DURHAM, N.C. ( Ivanhoe Newswire) - It can kill kids before their first birthday. The infantile form of pompe disease is a death sentence if not treated, but now there's something keeping kids alive longer.
If Haley Hayes' parents could have one wish, it would be a cure for their six-year-old daughter. Haley was diagnosed with pompe disease, a fatal, genetic illness when she was six months old.
"It was awful," Krystal Hayes, Haley's mom, told Ivanhoe. "That was probably just the worst news you could ever hear."
Haley lacks an enzyme that helps break down sugar so it builds up in her heart and skeletal muscles, damaging them. She can't walk but she canget around, and she loves to talk.
"I do art and I watch TV, and I play Wii or Nintendo sometimes," Haley Hayes said.
When Haley was diagnosed, most babies with pompe disease died. But, a once-a-week infusion given while Haley paints has changed everything.
"We know it's basically keeping her alive at this moment," Krystal said.
Myozyme replaces the enzyme Haley lacks. Without it, most babies didn't make it to their first birthday.
"It's similar to providing insulin to someone who has diabetes, so she needs to have this enzyme given to her throughout her life course to be able to live," Priya S. Kishnani, M.D. at Duke University Medical Center, explained.
Some patients create antibodies that prevent them from responding to myozyme. Duke Doctors found three chemotherapy drugs that wiped out the harmful antibodies in infants, allowing them to respond to myozyme. These babies would have died, but the oldest is now five.
"It allows children to live," Dr. Kishnani said. "It allows them to have dreams, to be able to go to school, to ride a bicycle, to celebrate birthdays."
Haley doesn't let it slow her down. Her parents cling tight to hopes for a cure and enjoy each precious day.
"Just treasure every milestone," David Hayes, Hayley's dad, said.
While Haley takes myozyme once a week, most patients take it once every two weeks.
Myozyme is not a cure. Since it's so new, doctors don't yet know how long kids treated with it will live. The oldest living child taking it is 13 years old. Doctors said it's vital to start children with myozyme as soon as possible.
BACKGROUND: Pompe disease is an inherited, neuromuscular disorder that causes progressive muscle weakness. It is a rare disease, affecting about 1 in every 40,000 births. Pompe disease is caused by a defective gene that results in a deficiency of an enzyme known as acid alpha-glucosidase (GAA). The lack of this enzyme results in excessive build-up of glycogen -- a form of sugar -- in a specialized compartment of muscle cells throughout the body. Researchers have identified up to 300 different mutations in the GAA gene that cause the symptoms of Pompe disease. The severity of the disease and the age of onset are related to the degree of enzyme deficiency. There are two types of Pompe disease. These include: • Early onset (the infantile form): This is the result of complete or near-complete deficiency of GAA. Symptoms such as feeding problems, poor weight gain, muscle weakness, floppiness, and head lag usually start during the first months of life. Respiratory difficulties are often complicated by lung infections. The heart is also very enlarged. Many infants with Pompe disease also have enlarged tongues. Most babies die from cardiac or respiratory complications before their first birthday. • Late onset (juvenile/adult form): This is the result of a partial deficiency of GAA. The onset can be as early as the first decade of childhood or as late as the sixth decade of adulthood. The primary symptom is muscle weakness that progresses to respiratory weakness. The heart is usually not involved. (SOURCE: NIH)
MYOZYME: Myozyme is a lysosomal glycogen-specific enzyme that essentially replaces the enzyme Pompe disease patients are lacking. The treatment has to be given throughout the course of a patient's life. "This is the first lifesaving treatment that is FDA approved for Pompe disease," Priya S. Kishnani, M.D., C.L. and Sue Chen Professor of Pediatrics/Division Chief, Medical Genetics, Duke University Medical Center, told Ivanhoe. "Prior to 2006, there was no treatment for Pompe disease other than symptomatic care."
HELPING MORE KIDS SURVIVE LONGER: Some children develop an immune reaction that blocks the effects of Myozyme treatment. However, researchers at Duke, along with collaborators at other centers, have found that a very low-dose combination of medicines typically used to treat cancer is successful in eliminating or preventing the immune response in these patients. The drugs -- rituximab, methotrexate, and gammaglobulins -- are a mix of chemotherapeutic agents. The chemo drugs allow the patients to tolerate and respond to the Myozyme treatment, which is the only therapy for these kids. "It was really rewarding because the babies did not make antibodies and continued to do well clinically," Dr. Kishnani said. "The oldest child is now over 5 years of age, remains antibody-negative and has come off all chemotherapy." Dr. Kishnani says prior to the chemo discovery, children who developed antibodies and could not benefit from Myozyme would have died. (SOURCE: Duke University press release)
Dr. Priya S. Kishnani, a professor of Pediatrics, Division Chief of Medical Genetics at Duke University Medical Center, talks about helping kids with a fatal genetic disease live longer than ever before.
