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[start page][clinical
aspects][biochemical info][genetics][therapeutic approaches]
Alpha Mannosidosis: Information for Families & Professionals
There is a possibility of prenatal diagnosis. The frequency of these genetic metabolic diseases is low (between 1:10.000 to less than 1:100.000, unless diabetes or hyperlipoproteinemia is included). Prenatal diagnosis, which means diagnosis of the child before birth, of potential inherited diseases is therefore only done when one child in the family (The so called Index Case) is found to have a lysosomal disease. If the fetus has a serious disease, abortion can be performed if the family wish to. Prenatal diagnosis is a two step procedure, with sampling of fetal tissue, followed by analysis. The trend in the later years is to perform chorionic villus sampling, which means that a small specimen is taken from the placenta by needle aspiration under the guidance of an ultrasound probe. It is performed in local anesthesia and sampling may be carried out as early as in the 6-8 week of the pregnancy, although sampling somewhat later is safer for the fetus. The fetal cells are separated from cells from the mother and analyzed biochemically or with DNA analysis. Early amniocentesis means that a sample from the fluid surrounding the fetus is aspirated. This fluid contains both metabolites useful for the diagnosis as well as cells from the fetus, which can be cultivated and analyzed. Culture of cells taken at 7-11 weeks age of pregnancy is proving to be more difficult than from fluid sampled after 11 weeks.
When lysosomal storage diseases were discovered, hopes were raised that this could be treated by enzyme substitution. When exogenous lysosomal enzymes are injected into the patient, this enzyme can eventually be taken up by enzyme-deficient cells. This uptake is regulated by certain receptors on the cell surface. Different tissue have different receptors. It is therefore necessary to change the natural enzyme to enable uptake into the tissue of interest. If properly designed, the missing enzyme could be injected regularly like the diabetic subject injects insulin. In many in vitro studies with the purified active enzyme added to the media of enzyme-deficient fibroblasts, the lysosomal substrate accumulation was corrected, but in vivo treatment has been hampered through the problem of producing the sufficient quantity of enzymes, immunological problems, and that the substituted enzyme does not pass the blood-brain barrier. Since it can be expected that enzyme supplied from outside does not pass the blood brain barrier, suitable candidates for enzyme replacement are disorders without neurological involvement (e.g. Maroteaux Lamy, Morquio B, Fabry, late onset Pompe disease).
However, it took 15 years after the publication of the paper "Toward Enzyme Therapy for Lysosomal Storage Diseases" before the first patients with Gaucher disease were treated successfully. This reflects the time lag between idea and reality. However, compared to other lysosomal storage diseases, the prerequisite for enzyme replacement are especially favorable in Gaucher, since accumulation of storage material is restricted to the cells which preferably take up the substituted enzyme. Gaucher patients frequently suffers from skeletal abnormalities and it seems that after start of enzyme replacement, no new skeletal abnormalities will develop and bone abnormalities may also be reversed.
Mannosidase substitution has never been tried in humans since the correct gene has been discovered only recently. If mass production evolves, special designed enzyme could possibly relieve the symptoms in muscles, immune system and so on. It could probably prevent the development of complication on skeleton or joints. However, an effect on the current or future brain function is not to be expected.
1. The principle and the procedure:
Blood is one of the largest organs in the human body. It contains a large number of cells with unique properties. One of them is the ability to produce enzymes which can be secreted from the cells. The principle of BMT in lysosomal storage diseases is to replace the bone marrow of the patient (and thereby his whole blood system) with the one of another person who is healthy. This is called allogeneic transplantation. The transplanted tissue contains the hemopoetic stem cells, who are the origin of all blood cell and other tissue, such as tissue macrophages in the skin, lung, and liver tissue, for example. This is called the graft, and the incorporation of the graft in a new host is called engraftment. If successful, the diseased body then contains a healthy blood system.
