Alzheimer's disease (AD) or senile dementia of Alzheimer’s type (SDAT): ultra-early molecular biological diagnosis and bone marrow restitution

What is Alzheimer’s disease (AD) or senile dementia of Alzheimer’s type (SDAT) and where are we now? AD and SDAT are considered incurable, fatal neurodegenerative diseases. In AD and SDAT, the accumulation of beta-amyloid proteins and other specific proteins in the cerebral cortex is detected. AD and SDAT are diagnosed only when at least 50-60% of neurons have already died and it is impossible to help the patient. Dementia in AD and SDAT is diagnosed when at least 50% of neurons in the cerebral cortex have died and severe cognitive impairment has appeared. Until now, there is no real therapy for these diseases, and symptomatic therapy is extremely ineffective. All known treatments do not work. Drugs approved in regulatory bodies around the world, so far only "imitate" the treatment of these diseases and do not extend the life expectancy of these patients in practice.

AD and SDAT patients create a big problem for their relatives, who apart from the burden they have to carry also have to live in the insecurity about their own future not knowing whether they will have this disease or not. Today even before the manifestation of clinical symptoms, it is possible to detect in advance the proteomic defect in one's own cells and to take measures to prevent the occurrence of this disease in the familial form. We are convinced that the disease of cortical neurons in AD and SDAT is not a cause, but a consequence of a systemic blood disease, or, rather, a genomic-postgenomic disease of hematopoietic (blood producing) personalised therapy. We have proven in our own research that these patients have genomic and post-genomic damages of the molecular structure of the cells and develop pathological clonal hemopoiesis (blood production). On this basis we can diagnose these diseases at ultra-early stage by the protein markers of the cells surface (the Russian Federation patent) and by clonal genes sequencing (Bryukhovetskiy A.S., Grivzova L.Yu., 2019). Our pre-clinical trials in the transgenic mice models of Alzheimer’s disease (AD) and ALS have shown that processing of their own cells under special basic conditions and their administration to the trial animals helps avoid manifestation of the clinical symptoms of the genetic diseases of AD and ALS, and delay lethal outcome by 25% and 17%, respectively, improving their life quality and extending the lifespan. We have named our therapeutic method the personalized restitution of the bone marrow, which is not able to cure the disease, but is capable of arresting its progression and of delaying lethal outcome.

It would be absolutely wrong and tactless to claim that we have created a technology for curing a disease. We do not aim to cure AD and SDAT. Our goal is to stop the progression of a lethal disease and increase the life expectancy of AD and SDAT patients. We have experience in extending the life expectancy of patients under the protocol of intrathecal administration of autologous personalised therapy up to 7-10 years. About 100 patients with AD and SDAT including the USA residents have been treated with therapy for 20 years in our hospital. Currently, we are using a bone marrow restitution protocol that has passed preclinical trials and is used in the clinic now.

What is the personalized restitution of the bone marrow? For the first time we have conceived the fundamental principles of the novel medical field in the personalised medicine that we have been using in our clinical hospital for the past five years under the guidance of Prof. Andrey S. Bryukhovetskiy, and we named it the restitution of the bone marrow (RBM) and/or restitution of the hematopoietic personalised therapy (Rcells) in the therapy of the diseases of civilization complicated by clonal hemopoiesis.

The AD and SDAT are the group of incurable nervous diseases in the cohort of lethal degenerative-dystrophic diseases of civilization (DCs). We have detected the fundamental cause of the disease, or, its “biological engine”: the clonal hemopoiesis. A new theoretical understanding of the problem of clonal hemopoiesis is now being actively developed by the medical academic community; and our more than 20 years long research of the cells in the pathogenesis and therapy of the most of the neurological DCs extended and even resulted in a new scientific definition of the term “restitution of bone marrow”. It also described the clinical content of different stages of RBM and Rcells and described its efficiency (application to the Russian Federation patent for invention).

In English language the word restitution is know from the 14^th century and means “making good or equivalent for crime, debt or injury” and “restoration of goods, land, etc. to a former owner”. It originates from Old French restitucion or directly from Latin restitutionem. Now the term is use predominantly in legal sphere meaning the act of giving back something that has been lost or stolen, or the act of compensating for loss or injury by reverting as far as possible to the position before such injury occurred. It is also used in cytogenetics to denote the spontaneous rejoining of broken chromosomes to reconstitute the original chromosome configuration.