What is Pompe disease?
Dr. Kishnani: Pompe disease is a genetic condition. It is a neuromuscular disorder which affects primarily the heart and skeletal muscles. It affects individuals at all ages right from birth to as late as the sixth decade of life. It is caused by the deficiency of an enzyme which is called acid alpha-glucosidase. This enzyme helps breakdown glycogen. When this enzyme is deficient, glycogen builds up in the various muscle tissues of the body including cardiac and skeletal muscle.
What is the prognosis for a young child who has this?
Dr. Kishnani: Pompe disease is a continuum of disease spectrum. At one extreme is the infantile presentation where babies are extremely hypotonic, have significant cardiomyopathy and typically die within the first year of life without any intervening therapy. The cause of death is usually cardiorespiratory failure. It is a lethal disease. For patients who have the later onset forms of Pompe disease, survival is increased, but there is still significant morbidity and early mortality even with adults with Pompe disease.
Can live to be an adult with Pompe disease?
Dr. Kishnani: It is important to recognize that it is a genetic condition, so all of patients who have the genetic defect have Pompe disease right from birth. It is the nature of the mutations of the genetic changes which determine when individuals start manifesting symptoms of the disease. For the infantile form of the disease, they have what we call 2 deleterious mutations, which results in minimal to no residual enzyme activity of the acid alpha-glucosidase. As such, they present very early and die within the first year of life. In contrast, adults have genetic changes, which are not as severe as in the infantile form and thus they have some residual enzyme activity. . As such, they can present later in life and thus live to be older.
Can you tell me about Hailey?
Dr. Kishnani: Hailey has what we call classic infantile Pompe disease, where the residual enzyme activity is close to zero. Hailey presented in the first few months of life with cardiac involvement. She had a thickening of the heart muscles and also progressive skeletal muscle weakness. She became progressively weaker. She was unable to lift her head, unable to roll, unable to sit. Without therapy, Hailey would actually never learn to walk on her own and she would have typically succumbed to Pompe disease by the time she reached her first birthday.
What is the treatment for Hailey's type of Pompe Disease?
Dr. Kishnani: Hailey has infantile Pompe disease and as I mentioned, in this form of the disease, there is minimal to no residual enzyme activity which is acid alpha-glucosidase. That is the enzyme missing in Pompe disease. For Hailey to live, she required replacement of the missing enzyme in her body, which is acid alpha-glucosidase. It is similar to providing insulin to someone who has diabetes. She needs to have this enzyme given to her throughout her life course to be able to live. The treatment that was developed at Duke in collaboration, with Genzyme Corporation and with the patient foundations, started with clinical trials enrolling babies with the infantile form of the disease to see if they would benefit from providing the missing enzyme acid alfa glucosidase. .
And so before the clinical trial, was there any kind of treatment at all?
Dr. Kishnani: This is the first life-saving treatment that is FDA approved for Pompe disease. Prior to 2006, there was no treatment for Pompe disease other than symptomatic care. What one could do was provide palliative care such as medications, to help the heart failure, helping the child breathe with ventilator support, providing nutrition via nasogastric or G-tube feeds and comforting the baby. But the outcome no matter what we did was death, still within 1 year of life.
If Hailey was born prior to 2006, she would not have lived as long as she has, correct?
Dr. Kishnani: Correct. There were clinical trials that were ongoing from as early as 1999 and 2000 at Duke University Medical Center, but this was just for a handful of babies that qualified for this clinical trial. In reality, prior to 2006, there were only a few centers that were participating in clinical trials where these babies had an opportunity of life. Otherwise, these babies succumbed to the disease.
Does everybody respond to this treatment? Can you become resistant to it?
Dr. Kishnani: In essence, the therapy is to provide the missing enzyme. However, we have to recognize that if we start the therapy late, if the baby is very involved and has suffered what we call, irreversible muscle damage, then the therapy has limited benefit except the heart muscle, which we know is extremely responsive no matter what stage of the disease we identify the children. For skeletal muscle there is a point of no return in the sense that if there is fibrosis or scar tissue, or end-stage damage to the skeletal muscle, then giving the enzyme does not help the situation. This comes to the point of early diagnosis and the role of newborn screening for Pompe disease especially for the infantile form of the disease. There are some babies who do not respond as well even if you start them early. These are babies that we call CRIM negative or cross-reactive immunological material negative. These are babies who have absolutely no residual enzyme. There are also some babies who may have some residual enzyme, what we call CRIM positive, but in essence although these babies have the native enzyme, it is so unstable that they are acting like a CRIM negative baby. These babies, when they receive the recombinant enzyme or the treatment, start to recognize this as a foreign agent because the body has never been exposed to it before. They mount what we call an antibody response to the administered enzyme, and as the antibodies start to rise, it blocks the efficacy of the administered enzyme and over time these children start to decline. They can show an initial improvement, but once the antibodies start to rise, we see that these children start losing motor benefits as well as cardiac benefits. They actually succumb. Duke was involved in the understanding of the role of antibodies in Pompe disease, but I think it is really opened it up for the field of therapeutic proteins that there is a negative impact of antibodies when they are high and sustained for a prolonged period of time.
