Huntington’s disease

What is Huntington's disease (HD)? Huntington's disease (Huntington's syndrome, Huntington's chorea) is an autosomal dominant genetic disease of the nervous system, characterized by a gradual onset, usually at the age of 30 to 50 years, and a combination of progressive choreic hyperkinesis and mental disorders. The disease is caused by the multiplication of the CAG codon in the HTT gene. This gene encodes a 350-kDa huntingtin protein with an unknown function. In 1872, American physician George Huntington noted a hereditary variant of chorea with onset in adulthood. Subsequently, this disease was called "Huntington's disease" (HD). It is also called Huntington's chorea, hereditary or degenerative chorea. The word chorea in the name of HD comes from the Greek word for "dance" due to violent and involuntary inconsistent movements (hyperkinesis) in patients with HD.

Two main clinical forms of HD have been described:

1. Hyperkinetic, the most common, is characterized by a later onset, gradual progression of choreic hyperkinesis (violent excessive motor actions that occur against the will of the patient), as well as dementia with a slowdown in cognitive functions, decreased criticism, depression, various psychoses;
2. Akinetic-rigid with onset at an early age (Westphal variant) observed in 5-10% of cases, characterized by a rapid increase in muscle weakness, contractures (limited joint mobility), behavioral and mental disorders, epilepsy; observed when the mutant gene is transmitted from the father.

Huntington's disease is considered an incurable disease, so the therapy is symptomatic and supportive. Despite this, treatment can significantly improve the quality of life of patients and prevent further progression of the disease.

Scientific grounds of our approach: HD belongs to the group of 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. 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 types of hereditary diseases of nervous system, we noted that these patients are quite compensated and remain absolutely healthy until a certain time, 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. The patient must have progression of this hereditary disease. In most cases, an avalanche-like increase in degenerative-atrophic processes is formed in various parts of the central nervous system (CNS), leading to pronounced neurological deficit. In some cases, decompensation leads to deep disability due to autoimmune disorders or even to death due to oncological complications. Vital complications are conditioned by the genomic-proteomic structural disorders (deletions, inversions, translocations, duplications) in hematopoietic personalised therapy (cells) as a result of DNA damage. Thus, the additional gene mutations lead to profound disability, dementia, or death as a result of autoimmune inflammation, degeneration of the nervous tissue, or carcinogenic degeneration of tissues.

Therapy principle. The special importance of this problem is associated with the lack of effective methods of treatment the progressing HD and the possibility of repeated cases of the disease in subsequent generations. The main hopes in the treatment of HD 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.

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 HD, 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 HD 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 HD in healthy compensated family members with family burden. Harvest of their own cells and PBMCs form a person with HD family history in a compensated state and, thereby, provides bio-insurance from the possible progression of a hereditary disease in case the disease occurs.