Already in 1981, it was proposed that a bone marrow could serve as a permanent source for the missing enzyme in patients with lysosomal enzyme deficiency, and by 1996, more than 200 patients have been transplanted on this or similar indications. Following allogeneic BMT in a patient, all the offspring of the engrafted stem cells will produce the enzyme which the patient needs. This enzyme is transferred from the competent graft cells to the incompetent host cells via cell to cell contact or via secretion to the blood stream were it is taken up by the host cells. Since bone marrow derived macrophages are able to cross the blood brain barrier and reside as microglial cells in the brain, they might turn out to be a useful vector for enzyme delivery into the brain. However, the effect of BMT in lysosomal storage diseases depends highly on the type of storage disease, and at what age it is performed.
Before transplantation is performed, the blood cells of the patients needs to be killed to create space, achieve engraftment, and prevent rejection of the graft, the so called Host Versus Graft Reaction. Therefore, the patients are pre-treated or "conditioned" with cell-killing medication to reduce or exterminate his own blood cells. When the number of the own blood cells is low enough, the bone marrow from the donor is infused. After that follows a period of total 4-8 weeks (and may be even longer, depending on the procedure) in which the patient is severely exposed to infection and must be kept in isolation. Further, reactivation of previous viral infection is another problem. This makes the procedure potentially dangerous.
Another problem is tissue compatibility. Every cell in the body carries on their surface certain proteins which identify them so that the immune cells accept these other cells as "Self". It is like the ID-batches or dog-tags used by the employees of many firms. If the cells have the wrong ID, they are destructed. If the cells of the patient attack the graft from the donor, we call it a Host versus Graft Reaction (HvGR). If the graft attacks the cells of the patient, we call it a Graft versus Host Reaction (GvHR). Both are feared complications of the procedure, and may lead to disease or even death. To reduce the probability of these reactions, tissue-typing of patient and donor is performed. The most important group of identification proteins are the HLA-proteins. If the patient and donor has identical HLA-proteins, we call it a HLA-match or HLA-compatibility. If they have dissimilar HLA-type, also if only partially, we call it a HLA-mismatch or HLA-incompatibility. In this case, procedure-related complications occur more often.
To prevent these problems, HLA-matched BMT is preferred. In the huge registers of tissue types world-wide, there is always a possibility of finding a donor who is HLA-matched. With a registry of 200.000 Caucasians, 50-75% of Caucasian patients will have a match for all HLA-types. There are, however, other identification proteins, also many that we do not know of and which can not be detected in any test so far. This problem is significantly reduced if the HLA-matched donor is in the patients family (mostly siblings) and not outside. Due to the Mendellian mode of heritage there are 4 combinations of parental HLA-types possible. This means that there is a 25% chance of any of the siblings to be HLA-identical to the diseased brother or sister.
Survival of the patient is approximately 90% if a HLA-matched family donor is available and approximately 75-80% in HLA-matched non-familiar donor, whereas the success rate falls to approximately 50% if marrow from a non-HLA-identical sibling is used. Cause of death is usually GvHR, untreatable bacterial or fungal infection or reactivation if various "slumbering" viral infections, that the patient has gone through at an earlier stage. Recipients from unrelated donors show increased severity of GvHR and increased risk of graft failure. However, the success rate can vary from center to center, and some centers claim to have a 95% survival in HLA-matched non-familiar donors.
2. Indications for BMT in lysosomal storage diseases:
The ultimate law of the international medical ethics is presented in the Oath of Hippocrates. According to this oath, the duty of the doctor is to cure the patient, but even more important it is not to cause damage. Since the BMT as such can cause disease and even death, it is necessary for the medical doctor to be convinced that the disease involve a much greater risk than the cure itself, and that the cure is effective. This is often decided by local Ethical Commissions. However, it is noteworthy that Gaucher disease, a normally not deadly disease has been approved for BMT. One of the major issues concerning the role of BMT in metabolic diseases is whether metabolic correction in brain occurs and whether this results in alleviation or correction of symptoms. Circulating enzyme cannot pass the existing barrier between blood and brain to enter the brain tissue, but infiltration of cells from the donor into brain tissue may contribute to metabolic correction. Circulating enzyme can reach the outer part of the brain, resulting in a decrease of storage in these structures, which may lead to a diminution of the often associated hydrocephalus. However, the effect of BMT on brain function is variable and has to be evaluated in every single type of lysosomal disease. However, one should not focus on the brain function alone. Whatever brain function, quality of life is even more reduced if skeleton, joints, muscles, hearing or vision is disabled. Further, the individual patient and his/her potential future quality of life must be regarded in view of the society in which it lives. Some societies takes more care of its disabled citizens, whereas other societies are not able to take this responsibility.