The term restitution in Russian has additional medical meaning and is used to denote restoration of lost health, return to previous condition. In neurology restitution is understood as the development of restorative mechanisms in the pathology of the nervous system and it is the key to the success of rehabilitation measures, since the essence of sanogenetic mechanisms is manifested by their focus on adaptation to the environment at a qualitatively new level in connection with the existing pathological process in the body. Such sanogenetic mechanisms, which in close interconnection and interdependence provide an adaptive effect, and in case of pathology - restoration of impaired brain functions, personal and social status of patients, are restitution, regeneration and compensation. These notions ae synonyms in neurology and restorative medicine. According to Professor V.A. Epifanov (2013): “Restitution is the process of restoring the activity of reversibly damaged structures” of the human and animal body “by “activating morphologically preserved, but functionally inactive structures that are in a state of deep depression, to a large extent.”

We presume that this is the most science-driven and science-grounded definition of the medical understanding of the term restitution that reflects what is happening in the damaged organs, tissues and cells of the organism and permits development of effective strategies of the restoration of any tissue and organs damages. We formulated the essence of the restitution as a medical term as "the act of restoring the original state of the organ or tissue of the human and animal body by activating its structural components inhibited by the disease and replacing the damaged molecular biological structures."

Restitution sanogenetic mechanisms in damaged organs and tissues are closely tied to hematopoiesis and immunity. It is the system-forming and regulatory, controlling role of cells that forms the restorative sanogenetic mechanism for the restoration of damaged organs and tissues. In case, the hemopoiesis is polyclonal (all or most of the existing 100.000 clones of cells function), the sanogenetic mechanisms function accurately and precisely. However, during life or due to stress exposure, a number of additional somatic mutations (ASMs) accumulate in long-living systems. Some of these ASMs in such long-living cells as cells become driver and dramatic and lead to the development of clonal hematopoiesis. One or more dominant hematopoietic clones are formed in the blood, which "win the competition" among other hematopoietic personalised therapy. Gradually expanding in volume, the descendants (cells and hematopoietic precursors) of the dominant hematopoietic clone(s) are the parents of most immunocompetent cells (ICCs) of all circulating blood.

Sometimes the number of ICCs of the dominant clone (clones) of cells in the general circulation of blood cells reaches 70% to 93% and determines the occurrence and manifestation of the majority of fatal DCs. We consider clonal hematopoiesis to be a genomic-postgenomic disease of cells and the key fundamental process of etiopathogenesis of most immune-associated diseases of civilization. Its result is the formation of an immunotolerant or immunoaggressive restorative systemic response of the immunity to the pathology of tissue-specific cells and tissues of organs and systems. To overcome the negative systemic influence of clonal hematopoiesis on the physiological restitution of organs and tissues, the main strategy of nowadays medicine should be the strategy of bone marrow restitution, capable of restoring the status quo (status quo - return to the original state) of bone marrow personalised therapy. In some cases, the effect of partial restitution in fatal DCs can be achieved by bone marrow transplantation (Immunotherapy technologies, Immunotherapy techniques, Gene technologies) or cells transplantation. Sometimes the number of ICCs of the dominant clone (clones) of cells in the general circulation of blood cells reaches 70% to 93% and determines the occurrence and manifestation of the majority of fatal DCs. We consider clonal hematopoiesis to be a genomic-postgenomic disease of own cells and the key fundamental process of etiopathogenesis of most immune-associated diseases of civilization. Its result is the formation of an immunotolerant or immunoaggressive restorative systemic response of the immunity to the pathology of tissue-specific cells and tissues of organs and systems. To overcome the negative systemic influence of clonal hematopoiesis on the physiological restitution of organs and tissues, the main strategy of nowadays medicine should be the strategy of bone marrow restitution, capable of restoring the status quo (status quo - return to the original state) of bone marrow personalised therapy. In some cases, the effect of partial restitution in fatal DCs can be achieved by bone marrow transplantation (Immunotherapy technologies, Immunotherapy techniques, Gene technologies) or cells transplantation. However, the risk of fatal complications from the high-tech Immunotherapy technologies, Immunotherapy techniques, Gene technologies procedure makes 6-9%, and this risk overweighs possible advantages of using this technology for non-fatal DCs. In some cases, the transplantation of pathological cells does not remove the monoclonal hematopoiesis. In our technology it cannot happen and we are able to restore the polyclonal hemopoiesis without death risk and to arrest the progression of fatal DCs.

