Hereditary neural amyotrophy (Charcot-Marie-Tooth disease)

What is Charcot-Marie-Tooth disease (CMT). According to world statistics, CMT is considered an orphan (rare) hereditary disease, but at the same time the most common hereditary disease of the human peripheral nervous system, which affects approximately one person out of 2500 people. It was first simultaneously described in 1886 by the French physicians Jean-Martin Charcot, Pierre Marie and the English physician Howard Henry Tooth. CMT leads to the damage of peripheral nerves and impaired conduction of electrical impulses from the brain and spinal cord to various parts of the body and organs and vice versa. CMT belongs to the group of slowly progressive hereditary diseases of the nervous system (HDNS). It is known that all HDNS are diseases transmitted from generation to generation or through generation, caused by gene or chromosomal mutations. With chromosomal mutations, in some cases, there is a violation of the number of chromosomes (doubling, tripling, absence) or there is a violation of the structure of the chromosome (deletions, inversions, translocations, duplications). With gene mutations, changes are observed, respectively, in the genes on certain parts of the chromosomes. Mutations can involve either a single DNA sequence (simple mutations) or exchanges between allelic or non-allelic DNA sequences. These changes are the cause of monogenic diseases, a group of diseases that is quite heterogeneous in terms of clinical manifestations. Hereditary neural amyotrophy refers to monogenic diseases of the nervous system. At the same time, CMT arises due to defects in the genes encoding proteins of the axon or its myelin (myelin protein is an electrical insulator of nerve axons), which, in turn, affect axons, the fibers that conduct electrical signals between the brain and spinal cord and the rest body areas. More than 83 genes are known, the defects in which can lead to the manifestation of CMT. The mutation of each gene is manifested by a certain type of CMT, and in many cases, with several types of CMT (CMT 1A, CMT 1B, CMT2, CMT 4, CMT, etc.). The types of CMT vary in age of onset, inheritance patterns, severity, and whether they are associated with axon or myelin defects.

Several variants of inheritance of CMT have been established:

1. autosomal dominant inheritance (through a defective gene from one of the parents);
2. autosomal recessive inheritance (through a defective gene from each parent);
3. X-linked inheritance (through a defective gene on the X chromosome from one of the parents).

The pronounced phenotypic polymorphism leads to variations of clinical signs even in the members of one family.

Neurological symptoms can be represented by classic extended forms, a variety of atypical manifestations and inapparent clinical symptoms. When studying the prevalence and outcomes of severe progressive HDNS, we noted that until a certain time these patients are quite compensated and remain absolutely healthy, while the disease debuts at different periods of their lives (in childhood or puberty or at the age from 35 to 60 years) as a result of various etiopathogenetic factors. A person learns about the disease only when it begins to progress and this is the main requirement to be included in our protocol.

Types of patients: The patients with a clinically, neurophysiologically and genetically confirmed diagnosis of Charcot-Marie-Tooth disease. The patient must have progressive hereditary disease. In some cases, decompensation leads to profound disability of the patient due to autoimmune disorders or neurodegenerative complications. These complications are primarily conditioned by the genomic-proteomic structural disorders (deletions, inversions, translocations, duplications) in hematopoietic personalised therapy as a result of DNA damage. Thus, the additional gene mutations lead to profound disability, dementia, or even death as a result of autoimmune inflammation, degeneration of the nervous tissue, or carcinogenic degeneration of the tissues of a patient with HDNS.

Therapy principle. The special importance of this problem is associated with the lack of effective methods of treatment the progressing CMT and the possibility of repeated disease in subsequent generations. The main hopes in the treatment of HDNS are assigned on future genomic editing technology. But what do we do today if the disease keeps progressing? Is it possible to stop it? Yes, it is possible; and the answer has been received in our experimental work on the restoration of lethal mutations of damaged cells using the nature-like technology of homologous recombination (equivalent replacement) of mutant DNA with double stranded DNA (dsDNA) of a healthy donor. Molecular studies of the restoration of lethally damaged cells and MScells with a large number of mutations and damages of DNA caused by 3-5 multiple fatal doses of ionizing irradiation made it possible to develop a revolutionary nature-like innovative biotechnology of restoration and replacement of mutant areas of DNA with analogous parts of healthy donor DNA during the division of the cells.
Patient’s own peripheral blood mononuclear cells (PBMCs) and cells are harvested by leukapheresis, incubated with dsDNA of a healthy donor (therapeutic substance approved in the Russian Federation).

Part of these restored cells and PBMCs is used for blood infusions, and the other part is used to restore damaged nerve cells of the brain by intrathecal administration of these cells in the spinal canal.

Result. The technology does not allow to cure all the genetic diseases, especially such complex as CMT, and it is not its goal. The technology gives a real chance to arrest the progression of hereditary nervous disease with the nature-like molecular mechanism of the homologous recombination of mutant and damaged pieces of DNA of cells and PBMCs with dsDNA of a healthy donor. It is able to stabilize the molecular biological structure of the unstable neurons’ genome, block the clonal hematopoiesis in CMT patient, as well as compensate for the neurological and somatic state of the patient. The technology is able to prevent the decompensation of various forms of HDNS in healthy compensated family members with family burden. Harvest of their own cells and PBMCs form a person with CMT family history in a compensated state and, thereby, provides bio-insurance from the possible progression of a hereditary disease in case the disease occurs.