Clinical trial NCT02957123: Intranasal Inhalations of Bioactive Factors Produced by M2 Macrophages in Patients With Organic Brain Syndrome
Official title: Safety/Efficacy of Intranasally-Administered Bioactive Factors Produced by Autologous M2 Macrophages in Patients With Organic Brain Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: 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
Keywords: macrophages M2 type
cytokines
intranasal administration
neuroprotection
neuroregeneration
organic brain syndrome
neurocognitive disorders
Lead sponsor: Russian Academy of Medical Sciences
Sponsor class: OTHER
First posted: 2016-11-06
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: The Number of Patients With Severe Adverse Events and Adverse Reactions
timeFrame: up to 6 months after treatment
Secondary outcomes:
measure: Change in Subjective Assessment of Clinical Symptoms (SACS)
timeFrame: Baseline and 6 months after treatment
measure: Change in Hospital Anxiety and Depression Scale (HADS)
timeFrame: Baseline and 6 months after treatment
measure: Change in Functional Mobility Assessment (FMA) Scale
timeFrame: Baseline and 6 months after treatment
measure: Change in Montreal Cognitive Assessment (МоСА)
timeFrame: Baseline and 6 months after treatment
Other outcomes:
Locations:
city: Novosibirsk
country: Russian Federation
facility: Institute of Fundamental and Clinical Immunology
Study officials:
affiliation: Institute of Fundamental and Clinical Immunology
name: Elena R Chernykh, MD, PhD
role: STUDY_CHAIR
affiliation: Institute of Fundamental and Clinical Immunology
name: Alexander A Ostanin, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chernykh ER, Shevela EY, Sakhno LV, Tikhonova MA, Petrovsky YL, Ostanin AA. The generation and properties of human M2-like macrophages: potential candidates for CNS repair? Cell Ther Transplant., 2010 DOI: 10.3205/ctt-2010-en-000080.01
citation: Sakhno LV, Shevela EY, Tikhonova MA, Ostanin AA, Chernykh ER. The Phenotypic and Functional Features of Human M2 Macrophages Generated Under Low Serum Conditions. Scand J Immunol. 2016 Feb;83(2):151-9. doi: 10.1111/sji.12401.
citation: Chernykh ER, Kafanova MY, Shevela EY, Sirota SI, Adonina EI, Sakhno LV, Ostanin AA, Kozlov VV. Clinical experience with autologous M2 macrophages in children with severe cerebral palsy. Cell Transplant. 2014;23 Suppl 1:S97-104. doi: 10.3727/096368914X684925. Epub 2014 Oct 9.
citation: Chernykh ER, Shevela EY, Starostina NM, Morozov SA, Davydova MN, Menyaeva EV, Ostanin AA. Safety and Therapeutic Potential of M2 Macrophages in Stroke Treatment. Cell Transplant. 2016;25(8):1461-71. doi: 10.3727/096368915X690279. Epub 2015 Dec 14.
citation: Shevela EY., Davydova MN, Starostina NM, Yankovskaya AA, Ostanin AA, Chernykh ER. Intranasal delivery of M2 macrophage-derived soluble products reduces neurological deficit in patients with cerebrovascular disease: A Pilot Study. Journal of Neurorestoratology, 2019; 7: 89-100 doi:10.26599/JNR.2019.9040010