NEUROLOGICAL

ENHANCING THE EFFECTIVENESS OF CELL PREPARATIONS IN THE COMPLEX THERAPY OF NEUROLOGICAL DISORDERS: FROM THE TRANSPLANTATION OF MOBILIZED STEM CELLS OF PERIPHERAL BLOOD TO BIOENGINEERING OF THE BRAIN AND SPINAL CORD AND MOLECULARLY TARGETED CELL PRODUCTS.

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STEM CELLS

REGENERATIVE TECHNOLOGIES IN CANCER THERAPY

MOLECULARLY TARGET CELL PREPARATIONS IN THE THERAPY OF NEUROLOGICAL DISEASES: REALITY AND FUTURE

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Andrey S. Bryukhovetskiy

Cell therapy in neurology is a novel solution to improve effectiveness and safety of the technologies of regenerative medicine in the treatment of neurological and psychiatric diseases.

NeuroVita Clinic of Interventional Restorative Therapy and Neurology, Moscow, Russia.

Research advisers:

Head of the Department of Bone Marrow Transplantation of the Research Institute of Clinical Oncology of Blokhin Cancer Research Center, Professor Kapitalina Nikolayevna Melkova, PhD, MD.  

Head of the Laboratory of the Immunology of Hematopoiesis of the Research Institute of Clinical Oncology of Blokhin Cancer Research Center, Professor Tupitsin Nikolay Nikolayevich, PhD, MD

Research Coordinator:

Director of  ZAO NeuroVita Clinic of Interventional Restorative Therapy and Neurology, Professor Andrey Stepanovich Bryukhovetskiy, PhD, MD

Introduction. Global market volume of cell preparations used for medical purposes in 2015 exceeded USD 2.5 billion [1,2], and by 2020 the analytics predict USD 10 billion [2]. The preparations of stem cells (SCs) are safely used for treating some of the human diseases for a period by now [3,4]. The clinical effectiveness of therapeutic effect of the cell preparations for the diseases of the central nervous system (CNS) varies from 35 to 51% [5], which is not very high, especially if we keep in mind that according to the information from the manufacturers this rate varies from 80 to 85% [5,6]. On the other hand, if effectiveness is evaluated by the clinical doctors, we will see that 90%-92% patients with the neurological diseases are incurable by conventional methods [7]. Consequently, the patients start looking for stem and/or progenitor cells therapy. Considering the CNS structural characteristic and clinical features, the administration of stem and progenitor cells frequently remains the only possible solution. However, the effectiveness of the cell therapy is still thought to be unconvincing and doubtful [9]. The preparations of stem cells have not taken the place they deserve among the contemporary therapeutic means to treat the CNS diseases. In order to improve the effectiveness, it is necessary to understand the mechanism of cell therapy and the reasons for low effectiveness.

The goal of the article The present paper, as a retrospective study, analyzed the effectiveness and safety of the application of SCs in the therapy of various neurological and psychiatric disorders. At the same time, the reasons potentially leading to the low effectiveness  are provided. A new strategy of highly effective molecularly targeted cell therapy in treating neurological diseases and psychiatric disorders is presented.

Materials and methods. In the present retrospective study, 2780 files of the records of 458 cases of various organic diseases of the CNS are presented. The cases received the long-term treatment and were followed up in the NeuroVita Clinic of Restorative Interventional Neurology and Therapy, Moscow, Russia. The treatment was given within the framework of the branch program of the Russian Academy of Medical Sciences New Cell Technologies to Medicine.  The program was headed by the member of the Russian Academy of Medical Sciences, Prof. Vladimir K. Yaryghin, and the research was coordinated by Prof. Andrey S. Bryukhovetskiy. The distribution of the diseases is shown in Table 1.  

Table 1.

The cases of neurological disorders that received stem cell therapy

 

Disease

Number of the records

Number of the cases in experimental arm

Control arm

1.

Traumatic disease of the spinal cord

1714

309

88

2.

Traumatic disease of the brain

216

31

34

3.

Multiple sclerosis

92

16

12

4.

Amyotrophic lateral sclerosis

104

22

24

5.

Late hemorrhagic and ischemic strokes

179

27

79

6.

Dyscirculatory encephalopathy

164

26

56

7.

