Exploring Mucopolysaccharide storage disorders (MPS) and therapies over the last one hundred years.
Mucopolysaccharide storage disorders (MPS) are rare inborn metabolic diseases with genetically based enzyme defects involved in the internal cell metabolism of each cell. These enzymes are responsible for the degradation of glycosaminoglycans, complex sugar molecules in the matrix of connective tissue, such as the responsible material in the fibre and cell surrounding substance in the bones, the cartilage and fibrous tissue.
Glycosaminoglycans (GAGS) are composed of many glucose and galactose molecules and have further chemical side chains, involving acidic acid and sulfate groups. MPS are produced and formed properly by the cells, but they have to be exchanged and renewed because of aging and damaging processes. During this process, the GAGs need to be cut into smaller pieces, to bring them into the cells by phagocytosis (‘cell-eating’), breaking them down into the smallest molecules by the lysosomes.
MPS’ are caused by deficient enzymes
For the GAG chain degradation, at least 11 enzymes are known to date. As each enzyme is the gene product of a responsible gene, there are at least 11 genes involved, which can be – in case of the MPS – mutated. So far, we know of 11 different forms of MPS, numbered from MPS I to MPS IX, also known by the names of the first describers: Hurler, Hunter, Sanfilippo, Morquio, Maroteaux-Lamy, Sly etc.
Some of these MPS types show similarities to the clinical symptoms, such as the storage of non-degraded material in skin, mucosa, and organs or brain (MPS I, II, VI or VII). Others, however, show severe skeletal deformities (MPS IVA and MPS IVB). Furthermore, some of them show severe storage in neurons with the consequence of increasing damage to the central and vegetative nervous system (MPS IIIA-D). In all of these genetically caused diseases, symptoms are increasing over time, leading to severe chronic diseases with death in childhood or adolescence if not treated correctly.
First published patients one hundred years ago
More than a hundred years ago, the first patients were examined by medical doctors and researchers. Since that time, the first therapies started to prevent the chronic disease and escalating problems. The swollen appearance of the patients combined with impaired intellectual abilities showed some similarities with patients suffering from low function of the thyroid gland (hypothyroidism). It is therefore not surprising that the first patients of Gertrud Hurler and Meinhard v. Pfaundler were treated with iodide supplementation, which did not show a positive effect.
Soon afterwards, a connection of the MPS disorders with connective tissue was suspected and treatment was started with supplementation of ascorbic acid and corticosteroids, known to be beneficial for connective tissue. In the 1960s, Elizabeth Neufeld and her co-workers observed a decreasing storage of cell cultures with fibroblasts from different patients via unidentified ‘corrective factors’ in the culture media, transported from one cell type to the other. If cells in culture were able to produce something which could reach other cells, it should be possible to treat patients with blood transfusions and leucocyte or plasma infusions. In fact, there were many reports describing a positive effect, but infusions, immune-tolerance and improvement of clinical symptoms were limited. The implantation of fibroblasts from healthy donors and even organ transplantation were performed with very limited effect. The other method came with the high risk of rejection and death. At this time, this was not safe and effective enough for a prevalent treatment.
The need of a well-tolerated treatment
From that point of view, it is understandable, that one was looking for immunologically well tolerated cells obtained in high numbers, and those cells were placental cells and amniotic membranes. The next stage of treatment was the implantation of folded amniotic membranes into the abdomen of affected patients, under the skin or even under the conjunctiva of the eyes in the cases with corneal clouding due to storage. Effects were promising, but limited.
Hand in hand, the first therapies started by influencing the production of glycosaminoglycans with all necessary components. Wasn´t it possible to reduce the production by offering decreased amounts of sulfate groups?
The first trials included a diet with low methionine concentration and started as the so-called methionine-restricted diet. Methionine is known to be the main source of sulfate groups in the organism. Therefore, if affected patients get food, fruits, vegetables, and drinks, these were always offered with the lowest content of methionine. The methionine content could be seen in alimentary lists with all ingredients, vitamins, and smaller molecules. The effect could not be proven, and methionine was recognised as necessary for the proper function of vitamin B complex.
Enzyme deficiencies are responsible for MPS
Enzymes have been recognised as responsible for the clinical symptoms of affected patients. They’re produced by both humans and animals and could be extracted from fluids and tissues. At this time, the necessary methods and columns for extraction and purification were known. Extensive productions were made out of human placental tissue, but even the human enzymes were not effective enough as the stability was low, and the protein-rich material was the source for allergic reactions. Much later, a different modification of enzymes in other species was observed, which also explained the missing effect in human organisms.
At the same time, brewer´s yeast was also offered to patients to drink. The yeast contains numerous enzymes, including enzymes that are deficient in MPS patients. Since there was no real effect, the enzymes – which consist of protein – were degraded from the digestive tract.
Wouldn’t it better to implant directly into patients these enduring, enzyme producing cells which could even migrate to different organs? The consequences were the first bone marrow transplantations starting more than 30 years ago. However, the procedure was dangerous. Two main problems were identified after the first experiences: some patients suffered from rejections or severe graft versus host reactions which were life-threatening; furthermore, the effect was minimal when the patients were older at the time of treatment. Any damage caused by the disease could not be reversed and cell migration into the brain was observed only within the first 18 to 24 months. In cases of severe brain involvement, the low numbers of invading cells were not enough to show a positive effect.
New strategies for the treatment of MPS
Lessons learned in the past regarding treatment regarding all successes and failures, influenced therapeutic options in the future greatly. In reality, the treatment with haematopoietic or umbilical stem cell transplantation is an effective and routinely performed treatment for some of the MPS types. In the very near future, there could even be autologous transplantations of genetically corrected cells from the patient themselves, for instance with viral vectors combined with an unmutated enzyme producing gene. One of the main conditions for this however is an early diagnosis. Some countries have already started to include treatable MPS types into newborn screening.
In patients with some residual activities of enzymes, stimulation of a higher gene expression or reduction of the substrate (GAGs), could be an option for the future, as it is already performed in other lysosomal storage diseases such as Gaucher´s disease. In the past, many efforts were exerted to distribute human recombinant enzymes in sufficient amounts and in a safe manner. This very important and successful milestone began 15 years ago, with the first enzyme replacements therapies, which are available now for MPS I, MPS II, MPS IVA, MPS VI and MPS VII.
These encouraging strategies and results will facilitate in the future that every MPS patient will get his or her individual and personalised therapy. However, this aim is not yet reached. Efforts, pharmaceutical research, medical understanding of the diseases and political responsibility must continue.