Types of patients: the individuals aged over 18 with Alzheimer’s disease (AD) or senile dementia of Alzheimer’s type (SDAT), independent on the disease stage and localization of the process.

Therapy goal: Ultra-early molecular biological diagnosis of AD and/or SDAT by the profile of membrane proteins of the hematopoietic (cells) and arrest of the progression and prevention of recurrence of AD and/or SDAT by drastic modification of the immune response to the damage of motor neurons, as well as switching from mono- and oligoclonal hematopoiesis to polyclonal hematopoiesis as a guarantee of the block of the pathological process.

Diagnosis and therapy principle: Thirty years of genomic and proteomic studies of hematopoietic personalised therapy (cells) brought important scientific evidence to our team that has been summed up in 15 scientific monographs and more than 200 publications in journals. First, we have shown that the neurodegenerative diseases (NDDs) including AD and/or SDAT are burdened by clonal hemopoiesis in most cases and should be considered as the disorders induced by genome and post-genome damages of the cells (blood producing personalised therapy); while the damage of motor neurons, cortical neurons, and other neuros of the brain and spinal cord is not the cause of the brain disease but the consequence of the genome-post-genome disease of the cells and is conditioned by the disorder of immunity. Therefore, a molecular study of a patient's cells helps us diagnose the disease at its preclinical stage and prevent the progression of the disease.
Second, the main pathogenetic element of these diseases is the formation of a pathological cells clone, the emergence of which is conditioned by molecular biological structural changes in these cells. Today we are able to prove its presence at the genetic and proteomic levels and describe its extent as a percentage in the general blood circulation. Third, under the influence of a pathological clone of cells, clonal hematopoiesis (blood production) develops, which leads to autoaggression of immunocompetent blood cells (descendants of pathological cells) towards the cells of their own nervous tissue in general, and neurons of the brain cortex in AD and SDAT in particular. Fourth, the pathological hematopoiesis leads to a deadly "immune loop" of the immunity that comes from the descendants of pathological cells; this loop kills brain neurons. The approach that we propose removes this immune “death loop”, offers a basically new therapy of these diseases, that we named the restitution of bone marrow. It blocks pathological clones of cells, restores polyclonal hemopoiesis, and arrests the progression of the diseases.

Method: At the first stage, pathological hematopoiesis is diagnosed in a patient with AD or SDAT by molecular genetic and proteomic tests of the patient's cells. If mutations in the genes of hematopoiesis clonality are detected, the CD34+ fraction of the peripheral blood mononuclear cells (PBMCs) is harvested from the patient on a cell separator, using a disposable system; then the cells are cryopreserved with the therapeutic substance, under special basic conditions. One séance provides the material that is sufficient for the restorative therapy. The obtained cell material is preserved at low temperature. Further, the dominant pathological cells clone is immunosuppressed, the restored cells are administered and the immune response is stimulated.

The blocking of the pathological clone (clones) of the cells “castrates” this clone and it becomes incapable of further reproduction. Five to six months later, the immunocompetent cells of the clone “die out”, and do not form any progeny. This activates suppressed clones of healthy cells and restores polyclonal hemopoiesis. Genetic and proteomic diagnosis repeated in three and six months helps confirm the fact of the restored polyclonal hemopoiesis and modification of the systemic immune response of the organism. The treatment arrests the progression of the most types of AD and SDAT even including the familial types.

Result. The progression of the lethal disease of the brain and spinal cord is arrested in 60% of the cases. The systemic immune response is changed from one pathological clone to other recessive clones of hematopoiesis. Further neurorestorative personalised and pharmaceutical therapy as well as active specialized rehabilitation aimed at the development of new function provides for even better functional results and improves the neurological function in 50 to 60% of the patients depending on the type and duration of neurodegeneration.