3. Conclusions:
Despite the growing number of BMT performed in patients with lysosomal storage disease, it is still unclear to which degree this form of experimental therapy is of benefit. In contrast to inbred animal models, the natural course of the disease in humans suffering from lysosomal storage diseases is variable, sometimes even within one family. This calls for caution in evaluating the possible effects of BMT in individual patients. Notwithstanding these warnings, various common patterns emerge from the data reported so far. But all data depend on the type of storage disease in question:
To summarize, the indication of BMT in lysosomal storage diseases must be an agreement between the doctor responsible and the patient family. It is highly depending on the type of lysosomal storage disease, the age of the patient, the risk of development of complications, the already existing damage, the donor available and last not least, the standard of medical services where the diseased lives.
Conclusions for Mannosidosis: In 1996 Walkley et al published a paper on 3 kittens with mannosidosis that were treated with BMT in 1991. In the 2 animals that were sacrificed a normalization was seen, not only in the body, but more importantly, also in brain. The 3 cat is now 6 years and well. Normally, a untreated cat dies with 3-6 months. In 1987 a child with mannosidosis was treated with BMT. He died after 18 weeks due to procedure related complications. In brain little enzyme activity was found. This disappointing result could be explained by heavy immunosuppressive treatment before death, or that it takes time for the enzyme activity to increase in brain after BMT. The donor was the mother (who as carrier must be expected to have less than 50% enzyme activity) or it may be BMT in man has no effect on enzyme function in brain.
Note: for further information on BMT for mannosidosis, Professor of Pediatrics, Dr. William Krivit, University of Minnesota has much experience and will gladly accept your inquiries.
1. Introduction
The ultimate goal of treatment of genetic disease is repair of the genetic defect, which means gene therapy. The possibility of gene therapy was first discussed in the late 1960s and early 1970s, and still, in spite of extensive research, no true gene therapy has taken place in patients. This displays the immense methodological problems behind this "high-tech therapy".
2. Principles of Gene Therapy
The principle is to introduce the correct gene into the diseased cells with the incorrect gen. Usually the nucleic acid is double-stranded DNA that encodes a therapeutic protein. The correct gene must be introduced by means of a transporter, called a vector. One such vector might be viruses which have specialized for this purpose for million of years. A construct with the correct gene is introduced into the virus which no longer can replicate and cause disease. Then the diseased cells are infected with the virus, which insert the correct gene into the diseased cells. Virus like adenovirus can infect non-dividing cells, but the DNA is deposited in the cytoplasm which means that it works only for a certain period of time before it is degraded. Virus like retrovirus infect only dividing cells, but in this case the gene of interest is integrated into the cell genome. This means that it may work (be expressed) for a much longer or even infinite period of time. Therefore, one of the current strategies is to take out dividing blood cells from the patient, infect them with retrovirus with the appropriate gene, and then put them back into the patient. These blood cells might be bone marrow, or the progenitor cells which partly circulates in peripheral blood. These cells are called stem cells who will divide and produce numerous blood cells with the ability to produce the lacking enzyme. This method is not yet established since many practical problems have to be solved first:
2. Conclusions
Theoretically, the principle of gene therapy on cells from the diseased person seems like a safe and ideal approach. However, gene therapy is more a reality in the tube than it is in a living organism. There are many factors not understood and it will take many years before it is in clinical use. The enthusiastic climate surrounding gene therapy should lead to more concentrated efforts in all of these important areas of research.
Page title: Therapeutic
Approaches for Alpha Mannosidosis
URL: http://www.mannosidosis.org/alphaman/amanther.htm
Editor: Dag Malm; Webmaster: Paul Murphy
Last Update: July 11, 2000