Chronic vegetative state

43

6

5

8.

Cerebral palsy

24

5

2

9.

Glioblastoma multiforme

156

5

75

10.

Neurodegenerative diseases

88

11

21

11.

Total

2780

458

391

 

The general information of the patients is given in Table 2.  

Table 2.

Distribution of the neurological patients who received stem cell therapy by age and sex.

Disease

Males/

Average age

 

Absolute %

Females/

Average age

 

Absolute %

Control group

Males

Average age

Absolute %

1.

Traumatic disease of the spinal cord

253/33.46

34. 5

56/50.4

42.4

88/36.25

33.8

2.

Traumatic disease of the brain

23/31.85

28.6

8/7.2

31.2

34/9.1

39.5

3.

Multiple sclerosis

5/40.8

41.2

11/9.9

35.5

12/3.42

29.9

4.

Amyotrophic lateral sclerosis

13/46.5

52.1

9/8.1

56.6

24/6.5

49.1

5.

Late hemorrhagic and ischemic strokes

19/49.0

64.4

8/7.2

51.2

79/15.1

66.1

6.

Dyscirculatory encephalopathy

19/48.47

62.3

7/6.3

65.1

56/50.8

55.9

7.

Chronic vegetative state

4/36.4

27.4

1/0.9

19

5/1.4

34.6

8.

Cerebral palsy

2/25.50

19.3

3/2.7

22.6

2/0.5

21.1

9.

Glioblastoma multiforme

4/29.50

41.2

1/0.9

55

75/20.2

61.4

10.

Neurodegenerative diseases

7/2.02

66.4

4/3.6

53.7

21/5.6

57. 6

11.

Total

347/75.8

111/24.2

370/100

 

As shown in the tables, the patients of different ages were included into research. The control group correlated with the experimental group by age. However, the control group included only male cases, but the influence of gender on the results of the research was minimal.

Results.

 As shown in Table 3, the situation of the therapeutic method is given.  Stem cell therapy was the main strategy (72.4%). Tissue engineering was used for 13.8% cases, while the combinative strategy of the tissue engineering and stem cells therapy was employed for 13.7% cases .

Table 3.

The neurological cases and the therapeutic methods  

 

Disease

Conservative strategy (cell therapy)

Absolute %

Surgical strategy

(tissue engineering)

Absolute %

Combines strategy (tissue engineering and cell therapy)

 

Absolute %

1.

Traumatic disease of the spinal cord

220/71.9

47/15.2

42/13. 4

2.

Traumatic disease of the brain

14/45.1

2/6.4

15/48.4

3.

Multiple sclerosis

10/62.5

6/37.5

 

4.

Amyotrophic lateral sclerosis

17/77.3

3/13.6

2/9.1

5.

Late hemorrhagic and ischemic strokes

20/74

3/11.1

4/14.8

6.

Dyscirculatory encephalopathy

26/100

-

-

7.

Chronic vegetative state

6/100

-

-

8.

Cerebral palsy

5/100

-

-

9.

Glioblastoma multiforme

5/100

-

-

10

Neurodegenerative diseases

11/100

-

-

11.

Total

334/72.4

64/13.8

63/13.7

 

Neurological patients that were involved in the present study were followed up for 3 to 8 years every three months. The standard regular examination included neurological examination, contrast enhanced MRI of the brain or spinal cord (50 cases of spinal cord injury had tractography of the conducting pathways based on the diffusion tensor MRI), electroneuromyography (ENMG), somatosensory evoked potentials ENMG, tests for ASIA and FIM scores, X-ray of knee and hip joints according to the protocol approved by the Scientific Board and Ethics Committee of Pirogov Russian State Medical University (RSMU). All intermediate and final reports were provided to the RSMU administration and Ministry of Health of Russia. Different types of cell preparations were used for different damages of the brain and spinal neural tissue: preparation of the mobilized hematopoietic stem and progenitor (CD34+,CD45-)  cells (HSCs) (produced by Blokhin Russian Cancer Research Center), neural stem cells (CD 133+) isolated from the olfactory sheath of a nose of the patient (produced by Serbski State Research Center of Social and Forensic Psychiatry) and mesenchymal stromal stem cells isolated from the bone marrow of the patient (produced by the federal research and Clinical Center of FMBA of Russia).  The cell material is standardized and certified by the state research institutions; the state certificates of the quality are attached to the case histories.

