What are genetic diseases?
Genetic diseases are diseases caused by errors in the DNA. When errors affect only one gene, these diseases are called monogenetic diseases. Pompe disease and Hunter syndrome are monogenetic diseases. In Pompe disease, there are errors in the GAA gene. In Hunter syndrome, the errors are in the IDS gene. Monogenetic diseases can in principle be treated with gene therapy.
What are lysosomal storage diseases?
LentiCure focuses on rare monogenetic disorders and, for the time being, specifically on the group of lysosomal storage diseases. In lysosomal storage diseases, the lysosome does not function properly due to a missing or defective special protein, an enzyme. A lysosome is like a waste processing and recycling center within a cell. Just as a city has waste processing plants that break down waste and recycle useful materials, lysosomes help clean up and recycle waste in a cell. The special proteins in the lysosome, the enzymes, break down the cellular waste. When an enzyme is missing, the lysosome does not work properly: waste products accumulate in the cell and can cause damage to various organs in the human body. This is what happens in lysosomal storage diseases.
In Pompe disease, the lysosomal enzyme GAA does not work properly. As a result, glycogen (a large sugar molecule) is not broken down properly and accumulates in organs and tissues. The main tissue where this accumulation occurs is muscle tissue. In the most severe form of the disease, the heart and brain are also affected.
In Hunter syndrome, the lysosomal enzyme IDS does not work as it should. As a result, glycosaminoglycans (large molecules made of sugars) cannot be broken down and accumulate in the patient's body. The main tissues affected by the malfunctioning of IDS are the liver, spleen, cartilage and bones. In the most severe form of the disease, the brain is also affected.
What is gene therapy?
In gene therapy, the patient is given healthy DNA to compensate for the error in the patient's DNA. This healthy DNA is a correct copy of the affected gene. LentiCure aims to use gene therapy to treat monogenetic diseases.
Healthy DNA can be administered in various ways:
- In vivo: The healthy version of the gene is given directly to the patient, for example via an injection of the healthy gene into the liver.
- Ex vivo: Cells are taken from the patient's body and given a healthy copy of the gene in the laboratory. The corrected cells are then returned to the patient. An example of this is the modification of hematopoietic stem cells outside the patient's body.
In gene therapy, it is important that the healthy DNA reaches the right cells. Vectors can be used for this. Vectors are the carriers that deliver the healthy DNA to the right place. There are various types of vectors, such as inactivated viruses (so-called viral vectors), polymers, liposomes and peptides.
What is lentiviral gene therapy?
A specific type of viral vectors are lentiviral vectors. Lentiviral vectors are derived from lentiviruses that have been modified and made safe to deliver a healthy copy of a gene. LentiCure uses lentiviral vectors to deliver a healthy copy of a gene ex vivo. This therapy works as follows:
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Doctors collect hematopoietic stem cells from the patient’s bone marrow.
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In a special clean room, the lentiviral vector is added to the patient’s stem cells. This vector delivers the healthy gene to the stem cells.
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The patient receives a treatment to make room in the bone marrow for the modified stem cells.
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The patient receives their own modified stem cells back, administered into the bloodstream.
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The stem cells travel to the bone marrow, where they remain and produce all types of blood cells.
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The new formed blood cells contain the healthy gene and can travel to different parts of the body
How is lentiviral gene therapy used in lysosomal storage diseases?
Once the corrected cells are returned to the patient, they engraft in the bone marrow, where they begin to produce and secrete the missing enzyme. These cells will also differentiate into the different types of blood cells, that can travel through the blood to different parts of the body, where they can secrete the missing enzyme. This enzyme can then be taken up by the neighboring cells and break down the molecules that have built up – sugars in the case of Pompe and Hunter – in those cells, preventing these molecules from causing damage to the organs and tissues. A special quality of our technology is that the modified cells also reach the brain and can stop the disease there; this is generally not the case with other forms of gene therapy.
This therapy holds the promise of providing a long-term, possibly lifelong solution. However, this must first be proven in a clinical trial. This is unlike enzyme replacement therapies that require lifelong infusions. This promising new approach has been successfully applied to other diseases, such as metachromatic leukodystrophy (MLD). LentiCure aims to apply this approach to Pompe, Hunter and other lysosomal storage diseases.
Stories from the patients
Initially that of the Muscle Fund, later 'own' and new stories.
