Intranasal Inhalations of M2 Macrophage Soluble Factors in Children With Developmental Speech Disorders
Condition: Language Delay; Language; Developmental Disorder, Expressive; Language; Developmental Disorder, Receptive; Autism Spectrum Disorder; Attention Deficit-Hyperactivity Disorder; Speech Disorders in Children
MeSH terms: Speech Disorders; Language Development Disorders; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Developmental Disabilities
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 speech difficulties in children with developmental dysphasia (DD) are
      improved with intranasal inhalations of bioactive factors (BF), produced by macrophages of M2
      phenotype (M2-BFs). The rationale for this approach is the ability of central nervous system
      (CNS) to repair and the important role of macrophages in the regulation of this process. It
      was found that type 2 macrophages (M2) have anti-inflammatory and neurorestorative potential,
      in contrast to pro-inflammatory and neurotoxic effects of М1 cells. The influence of M2 is
      largely realized through the production of a wide spectrum 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 M2-BFs, as
      therapeutic tool, and intranasal administration focusing on nose to brain transport, as a
      mode of delivery. Expected clinical effects in treated children: improvement of speech
      understanding, word formation, grammatical structure of speech and formation of coherent
      speech.
    

Detailed description: 
      Neuroinflammation plays a central role in the pathogenesis of any damage to the central
      nervous system (CNS) profoundly affecting the ability of neural cells to survive and to
      regenerate. Macrophages play a key role in the regulation of neuroinflammation, but their
      role is ambiguous. In fact, macrophages can both induce neuronal and glial toxicity and
      promote tissue repair. The opposite effects of macrophages are largely due to their
      plasticity and functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1)
      are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In
      addition, M2 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]. The data indicate that M2, in
      contrast to pro-inflammatory M1, 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
      high IL-10 level. M2 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.

      Pilot clinical trials have demonstrated the safety and clinical efficacy of intrathecal
      administration of M2 in children with severe cerebral palsy [2, 3] and in nonacute stroke
      patients [4]. Moreover, intranasal delivery of M2 macrophage-derived soluble products reduces
      neuropsychological deficit in patients with cerebrovascular disease [5]. Given this data, the
      investigators expect that intranasal administration of the M2-BFs (Bioactive Factors) will
      reduce the severity of speech disorders in children, including improving speech
      understanding, sensorimotor speech level, word formation skills, as well as the formation of
      the grammatical structure of speech and coherent speech. Of note, intranasal administration
      of M2 soluble factors allow to delivery bioactive agents to brain through the olfactory and
      trigeminal ways across brain-blood barrier.
    

Intervention name(s): Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs).
Intervention type(s): Biological
Intervention description(s): Intranasal delivery of M2-BFs is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: M2 type macrophages; Cytokines; Intranasal administration; Neuroprotection; neuroregeneration; Speech disorders