The evaluation of the effectiveness of the therapy depended on the type of the disease and goals of using SCs. The analysis of the efficiency is shown at Table 4.  

Table 4.

Effectiveness of the long-term stem cells therapy for neurological disorders

Disease

Deterioration

Absolute %

No effect

Absolute %

Effective

Absolute %

Highly effective

Absolute %

1.

Traumatic disease of the spinal cord

6 1.9

85 27.5

165/53.4

53/17.2

2.

Traumatic disease of the brain

-

8/25.8

20/64.5

3/9.6

3.

Multiple sclerosis

2/12.5

5/31.5

6/37.5

3/18.7

4.

Amyotrophic lateral sclerosis

1/4.5

12/54.5

8/36.4

1/4.5

5.

Late hemorrhagic and ischemic strokes

 -

5/18.5

20/74

2/7.4

6.

Dyscirculatory encephalopathy

 -

3/11.5

23/88.4

 -

7.

Chronic vegetative state

 -

1/16.6

4/66.6

1/16.6

8.

Cerebral palsy 5

 -

 -

 -

5/100

9.

Glioblastoma multiforme 5

 

4/80

 1/20

 

10.

Neurodegenerative diseases 11

1/9

2/18.1

7/63.6

1/9

 

Total

10/2.1

125/27.2

254/55.4

69/15.1

 

 Table 5.

Effectiveness of conventional therapy of the control group cases of neurological

№ п/п

Disease

Deterioration

Absolute %

No effect

Absolute %

Effective

Absolute %

Highly effective

Absolute %

1.

Traumatic disease of the spinal cord

2/1.7

58/36.2

28/24.3

-                      

2.

Traumatic disease of the brain

-

22/18.9

12/10.4

 -

3.

Multiple sclerosis

4/3.45

5/3.1

3/2.6

 -

4.

Amyotrophic lateral sclerosis

15/12.9

6/3.7

3/2.6

-

5.

Late hemorrhagic and ischemic strokes

-

40/25

36/31.3

3/100

6.

Dyscirculatory encephalopathy

3/2.6

21/13.1

32/27.8

-

7.

Chronic vegetative state

2/1.7

3/1.8

-

-

8.

Cerebral palsy

2/1.7

3/1.8

-

-

9.

Glioblastoma multiforme

75/64.6

-

-

-

10

Neurodegenerative diseases

15/12.9

5/3.1

1

-

 

Total

116/29.6

160/40.9

115/29.4

3/0.7

 

Discussion

The results of our previous research showed that conservative use of the SC is the most effective and its effectiveness varies from 35% to 56% (Bryukhovetskiy AS, 2003). In this research we show that the therapy is effective in 55.4% cases, and high effectiveness was observed in 15.1% cases. Effectiveness of tissue engineering and bioengineering varies from 41 to 49.6%.  We were not able to enhance effectiveness of the technologies of regenerative medicine over 56%, despite the variety of the cell types. Still, as we previously reported, the use of the stem cell preparations appeared to be safe. Probably, the reason for the limitations of production and evaluation of the effectiveness and clinical application lies in the fundamental errors in the methodology of using the SCs, instead of being led by the goals, objectives and indications for their administration. Absence of clear molecular targets to affect the pathological cell leads to absence of the effect (proliferation, differentiation, etc) expected by the physician. Today, the main and only indication for cell therapy is regeneration of the cells of damaged neural tissue (NT) of the brain or spinal cord. For most prepared stem and progenitor cells, the goal of molecular effect is to stimulate the regenerative process of NT. Undoubtedly, other indications for stem cell therapy were reported, such as immune system cell replacement in multiple sclerosis, regulation of effector functions for malignant neoplasms of the brain. The phenomenon of intra-tissular regeneration became the widely accepted indication for employing SCs, and it even has determined the title of a new branch of medicine. Still, the regenerative medicine, as a new sphere of global healthcare, uses the SC preparations mostly in a systemic way (intravenous, intra-arterial, intrathecal) or purposefully for the stimulation of general processes of regeneration in all organs and systems of the  human body (subcutaneous or intra-muscular administration). For the purpose of stimulation of local regeneration, the stem and progenitor cells are used in tissue engineering of the organs and tissues.

