Intranasal Inhalations of Bioactive Factors Produced by M2 Macrophages in Patients With Organic Brain Syndrome
Condition: 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
MeSH terms: Brain Diseases; Brain Ischemia; Chronic Traumatic Encephalopathy; Syndrome; Mental Disorders; Psychotic Disorders; Neurocognitive Disorders; Cognitive Dysfunction; Cognition Disorders
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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: 
      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.
    

Intervention name(s): Intranasal auto-M2-BFs
Intervention type(s): Drug
Intervention description(s): Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
Other intervention name(s): Bioactive Factors, Produced by M2 Macrophage
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: macrophages M2 type; cytokines; intranasal administration; neuroprotection; neuroregeneration; organic brain syndrome; neurocognitive disorders