The goals of managing MPS I are to improve quality of life, slow down its progression, and to prevent permanent tissue and organ damage. Early intervention may help prevent irreversible damage.
The involvement of the brain in some people with MPS I presents a special challenge in devising effective therapy. This is primarily because the brain is protected from the rest of the body by a barrier (the blood-brain barrier) that controls what can and cannot enter the brain. This creates problems for treatments that are given via the bloodstream, such as enzyme replacement, for example (see below): the enzyme circulates throughout the body to treat the physical symptoms of the disorder but it does not readily enter the brain to stop the progressive decline in brain function. Researchers are therefore devising different methods by which to deliver enzyme to the brain, and progress is being made.
Several forms of treatment for MPS I are in use. These include:
Haematopoietic Stem Cell Transplant (HSCT)
Bone marrow transplant (BMT) and umbilical cord blood transplants are both forms of HSCT.
BMT involves the reduction or removal of an affected person’s bone marrow and replacing it with bone marrow cells from a tissue-matched donor who is not affected by the same condition. This donor may be a family member or an unrelated donor from a bone marrow donor panel. It can take a considerable amount of time to find a suitable donor match.
Umbilical cord blood transplant is based on the same principle as BMT but involves taking stem cells that are found in umbilical cord blood. Cord blood is collected from the afterbirths (placenta) of newborn babies (with parental consent). The baby donors are not normally related to the patient although the cord blood needs to be a suitable match for it to be considered. In all other aspects the two procedures are the same.
The principle of HSCT is that the donor cells (cord blood or bone marrow) will reproduce (or replicate) within the affected person to produce normal amounts of enzyme (alpha-L-iduronidase in the case of MPS I) to treat the disorder: the IDUA enzyme is not only produced within the transplanted cells but is also released by those cells into the circulation where it can be taken up by other cells of the body. If the procedure is done early enough in the disease course, some of the donor cells will establish themselves in the brain (by-passing the blood-brain barrier) and produce enzyme that may prevent its deterioration.
In contrast to people with cancers (where HSCT is regularly used) in the case of MPS I it is not necessary to completely remove the individual’s own bone marrow; the level of marrow reduction must be sufficient enough to allow room for the new bone marrow cells to establish and grow. A treatment necessary to reduce a person’s own marrow (known as ‘conditioning’) is used to minimise the risk of the transplant procedure. It is important to understand, however, that HSCT in all its forms is an extensive procedure that may require quite a long stay in hospital. There are still significant risks involved with HSCT, including infection, graft vs. host disease and other complications which may be life-threatening.
HSCT has been shown to have a positive outcome in altering the progression of MPS I and improving life expectancy. Many of the physical features (such as harshness of facial features, hearing, enlarged liver and spleen and heart function) may also improve following transplant. However, HSCT has less effect on the skeleton, and problems such as curvature of the spine (scoliosis), severe joint stiffness and pain, carpal tunnel syndrome and compression of the spinal cord can still occur. Considerable long-term physical, medical, surgical and psychological supportive care is necessary after successful HSCT.
In view of the risks, HSCT is not usually recommended as the first choice treatment for Hurler-Scheie or Scheie syndromes. However, it may be considered in these individuals where other forms of treatment are not available or considered inappropriate on medical grounds, or where the risks of the treatment are higher than the transplant procedure.
Currently, HSCT is the treatment of choice for Hurler syndrome. It is generally considered that if the procedure is performed within the first two years of life, brain deterioration may be stabilised or even prevented; however, once brain deterioration is significant, HSCT will not prevent further decline.
Enzyme replacement therapy (ERT)
Following extensive clinical trials ERT is now the treatment of choice for most individuals with Hurler-Scheie or Scheie syndromes. ERT is based on the same principle as HSCT except that the missing enzyme (alpha-L-iduronidase) is replaced with a pharmaceutical-grade enzyme prepared commercially and given by infusion into the bloodstream rather than being produced inside the body by transplanted cells. The advantages of ERT over HSCT are that (i) the problems and long-term risks associated with transplantation are avoided; (ii) there is no need to find a suitable donor; and (iii) there is no need for ’conditioning’. However, many of the same advantages and limitations apply: for example, the earlier ERT is commenced the better the outcome but skeletal and related problems can still develop.
The commercial name of the enzyme preparation for MPS I is called Aldurazyme. People who have received ERT over the long-term (up to 10 years) have shown it is safely tolerated. With the reduction in mucopolysaccharide storage resulting from ERT, sustained improvements have been demonstrated in endurance, walking and stair-climbing ability, joint mobility, lung function, growth and puberty. Marked improvements have also been noted in certain characteristics such as softening of the hair and facial features, and sometimes improved growth. Individuals have also noticed that their tummies are far less prominent due to the reduced liver and spleen size. However, whilst these improvements have contributed to better quality of life, patients usually continue to require physical, medical and surgical supportive therapy alongside ERT in the longer term.
ERT is not a cure and for it to be effective it needs to be given regularly during the person’s life. Currently, this is usually on a weekly basis. Infusions are usually given slowly over several hours to minimise the risk of reactions to the introduced enzyme. In Australia, infusions are usually done in a hospital setting.
In Australia, ERT is currently funded under the Commonwealth Government Lifesaving Drugs Program (LSDP) for people whose brain is not affected by MPS I. In young children where HSCT is recommended (generally those with Hurler syndrome and under two-years of age), ERT may be considered for a short period before and after HSCT: studies have suggested that it may improve the outcome of transplantation and reduce some of the risks associated with the procedure. At present, use of ERT in this way is not funded by the LSDP although this is under review. If there is uncertainty about whether an individual’s brain is affected, treatment may be approved until this becomes clear. Further information is available through the LSDP website (www.health.gov.au/lsdp) and should be discussed with your medical team.
Other combinations of ERT and HSCT are also being considered, and improved methods of HSCT are being developed. This may reduce the risks of these procedures and alter medical recommendations with regard to each treatment. The choice of treatment should always be made in discussion with your doctor and in careful consideration of all the available information.
Other forms of treatment that are being researched include:
Gene therapy, which aims to replace the defective gene with a functional one. The principle is that the functional gene will code for the normal production of the enzyme, reproduce within the cells of the body (and brain) and produce sufficient amounts of enzyme to remove stored mucopolysaccharide and prevent further storage. Unlike ERT, which requires repeated administration, it is hoped that gene therapy will be a once-off treatment.
Substrate deprivation/reduction therapy: this form of treatment aims to reduce the amount of mucopolysaccharide that is being made by the body, leading to a reduction in the amount being stored.
Chaperone therapy uses chemicals to protect and activate any enzyme that may be present in the lysosome, so as to increase its activity and ability to break down mucopolysaccharides and thereby reduce the amount being stored.
As a general rule, both substrate deprivation/reduction therapy and chaperone therapy will only work in those individuals whose mutations allow some active enzyme to be made by the body. Chaperone therapy is usually specific to the individual mutations.
For current information about clinical trials that are recruiting or underway, visit www.clinicaltrials.gov.
In common with all of the MPS disorders, treatment and management for MPS I continue to evolve so the information presented here will change with time. It is important to keep up a regular dialogue with your medical team. Regular monitoring is an important way of managing problems before they become potentially serious, and to maximise quality of life. Living with a progressive disorder such as MPS I can be difficult and challenging and this monitoring is also a way to share some of that difficulty. As knowledge is built up and shared new treatments can be developed and quality of life improved for all..