Neurorestoration with SC, as a new field of regenerative medicine on neurological diseases, was founded to restore the structure of injured NT (H.Honyung et al, 2012). Neurorestoration of the brain and spinal cord implies the structural reconstruction of the tissue with the elements replacement (cells, vessels, synapses, fibers etc). Neurorestoratology implies the strategy of using different types of cells for therapy, including native cells (isolated from umbilical blood, bone marrow, fat tissue, olfactory sheath) and cultured lines of autologous and allogeneic cells (embryonic, fetal, pluri-potent, genetically engineered) tissue-specific stem and progenitor cells: neural, hematopoietic, mesenchymal, stromal cells.

Different scientific and clinical approaches to CNS restoration by means of cell therapy are united by the fundamental evidence that demonstrate activation of the processes of regeneration in the zone of direct contact of the stem and progenitor cells with the cells of damaged NT The following key neurobiological phenomena that provide for the targeted SC transfer to the site of injury are studied and described: a) pathotropism of the stem and progenitor cells that means that the cells migrate to the site of injury following the inflammatory gradient; b) adhesion to the pathological cells; c) by stander effect that affects the cells of the injured NT in a maintaining and regulatory way. It has been shown in experiment that the main mechanisms of regenerative action of almost all cell preparations in the damaged brain are the following: 1) Fusion of the transplanted stem and progenitor cells with the cells of the damaged NT; 2) Establishment of new synaptic contacts between the cells of the damaged NT; 3) Biologically active secretory or regulatory effect of the SCs on the damaged neural cells (S. Kuroda et al., 2012).

Hence, to date research and medical community have gathered a lot of evidence about the stem and progenitor cells and it is still unclear how they can be systemized and applied in practice. However, we still expect that molecular biologists, cell biologists and neurobiologists would give us new evidence on the properties and markers of the SCs that will further promote the effect of the SCs. In the past 25 years almost all necessary discoveries about SCs have been done and today we have to learn how to use the available opportunities for clinical practice.

One of the delusions of the regenerative medicine was the desire to treat neurodegenerative diseases with the stimulation and activation of the universal intracellular mechanism of the systemic effect of cell preparations on the process of regeneration of NT. However, it has been forgotten that molecular mechanisms of the damage and restoration of the brain and spinal NT differ by the type of molecular damage, and the involvement of different informational characteristics of the cell in the pathological process, even though the processes seem similar clinically, morphologically and functionally. For example, if the metabolitic disorders of the neural cells initiated by the chronic vascular ischemization of the white and grey matters underlie vascular dementia, while dementia in Alzheimer’s disease is conditioned by proteomic disorders in tau-proteins and β-amyloid proteins exchange in the neurons of brain cortex. Meanwhile, the cognitive disorder in Parkinson’s disease is associated with disordered dopamine transfer in the synapses of striatal area of the brain, i.e. disorders in the secretome of neurons in subcortical area of the brain. Consequently, the functions of the damaged cells of different brain regions cannot be restored only through stimulation and activation of the general mechanisms of reparation and neuro-regeneration. The main targets of the stem and progenitor cells should be specific molecular pathways of signal transduction that are able to trigger or to arrest specific pathway for their regeneration. The choice of this specific pathway in the damaged neural cells can become the main target of the genome-postgenome research of the patients’ cells.

We presume that the main accent of contemporary research of the stem and precursor cells should be given to develop new classes of cell preparations with specific properties, which should develop the trends of molecular biology and molecular medicine, rely on the genome and whole transcriptome assays of gene expression and the role in the pathogenetic mechanisms of the diseases onset, as well as rely on the post-genome research of proteome and secretome of the applied cell preparations.