Can you tell me about your study?
Dr. Kishnani: We started to recognize quite early on that there was a subset of patients who did not do well. There are many factors that can result in this, including the age and the stage of the disease when you start these babies on the treatment. The one thing that we did recognize was that looking at 2 cohorts of children, started at similar age and stage of disease, there was one separating factor. Those who developed antibodies to the recombinant enzyme did poorly uniformly. When I say that is, after showing an initial response, they declined and either became ventilator dependent or they died by about 27 months of age. In contrast, the babies who did not develop an antibody response and were otherwise similar to these so-called CRIM negative babies, are actually alive and up to age 13 years old, going to school and continuing to make motor gains.
How about the chemotherapy drugs?
Dr. Kishnani: This made us realize that we had to do something to first identify these patients who are at risk of making antibodies. Second is to treat them in a way so that they do not mount the immune response or make antibodies. We worked collaboratively with Genzyme and with immunology colleagues at Duke and from around the world to come up with treatment strategies for babies that were at risk of making high , sustained antibody titers to the infused enzyme. . Our first step was to develop a CRIM assay which allowed us to identify the CRIM negative babies, the ones at greatest risk for developing antibodies to the infused enzyme. The second step was what do we treat them with? We used certain agents that have been used in autoimmune conditions, which are known to make antigens to antibodies to one's own body or self, and took the lessons from those conditions to say, could we use these agents in Pompe disease? We had success with use of an agent called Rituximab, which acts on B cells which is a source of making antibodies. We added methotrexate, which has been used as a chemotherapy agent, but in very low doses, and combined it with Rituximab because methotrexate acts on rapidly dividing cells including T cells as well as B cells. Both the T cells and the B cells play a role in making antibodies. When we use these 2 agents in combination at rather low doses, we had actually very good success. It was really rewarding because the babies did not make antibodies and continued to do well clinically. In fact, the oldest CRIM negative child treated with these agents is now over 5 years of age; remains antibody negative, has come off all chemotherapy and is doing well.
Is he still on Myozyme?
Dr. Kishnani: Yes. It is very important that they continue to receive the Myozyme. In the past, if they did not receive the chemotherapeutic agent, it was as though you were not giving them Myozyme, because essentially the antibodies were blocking the action of the Myozyme. As a result, it was not entering or reaching the target sites, which was the heart or the skeletal muscle and the babies were declining.
Is this a big breakthrough?
Dr. Kishnani: I think so as it has the potential to help in other conditions treated with a therapeutic protein where the patients develop antibodies. Pompe is a large part of my life, it is my passion and these babies are so fragile, to see them improve is very gratifying. . It has larger implications to other conditions, which are treated with a therapeutic protein where there is an antibody response. I think Pompe disease has paved the way on many fronts. One is, it is a perfect model because of the rapidity of the disease progression. We can tell if a therapy works or not as compared to other diseases which are more slowly progressing. In other conditions, even if they do develop antibodies, sometimes it takes years before you recognize the negative impact of those antibodies on the patient's clinical response. That is one way where Pompe has helped. The second is that the success that we have seen by using these agents in Pompe disease, I think clearly opens it up now for using in other conditions where antibodies are an issue.
Hailey is taking the Myozyme, but she did not use the chemotherapy drugs, correct?
Dr. Kishnani: This is correct. Hailey continues on Myozyme intravenously which is close to a 4-hour infusion. She has not required the need for any kind of immune tolerance induction therapies because she is CRIM positive and also because she has tolerized to the Myozyme. By this, I mean that she has not made antibodies and now is antibody titer free, several years into therapy.
Could she need it in the future?
Dr. Kishnani: No. The babies who would make antibodies to it, or even adults who may make antibodies to therapeutic protein, you typically see it when they are first exposed to it. Some of them do make antibodies at the earlier time points and then over time, they tolerize to it, in the sense that the antibody titers start to come down. The patients, who are at risk, where they are treating the administered enzyme as foreign, continue to make antibodies, so we would know that pretty early in the disease that these are the ones who are continuing to make antibodies.
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