Intranasal Inhalations of Bioactive Factors Produced by M2 Macrophages in Patients With Organic Brain Syndrome

Study Overview
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Brief Summary
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The investigators have designed an innovative proof-of-concept trial designed to provide data as to whether the treatment/rehabilitation efficacy and functional outcome of patients with organic brain syndrome are improved with intranasal inhalations of bioactive factors (BF), produced by autologous M2 macrophages (auto-M2-BFs). The rationale for this approach is the ability of central nervous system to repair and the important role of macrophages in the regulation of this process. It was found that type 2 macrophages have anti-inflammatory and reparative potential, whereas M1 cells possess pro-inflammatory and neurotoxic effects. Action of M2 macrophages is largely realized through the production a wide variety of bioactive factors (cytokines, chemokines, growth factors, neuropeptides, microvesicles etc) that inhibit inflammation, protect neurons from apoptosis, stimulate neurogenesis, the growth and remyelination of axons, the formation of new synapses and activate angiogenesis. This study uses auto-M2-BFs, as therapeutic agents and intranasal administration focusing on nose to brain transport, as a mode of delivery. Expected clinical effects in treated subjects: improvement of cognitive functions (memory, language, attention); correction of focal neurological deficit (paresis, spasticity, sensory disorders); reduction vestibular/ataxic disorders (vertigo, unsteadiness when walking); reduction of headaches; reduction of asthenia (weakness, fatigue); correction of emotional disorders (anxiety, depression).

Detailed Description
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Following injury to the central nervous system (CNS), immune-mediated inflammation profoundly affects the ability of neural cells to survive and to regenerate. The role of inflammation comprises mostly of macrophages, is controversial, since macrophages can both induce neuronal and glial toxicity and promote tissue repair. The opposite effects of macrophages may be conditioned by their functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1) are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In addition, M2 macrophages predominantly induce the Th2 response, which is particularly beneficial in CNS repair. Using low serum conditions the investigators have generated M2-like macrophages and evaluated their phenotypic and functional features [1, 2]. Our data indicate that M2 macrophages, in contrast to pro-inflammatory M1 cells, produced significantly lower levels of pro-inflammatory cytokines (IL-1β, tumor necrosis factor-α, IL-6, IL-18, IL-12), chemokines (IL-8, monocyte chemoattractant protein 1-1) and Th1/Th2-cytokines (interferon-γ, IL-2, IL-4) coupled with a higher IL-10 level. M2 macrophages were capable of producing neurotrophic- (brain-derived neurotrophic factor,insulin-like growth factor-1), angiogenic- (vascular endothelial growth factor), and other growth factors (erythropoietin, granulocyte-colony stimulating factor , basic fibroblast growth factor, epidermal growth factor) with neuroprotective and regenerative activity. Our pilot clinical trials have demonstrated the safety and clinical efficacy of intrathecal administration of M2 macrophages in children with severe cerebral palsy [3] and in non-acute stroke patients [4]. Since cell-free culture medium of M2 macrophages contains a wide variety of neurotrophic, immunoregulatory and pro-angiogenic factors, the investigators expect that intranasal administration of these auto-M2-BFs will improve the treatment/rehabilitation efficacy and functional outcome of patients with organic brain syndrome. Of note, intranasal administration of M2-macrophage soluble factors allow to delivery bioactive agents to brain through the olfactory and trigeminal ways across brain-blood barrier.

Official Title
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Safety/Efficacy of Intranasally-Administered Bioactive Factors Produced by Autologous M2 Macrophages in Patients With Organic Brain Syndrome

Conditions
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Organic Brain Syndrome, Nonpsychotic, Neurocognitive Disorders, Mental Disorder, Organic, Delirium, Dementia, Amnestic, Cognitive Disorders, Nonpsychotic Organic Brain Syndrome, Organic Mental Disorder, Encephalopathy, Post-Traumatic, Chronic, Encephalopathy, Ischemic, Brain Ischemia

Intervention / Treatment
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* Drug: Intranasal auto-M2-BFs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults: age 18 - 80 Persistent neurological deficits (cognitive, mental, motor, vestibular/ataxic disorders as a result of trauma, cardiovascular, neurodegenerative and others cerebral injuries), confirmed clinically and by CT or MRI A written informed consent of the patient or close relatives Exclusion Criteria: Psychiatric disorders Seizures Severe dementia Hepatic or renal dysfunctions Hemodynamic or respiratory instability HIV or uncontrolled bacterial, fungal, or viral infections Pregnancy Malignancy Intolerance to gentamicin and / or multiple drug allergies Participation in other clinical trials

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intranasal auto-M2-BFs<br>Intranasally-Administered Bioactive Factors, Produced by Autologous M2 Macrophage (auto-M2-BFs). M2 macrophages were generated in vitro from peripheral blood of patients during 7 days.Cell-free culture medium, containing auto-M2-BFs, was collected and aliquots of 2 mL/vial were cryopreserved. 30 patients with organic brain syndrome will receive auto-M2-BFs with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days. | Drug: Intranasal auto-M2-BFs<br>* Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.<br>* Other names: Bioactive Factors, Produced by M2 Macrophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Patients With Severe Adverse Events and Adverse Reactions | Occurrence of severe adverse events and adverse reactions (allergic, toxic, inflammatory reactions; neurological deterioration, convulsive syndrome) | up to 6 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Subjective Assessment of Clinical Symptoms (SACS) | Subjective Assessment of Clinical Symptoms (SACS) is a 5-point rating scale with standardized criteria (0 - no; 1 - mild; 2 - moderate; 3 - severe; 4 - intensive) subjective assessment of the severity of fifteen clinical symptoms most characteristic of neurological disorders (headache, dizziness, gait disturbance, speech, visual impairment, tremor et al). Minimum SACS total score is 0, and maximum SACS total score is 60. Neurological improvements are assessed by SACS total score as > 6 points' reduction from baseline. | Baseline and 6 months after treatment | 
| Change in Hospital Anxiety and Depression Scale (HADS) | Hospital Anxiety and Depression Scale (HADS) is used to diagnose anxiety/depression symptoms (absence - 0 7 points; subclinical form - 8 10 points; clinical form - 11 points or more). Minimum HADS total score (anxiety + depression subscale) is 0, and maximum HADS total score is 42. Improvements in patients with anxiety/depression symptoms are assessed by HADS total score as > 4 points reduction from baseline. | Baseline and 6 months after treatment | 
| Change in Functional Mobility Assessment (FMA) Scale | Functional Mobility Assessment (FMA) iscale is designed to evaluate parameters characterizing stability (0 24 points) and gait (0 16 points). The maximum FMA total score on stability and gait subscales is 39-40 and corresponds to the norm, minimum FMA total score is 0 and corresponds to the gross impairment. The degree of impairment of total score is divided into significant (0 20 points), moderate (21 33 points), and light (34 38 points), whereas 39 40 points indicate no impairments. Improved mobility is assessed as FMA total score enhancement > 4 points from baseline. | Baseline and 6 months after treatment | 
| Change in Montreal Cognitive Assessment (МоСА) | Montreal Cognitive Assessment (MoCa) is used to assess cognitive functions. The maximum MoCa total score is 26-30 points and corresponds to the norm, 19-25 points - mild cognitive disorder; 11-21 points - dementia. Improvements in patients with cognitive disorder are assessed as MoCA total score increase > 3 points from baseline. | Baseline and 6 months after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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macrophages M2 type, cytokines, intranasal administration, neuroprotection, neuroregeneration, organic brain syndrome, neurocognitive disorders