The development of molecularly targeted pharmaceuticals became the major trend of the most of the medical and pharmaceutical research. The development of target pharmaceuticals is based on the accurate and profound studies of the pathways of intracellular signal transduction (PICST) in the pathological cells for different neurological and psychiatric diseases, detection of the targets (acceptor proteins) on the membranes of the proteins or of the proteins in the structure of the PICST.  The optimal effect of the specific PICST can initiate and/or arrest the effector functions of the cells, such as apoptosis, proliferation, mitosis, invasiveness. Accurately targeted ligand proteins or such ligands as monoclonals antibodies (MCA) or iRNAa as the elements of targeted drug that hit acceptor proteins permit maintenance of the pathological cells and clinical effectiveness of the therapy.

However, the pharmacological target therapy (PTT) has a significant drawback that often surpasses its advantages.  The molecules of the ligand proteins and ligands represented as MCA and iRNA do not affect acceptor proteins selectively, and the PICST of most cells of the body that they contact when circulating thus causing severe adverse effects. Hence, for the accuracy of molecular targeting and avoiding adverse effects, the therapy is merely aimed at the pathology-specific of the PICST that results from the pathogenesis or carcinogenesis of the disease. That means, the targets of PTT only can be the ones with the characteristic of pathology-specific. This pharmacological therapy cannot be used to maintain healthy cell systems and to regulate the systems of cell with slight damages of the PICST. The development of the targeted drugs for the therapy of neurological diseases can significantly improve the life quality of the patients and provide unique condition for the regulation of biological processes in the NT of the patients.

Cell targeted therapy (CTT) opens the new horizon for both regulation and maintenance of effector functions of the damaged cells (neurons, neuroglia, microglia etc) and vessels of the NT. Due to the aforementioned biological phenomena (pathotropism, cell adhesion and bystander effect), the CTT can be used for therapeutic effect on the specific and non-specific PICST, i.e. those PICST that are not involved into pathogenesis.

To evaluate the opportunities of the CTT we propose to consider two neurological diseases with basically different pathogenesis: 1. Malignant glial tumor of the brain – glioblastoma multiforme (GM) and, 2. Chronic injury of the spinal cord (SCI).

In GM the main goal of the CTT is to suppress proliferation, migration and invasiveness of the cancer SCs (CD133+) of GM. In the therapy of SCI the CTT should be aimed at the activation of proliferation, mitosis and regeneration of the cells of nervous cells in the site of injury.

Our theoretical and experimental post-genome research of the GM  [10] showed that the main methodology to develop molecularly targeted cell preparations in neoplastic disorders of CNS must rely on the fundamental molecular and neurobiological evidence about the GM: 1. Mitotic, proliferative and migration processes in the cancer SC play a leading role and lead to 4 or 5 mutations in the neural SCs and development cancer SCs from them; 2. Oncospecific proteins take from 57% to 67% of the proteomic structure of the cancer SCs of GM; these are the proteins that are not found in healthy humans, thus the regulation of healthy cells through standard PICST is extremely limited.

Regulating and controlling effect on migration, infiltrative and proliferative processes in GM can be realized only affecting specific PICST in the cancer SCs that were not involved into carcinogenesis: focal adhesion pathway and integrin pathway. Membrane acceptor proteins of these pathways (CXCL1, CD81, TPT1, Cas6 and AXL proteins) can be the main targets for GM targeted therapy. The pathways can be blocked by ligand proteins secreted by neural SCs that are able to suppress proliferation and growth of GM.   It can be whole range of the proteins, capable of protein-protein interaction, including molecules of follistatine. In other words, the cell preparation should express molecules of follistatine. The analysis of the secretome of a neural SC is achieved by proteomic mapping and profiling of normalized signal intensity of the proteins, the molecules of which can provide horizontal (on the target proteins inside the PICST) or vertical (on the acceptor proteins of cell membranes) targeted effect on cancer SCs. Specific concentration of follistatine in the secretome of neural SCs permits using this cell preparation as one of the target preparations from GM. Our evidence confirms experimental research of the Swedish team (Staflin K, Zuchner T, Honeth G, Darabi A, Lundberg C, 2009) of the role of follistatine in the arrest of cancer SCs of GM proliferation. Hematopoietic SCs can also be considered as targeted cell preparations, if their secretome has appropriate concentration of follistatine. It can be achieved by the provisional processing of the transcriptome of hematopoietic stem and progenitor cells with low molecular chemical compounds (perturbagenes) that can modify expression of some of the genes of these cells. Common acetylsalicylic acid can be such a perturbagene [10] in certain concentration and exposition of the cells (Polyakov VG, Bryukhovetskiy AS, Shevchenko VE et al, 2015).

