p></o:p>

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Not at this point, we’ve just had such limited experience with this, but I think without treatment you can roughly expect them to live to around ten years of age. I don’t know how much we’re going to improve, I don’t think at this point you can say they will have a normal life expectancy, but it will improve quite a bit. The other half that makes this difficult is they do have an impact on the neurologic system, their brain development, and we’re not able to treat that yet. These enzymes are very big and don’t get across the blood brain barrier, so we can’t treat the brain manifestation. There is a lot of work, a lot of effort to improve the neurologic outcome, and that will be the next step for the treatment of this disorder<o:p></o:p>

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What kind of side effects would the drug have?<o:p></o:p>

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The side effects are very limited; this is an enzyme that people normally made, so you don’t see the toxic effects that you would see with a lot of medications. The problem that we do have is that you can have an allergic reaction to this. The enzyme is a protein, and if the patient is not making it, or recognizing it, you can have an allergic reaction to this medication. We do sometimes see some other infusion related reactions because it is a large amount of protein being infused all at once, we can see some problems there. The clinical trial has also shown that this is very safe and that the reactions are very minimal. We do have ways to treat these reactions if they occur, so overall very safe medications.<o:p></o:p>

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How big of a breakthrough is this for Hunters Disease?<o:p></o:p>

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For this disease, it is the first treatment for this disorder. Prior it was always a supportive improvement of the quality of life, but it did not stop the progression of the disease. This absolutely stops and improves this disease, so it is a true treatment for this disorder.<o:p></o:p>

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How important is this step in treating this disorder?<o:p></o:p>

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In the field of genetics it is great to be able to now start treating disorders. Genetics was a field that was primarily research based and how we’re able to translate those research results into treatment, to improve these disorders and improve patients’ lives, which as you know is a very big improvement, a very big step forward for the field.<o:p></o:p>

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Is there any reason to think that a patient would be able to take this type of treatment for the rest of their lives?<o:p></o:p>

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It’s a lifelong treatment; most of the problems we see with this are manageable. We can use other lysosomal storage disorders for which we have had enzyme replacement therapy for quite some time as a model. We’re not seeing any problems develop over the course of their lives and this is a very long-term treatment. The hope is that we are moving forward with better treatments and improved treatments so things would continue to get better and better.<o:p></o:p>

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What do you think is the next step?<o:p></o:p>

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The next step is getting around the blood brain barrier, so we can treat the brain manifestations. This enzyme will work if we can get it to the brain. Clinical trials are ongoing to test the delivery methods. There’s also development of new medications that are small enough to get across the blood brain barrier, and with the hope that some sort of infusion or oral medication can impact the neurologic manifestation, those are going to be the next types of treatments that come down the line. Ultimately, we talk about gene therapy and these disorders are very good candidates for that. We keep saying we’re ten years away from gene therapy being a reality, but ten years hasn’t improved in the last few years, but we’ll see, it will come.