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Correcting enzyme defects using stem cells

Bone marrow transplantation was originally developed for the treatment of leukaemias and other malignant diseases of the haemotopoietic system. Thanks to increasing technological process, it has been possible to considerably expand the treatment spectrum over the last few years. Dr. Ingo Müller, paediatrician at the University Hospital in Tübingen, now uses bone marrow transplantation for the therapy of genetic metabolic diseases – with highly successful results.

Haematopoietic stem cells are multipotent cells that give rise to all blood cells in the bone marrow, including red blood cells (erythrocytes), white blood cells (leukocytes), which are cells of the immune system defending the body against infectious disease and intruders, as well as blood platelets (thrombocytes) that play a key role in blood clotting. Patients suffering from acute leukaemia who are transplanted with the haematopoietic stem cells of a suitable donor have an excellent treatment outcome. In addition, benign bone marrow diseases such as aplastic anaemia or certain immune system diseases are increasingly being treated with stem cell transplants. For quite some time, doctors and scientists have even been going one step further and using stem cell transplantation for the treatment of hereditary metabolic disorders – with incredible success.

These metabolic disorders are often the result of a genetic enzyme defect and they lead to severe damage to the central nervous system (CNS). “When you first look at it, the fact that the transplantation of haematopoietic stem cells of a healthy donor can prevent the development of a neurological disease seems very surprising,” said Dr. Ingo Müller, chief physician in the University Children's Hospital in Tübingen. However, it appears that these haematopoietic stem cells are able to cross the blood-brain barrier and differentiate in the brain into supporting cells that are able to produce the missing enzyme. This enables doctors to correct the defective cell metabolism – at least locally. “This mechanism is referred to as cross correction,” said Müller who had already focussed on this phenomenon during a several-year research stay at the St. Jude Children’s Hospital in Memphis (USA). “It is not yet known in detail what happens,” said the scientist, but the results achieved so far are extremely promising.

Protective effect

Dr. med. Ingo Müller, chief physician at the University Children's Hospital in Tübingen, uses stem cells for the therapy of hereditary metabolic diseases. © private

When he returned to Tübingen, Müller, who has a degree in medicine and biochemistry, decided to establish the transplantation of stem cells for children suffering from metachromatic leukodystrophy (MLD), a disease that until then had been regarded as incurable. This rare neurometabolic disease is characterised by a deficiency of the enzyme arylsulfatase A as a result of mutations. The enzyme is involved in the fatty acid metabolism; without this enzyme, degradation products of the fatty acids cannot be processed and they build up in the body. The CNS is the area that is the most affected of all body tissues; the myelin sheaths protect nerve fibres. Without this fatty covering, the nerve fibres are eventually destroyed and cease to function. Affected children often develop severe neurological symptoms in the first years of life; they begin to have difficulty walking, further progression of the disease leads to paralysis, the loss of the ability to talk and blindness. The earlier the onset of the symptoms, the worse the prognosis.

Previously, doctors were helpless when faced with MLD. However, it is now known that stem cell transplantation prior to the occurrence of the first symptoms, can have a positive influence on the progression of the disease in children. "None of our patients has developed MLD symptoms after stem cell transplantation. We found that stem cell transplantation definitely had a protective effect in the children treated." However, the situation is not that clear in patients who already display neurological symptoms. Studies were carried out to clarify the situation but no final statements can be made.

Mesenchymal stem cells as supplement

Mesenchymal stem cells open up new options for the treatment of neurometabolic diseases such as metachromatic leukodystrophy (MLD). © Müller, UKT

"In all cases, it is necessary to carefully weigh up the benefits and risks," said Müller going on to add "stem cell transplantation is still a very risky intervention." Although the chemotherapy, which the patients need to undergo prior to stem cell transplantation, is not as aggressive as in leukaemia patients, serious unforeseen circumstances can still occur. The rate of complications in the department led by Prof. Dr. Handgretinger at the University Children's Hospital in Tübingen is fortunately very low - partly thanks to the comprehensive experience his department has of the method. "We carry out more than 50 stem cell transplantations per year. This puts us among the leading paediatric centres in German-speaking countries," said Müller.

Müller and his team of researchers are not only focussed on haematopoietic stem cells. For a number of years, the group has also been dealing with mesenchymal stem cells (MSC). These multipotent cells represent a very rare cell population in the bone marrow and can, just like the haematopoietic stem cells, cross the blood-brain barrier. A method developed by Müller now enables the researchers to produce high enough quantities of MSC to use them for therapy. "While haematopoietic stem cells mainly regenerate the haematopoietic system, MSCs can also be used to treat other body areas," said the scientist. This raises the hope that in future, alterations to the skeleton and peripheral nerves, which are associated with many innate metabolic diseases, can be positively influenced by MSCs.

Dubious stem cell tourism

However, for both mesenchymal or haematopoietic stem cells, the transplantation of stem cells for the treatment of neurometabolic diseases is still in an experimental stage. “Our first and foremost goal must be to be able to offer affected patients the chance of a good quality of life,” said Müller who is discussing the intervention with neuropaediatric specialists led by Prof. Dr. Krägeloh-Mann. If the chances of success are too low, for example due to the fact that the disease is already at an advanced stage, the doctors will chose not to carry out a stem cell transplantation. “We do not want to expose children to unnecessary risks,” said Müller. However, in his experience, the parents often cling to this as the last hope for their child.

“Over the last few years, we have seen a great deal of stem cell tourism,” said Müller. Many patients are lured to India or China with false promises, where they pay huge sums of money to have cord blood-derived stem cells injected. This often happens without prior chemotherapy and without HLA testing. “This kind of injections are of no help at all; in addition, there is a huge risk of infection. Cells of a different HLA type are immediately rejected by the recipient’s immune system. Müller also mentioned that dubious institutions in Germany have started to offer commercial stem cell transplantations. “This is nothing short of scandalous,” said Müller who fears such institutions might discredit stem cell research as far as the public are concerned. Although current results offer hope for the future, the method is still not mature enough. This is why it should only be carried out at highly specialised centres.

Further information:

University Hospital of Tübingen
Children's Hospital
Department of General Paediatrics, Haematology and Oncology
PD Dr. med. Ingo Müller
Hoppe-Seyler-Straße 1
72076 Tübingen
Tel.: +49 (0)7071 29-87199
Fax: +49 (0)7071 29-5203
E-mail: ingo.mueller(at)med.uni-tuebingen.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/correcting-enzyme-defects-using-stem-cells