The first specific treatments
When the VML association was created in 1990, no specific treatment was available. The first treatment appeared in 1992 for Gaucher disease. The method and means developed for this first treatment by enzyme replacement therapy (Enzymatic Substitutive Treatment) have been applied to other pathologies. Then the discovery of another method, substrate inhibition treatment , paved the way for treating other diseases.
Even if there is still a long way to go, since no current treatment is curative, today twelve diseases benefit from at least one treatment having received a marketing authorization (AMM).
Cholesterol ester storage disease
For certain pathologies and in certain cases, a bone marrow transplant is proposed as a treatment or as a complement. Today, new methods, in particular by gene therapy, are being studied and are being tested in lysosomal storage diseases. Each of these methods can be adapted to one or more diseases. It also appears that in some cases, the future may involve a combination of several treatments to combat the different symptoms of the disease.
All these advances bring hope and a brighter future, but the road to recovery will be long.
The different types of specific treatments
Several specific treatments exist to combat lysosomal storage diseases. They act specifically in the cell, where there is an anomaly. A distinction is made between enzyme replacement therapy, substrate inhibition, bone marrow or hematopoietic stem cell transplantation, gene therapy and chaperone molecules.
Enzyme replacement therapy
The principle of enzyme replacement therapy is to provide the enzyme (protein) which is missing or which is lacking in a person suffering from a lysosomal disease. For this, intravenous infusions of the specific enzyme are carried out regularly (every week or every 15 days).
The infused enzyme is produced in vitro, that is to say outside the body. This enzyme is actually modified to help it reach the cells in the body that need it most to recycle the metabolite implicated in the disease. Thus, once in the lysosome, this enzyme replaces the deficient enzyme. For each disease, it is necessary to produce a different enzyme.
The effectiveness of enzyme replacement therapy varies according to the type and stage of the disease but also according to the organ affected. Neurological disorders are not accessible with this type of treatment because the proteins do not reach the brain and the spinal cord.
For the moment, the administration of the enzymes is not done orally because they are too bulky. It is therefore only intravenously that they are administered and this must continue for life.
The substrate inhibition treatment must partially prevent the production of the substrate (metabolite) which is not recycled by the cells because of the genetic defect. It reduces the accumulation of the metabolite and thus the clogging of the cells.
Substrate inhibition can be used in the case of lysosomal storage diseases that affect the central nervous system (brain and spinal cord) or in addition to other treatments. However, it is only effective in certain cases.
. This is why it is generally performed on people with a very severe form of the disease or at risk of dying young.
The principle is to take cells from a healthy person who is compatible with the patient and then transplant them to the person suffering from a lysosomal disease. The goal is to provide the patient with stem cells so that he can produce the missing enzyme.
Information to become a bone marrow donor
The principle of gene therapy is to introduce into cells or tissues of a person, the normal copy of the deficient gene or to modify the expression of this deficient gene which is responsible for a disease. This makes it possible to treat the disease in question.
It is first necessary to identify the defective mutation then to clone replacement genes and finally to obtain a stable expression of these genes in the cells.
This allows the patient to produce the deficient enzyme.
This method is currently undergoing several clinical trials, with an introduction directly into the brain to try to act on neurodegenerative disorders.
The chaperone molecules
Chaperone molecules are proteins that control the correct three-dimensional (shape of the protein in space) folding of other proteins. They thus contribute to the maturation of these proteins so that they then become functional.
Many mutations generate proteins whose conformation is altered. Nonconformal three-dimensional folding of a protein leads to the loss of function of this protein. This causes various damage in the body. The role of chaperone molecules is to prevent this damage. These proteins with an abnormal structure are therefore taken over by chaperone molecules and are then degraded in the cell.
The treatment of abnormal proteins by so-called “pharmacological” chaperone molecules would make it possible to correct the folding of these proteins. Pharmacological chaperone molecules bind to the misconfigured protein and stabilize its conformation by stiffening it. This prevents its degradation and increases its activity.
Furthermore, chaperone molecules appear to increase the efficacy of enzyme replacement therapy. A combined protocol of these two treatments may be a solution.