In SCI the main goal is to initiate and activate PICST of mitosis, proliferation and regeneration of the injured cells of spinal cord. The main effector pathways to activate regeneration and specific molecules fir targeting are well known: STAT3 phosphorylation with molecular target STAT3/gp130 enhances regeneration; mTOR signaling with molecular target pTEN deletion promotes growth of axons in peripheral nervous system, SOCS3 deletion with molecular target JAK/STAT signaling is associated with axonal regeneration in CNS, PSAF expression with molecular target ERK-mediated signaling contributes to acetylation in associated regeneration, and other.

Hence, the main molecular targets of the acceptor proteins to activate the regeneration pathways (mTOR signaling, JAK/STAT signaling, Myc signaling, PI3K/Akt signaling, Atf3/CREB signaling, RAC1 signaling, STAT3&C-Jun, Rho signaling, Notch signaling, SMAD signaling, eIF5A signaling) permit influence on the regulation and feedback of the main pathogenetic neurobiological processes in the injured spinal cord: energy metabolism, inflammatory response, oxidative stress, cytoskeletal, vascular changes, axonal regeneration. The ligand proteins for the targeted molecular effect can be detected by the bioinformation computer analysis using international databases of protein-protein interactions. The list of ligand proteins to affect specific PICST targets is an important tool of the CTT. The analysis of the proteome mapping of the secretomes of hematopietic, neural stem cells and mesenchymal stromal cells permit selection of the cell systems with high concentration of the appropriate ligand proteins in the secretomes and their use in the effective SCI therapy.

Conclusion. Hence, use of the CTT in the contemporary technologies of regenerative medicine will significantly enhance both the effectiveness and safety of the cell therapy for neurological and psychiatric diseases, while the standardization and certification of the secretome of the cell preparation obtained from the stem and progenitor cells by proteome mapping will provide appropriate effect on the acceptor proteins of the CNS pathological cells. The main goal of the cell banks where the cell preparations are stored is the detection of active ligand proteins in the SC secretome of SCs. The selection of the cell preparations with appropriate ligand proteins that are capable of protein-protein interaction with acceptor proteins in certain CNS pathology can become the key factor in the development of the cell target therapy. In this case, the cell banks (banks of bone marrow cells, banks of umbilical cells, banks of fetal cells etc.) will be obliged to standardize their cell preparations according to the ligand proteins of their secretomes, which is easily achieved in the mapping and profiling of secretomes of the stored cell preparations.

Hence, if molecular biologists are included into the staff of the banks and they are able to detect the targets in the injured brain or spinal cord of the patient they can detect the cell preparation with appropriate molecularly targeted secretome with specific properties using the database or the registry of cell preparations. Selection of the cell preparations with appropriate ligand proteins in the secretomes will significantly enhance the effectiveness of the CTT and improve their neurorestorative properties in different neurological diseases.

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MICROWAVE ENCEPHALOGRAPHY (MWENC) PROJECT - NEW TECHNOLOGY OF DIAGNOSTICS OF THE CONDITION OF THE BRAIN

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CELLULAR TECHNOLOGIES

CELLULAR TECHNOLOGIES IN THERAPY CHRONIC SPINAL CORD INJURY

CELLULAR TECHNOLOGIES IN THERAPY CHRONIC SPINAL CORD INJURY

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Thank you for visiting our webpage!

Today cancer cannot be cured completely, but it can be transferred into a chronic and non-lethal disease, the survival rates can be significantly increased and the life quality can be improved. Alternatively, we can help provide a dignified departure from life, free from pain and humiliation.

Sincerely yours,
Professor,
PhD,
MD

Andrey S. Bryukhovetskiy

NeuroVita

Address

23 Kashirskoye shosse
Moscow
115478
Russia

Contact us

Telephone:
007 (499) 324-9339
007 (499) 324-9389
Fax:
007 (499) 324-9350
Email: neurovita@mail.ru

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Administration:
Monday-Friday from 9 am to 8 pm
Saturday and Sunday from 9 am to 4 pm
Patients are admitted 24/7