Gene Therapy News
Alexandra Bruter, Polit.roo
The Swiss pharmaceutical company Novartis has just set a new record – a record of the high cost of a drug with a single application. The record was set due to the fact that the US Food and Drug Administration (FDA) approved a gene therapy drug developed by Novartis called Zolgensma. For 2 million 125 thousand dollars, you can buy one dose of viral particles. Intravenous administration of this medication may allow a healthy child born with a genotype leading to spinal muscular atrophy to remain healthy.
Spinal muscular atrophy (SMA) is one of the most common fatal genetic diseases. Approximately 1 child per 10,000 is born with the corresponding genotype. About 50% of children with this diagnosis do not live up to two years. In fact, this is not one disease, but a group of diseases united by a common symptom – the death of motor neurons in the spinal cord. Different mutations in different genes can lead to this result and, depending on the specific mutation, the severity of the disease can vary significantly. The main danger to life is the defeat of the neurons that control the respiratory muscles. Most severe cases of SMA are caused by mutations in the genes encoding the SMN (survival motor neuron) protein. This protein plays a role in splicing, the maturation process of matrix RNA, during which non–coding fragments are cut out of it.
Genetic diseases, which are caused by the absence of any one protein in the body, seem to be the most promising for the use of gene therapy. In fact, to cure a person with such a disease, it is enough to introduce the correct gene encoding this protein into the right cells and ensure that the protein is synthesized. In theory, everything looks simple, but in practice it took almost 30 years to overcome technical difficulties that lead to low efficiency and severe side effects of therapy.
The main side effect of gene therapy is associated with viruses as a means of delivering genes to cells. By embedding themselves in the genome of a cell in an arbitrary place, they can change the activity of nearby genes and turn the cell into a malignant one. The probability of such a rebirth for one cell is small, but for the effectiveness of treatment, as a rule, it is necessary to introduce the gene into a large number of cells.
The drug Zolgensma is based on adenoassociated viruses. Their distinctive feature is that their DNA, once in the cell, is not embedded in the host genome, but continues to exist separately. This greatly reduces the likelihood of unwanted side effects. In this case, viruses deliver correct copies of the SMN1 gene encoding the SMN protein to cells.
About 150 patients received the drug as part of clinical trials prior to obtaining approval from the FDA. Novartis employees claim that with a single injection of the drug immediately after birth, even children with a severe form of the disease practically do not develop symptoms. However, it should be noted that the oldest children who took part in the trials are now only five years old. Novartis also expects to receive approval for the use of its drug in Europe and Japan in the near future.
Unfortunately, the very high price of the drug is explained not only by the arbitrariness of the monopolist company. Most modern medicines are relatively simple chemical compounds. The synthesis of such drugs is relatively cheap. If they are expensive, it is mainly due to the fact that the patent for them has not expired yet. The synthesis of drugs representing protein molecules is more expensive. These, for example, include many antitumor drugs of recent generations. Protein synthesis can only be carried out by eukaryotic cells, and costs more. Relatively cheap among such drugs are those that can synthesize one of the most primitive eukaryotes – yeast. The assembly of viral particles for gene therapy can only be carried out by specially cultured cells of human origin, grown in huge quantities using rather expensive reagents. Due to such a high cost of gene therapy drugs, the price for them will never become low, although it will probably decrease over time.
A similar gene therapy approach has recently been successfully applied against another congenital myopathy – X-linked myotubular myopathy. This disease is also characterized by muscle weakness, leading to problems with swallowing and breathing. Half of the children born with this disease die by the age of one and a half. Almost no one lives to be ten. The disease is caused by a mutation in the MTM1 gene encoding the regulatory protein myotubularin, which controls the differentiation of muscle cells. This gene is located on the X chromosome, so boys are mostly susceptible to the disease, since they have only one X chromosome. When there are two X chromosomes, one good copy of the gene is enough for normal development. Two faulty copies of this gene at the same time is an almost incredible event. To do this, it is necessary either that the father of such a girl was ill, which until recently was practically impossible, or that the mutation occurred randomly, which is extremely unlikely.
The developed drug is the already mentioned adenoassociated viruses carrying a correct copy of the myotubularin gene. Nine boys aged 8 months to 6 years participated in the clinical trial. The drug was introduced to the first participants a little less than a year ago. The condition of all nine boys has improved, but to varying degrees. Four of them can breathe on their own again, someone has learned to walk, and someone has only learned to sit.
Also in April of this year , optimistic results of the first stages of a clinical trial of gene therapy against severe combined immunodeficiency were published. Like myodystrophy, such immunodeficiency can cause different mutations. The most common is a mutation in a gene that encodes a common fragment for receptors for several immunoglobulins. Due to the lack of signals transmitted by these immunoglobulins, there is no development of T- and B-lymphocytes. This gene, called IL2RG, is located on the X chromosome, and one good copy is enough for the development of a functional immune system, so only boys suffer from this form. As a rule, children who do not receive treatment do not live up to a year. The only available method of "treatment" for a long time was the life of such children in sterile conditions in separate rooms or in special spacesuits. Bone marrow transplantation is now practiced, but not everyone has suitable donor relatives, and transplantation from unrelated donors is considered dangerous and is relatively often accompanied by a "graft versus host" reaction.
The gene therapy drug is a lentiviral vector carrying a serviceable copy of the IL2RG gene. Blood stem cells were isolated from the patients' bone marrow, infected with a therapeutic virus and injected back into the patients. Before administration, patients were injected with the drug busulfan, which was supposed to slow down the division of the patient's remaining stem cells, giving an advantage to the injected ones. Eight children took part in the trial of this treatment method. All had noticeable improvements; they recovered from the infections they had contracted before starting treatment. One child was injected with modified cells twice, because after the first injection, the improvements were insignificant. Four participants stopped being injected with synthetic immunoglobulins and were vaccinated, three had post-vaccination immunity.
It is noteworthy that during the treatment of this particular disease with a gene therapy drug, a tragic accident occurred in 2000, which greatly slowed down the development in this area. Although the medicine was effective and the immunity of the patients was restored, three of them fell ill with leukemia, and one died. Then a retroviral vector was used to deliver the gene, the embedding of which into the genome of lymphocytes caused their malignant degeneration. Since then, the safety of vectors for gene therapy has been given particularly great importance.
These and some other results give hope that, despite the initial failures, gene therapy will be able to improve the situation in the treatment of severe hereditary diseases.
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