Orphan diseases: hereditary disease of nervous system

Types of patients. The patients with the hereditary systemic diseases of the nervous system: diseases with cerebellar damage, combined degeneration of cerebellar tracts and peripheral nerves, diseases with a predominant damage of the extrapyramidal system: Parkinson's disease, hepato-cerebral dystrophy (Wilson disease), Huntington's chorea, familial essential tremor, generalized tic, deforming muscle dystrophy. Diseases with a predominant damage of the pyramidal tracks: Strumpell’s family spastic paralysis, familial amyotrophic lateral sclerosis. Diseases with damage of the peripheral nerves: hereditary neural amyotrophy (Charcot -Marie -Tooth disease).

To be included into the therapy program: Hereditary diseases of the nervous system (HDNS) are the diseases transmitted from generation to generation or through generation due to genetic or chromosomal mutations. In chromosomal mutations, in some cases there is a violation of the number of chromosomes (double, triple, absence) or there is a violation of the structure of the chromosome (deletion, inversion, translocation, duplication). Mutations may include one DNA sequence (simple mutations) or exchanges between allele or non-allele DNA-sequences. These changes are the cause of monogenic diseases’ and it is quite heterogeneous group of diseases in terms of clinical manifestations. The pronounced phenotypic polymorphism leads to various clinical signs among representatives within even one family.

The neurological symptoms can be represented by classical pronounced types, atypical manifestations and inapparent clinical symptoms.

The clinical picture of such damages is accompanied by the progressing disorder of the neuromuscular apparatus, speech and sensory activity. During the diagnosis, the specialist considers hereditary anamnesis, patient’s age, localization of pathological process and clinical symptoms. An individual plan of therapy of the hereditary disease of the nervous system is compiled only after detailed instrumental, laboratory, clinical and neurogenetic examination of the patient.

Mostly, the severe monogenic hereditary diseases are transferred in the autosomal recessive fashion, that is, conditioned by the recessive pathological gene, which is a part of the autosome and manifests if a homozygote forms. Such diseases are not associated with gender and an develop in case of phenotypically healthy parents. Some diseases are transferred by dominant type (myotonia, Huntington’s chorea). Such disorders as hemophilia, color-blindness, hereditary atrophy of optic nerves, are transferred in the gender-associated recessive fashion, with mutated X-chromosomes. The mode of inheritance can be specified in the medical-genealogical examination based on the family history. Now, the medical-genealogical consultation and medical genetic tests are the most important, when the patients with hereditary pathology and their families can get the answer about the opportunity of having a child with hereditary disease. In our hospital the individually tailored program of treatment of the hereditary diseases of the nervous system is developed after detailed the medical-genealogical consultation, medical genetic and proteomic tests and consultation of the neural geneticist and professor of neurology.

When we studied the prevalence and outcomes of heavy progressive HDNS, we showed that until a certain time, the condition of these patients was compensated and they were absolutely healthy people; their disease debuts in a variety of periods (in a child or puberty period or age 35 to 60 years ) as a result of different etiopathogenetic factors. A person learns about the disease only when it begins to progress and this is the key requirement to be enrolled into this protocol. The patient should have a progressing hereditary disease.

In most cases, an avalanche-like increase in degenerative-atrophic processes forms in various areas of the central nervous system (CNS), leading to pronounced dementia with atrophy of the cerebral cortex, severe atrophy of cerebellar cortex, akinetic-rigid disorders and dyskinesias in the degeneration of striatopallidal area of the brain or muscle atrophy in the motor neurons damage. In some cases, decompensation leads to deep disability induced by autoimmune disorders or even to death due to cancer. These vital complications are primarily conditioned by the genomic-proteomic structural disorders (deletions, inversions, translocations, duplications) in hematopoietic personalised therapy as a result of DNA damage and ruptures. Thus, the additional mutations of genes lead to deep disability, dementia or death as a result of autoimmune inflammation, degeneration of nervous tissue or carcinogenic degeneration of the tissues in HDNS.

Therapy principle. The importance of this problem is associated with the lack of effective methods of treatment the progressing HDNS and the possibility of repeated cases of the 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 two-strand DNA (tsDNA) 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 tsDNA 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 HDNS, 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 of a healthy donor. It is able to stabilize the molecular biological structure of the unstable neurons genome, block the cancer personalised therapy in HDNS 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 HDNS family history in a compensated state thereby provides bio-insurance from the possible progression of a hereditary disease in case the disease occurs.