Clinical Experience with Autologous M2 Macrophages in Children with Severe Cerebral Palsy

Abstract

Stem cell-based therapy is considered to be a new approach for the treatment of cerebral palsy (CP). Given the potent anti-inflammatory activity and high regenerative potential of M2 macrophages, these cells may be an alternative source for cell transplantation. To evaluate the safety and efficacy of autologous M2 macrophages, we conducted a pilot clinical trial in 21 children with severe CP. The primary outcome measure was safety, which included assessment of mortality of any cause, immediate adverse reactions, and serious adverse effects and comorbidities during 5-year follow-up. The secondary outcome measure was functional improvement in Gross Motor Function Measure (66-item GMFM) test, Peabody Developmental Motor Scale-Fine Motor (PDMS-FM) test, Ashworth scale, MRC scale, and an easy-to-understand questionnaire for evaluation of cognitive functions in our modification. Intradural injection of M2 cells (in mean dose of 0.8 × 10(6)/kg) into the lumbar spinal area did not induce any serious adverse events. No cases of mortality, psychomotor worsening, exacerbation of seizures, and long-term comorbidities, including tumors, were observed during a 5-year follow-up. After 3 months, GMFM score increased from 13.7 ± 7.8 to 58.6 ± 14.6, PDMS-FM score improved from 0.76 ± 0.42 to 5.05 ± 0.97, and the Ashworth score decreased from 3.8 ± 0.21 to 3.3 ± 0.24. Along with gross and fine motor function enhancement, an improvement of cognitive activity (from 1.62 ± 0.41 to 4.05 ± 0.64, according to questionnaire assessment) and reduction of seizure syndrome were registered as well. The neurological improvements did not diminish during the 5-year follow-up period. The data obtained suggest that cell therapy based on M2 macrophages is safe, does not induce early adverse effects and long-term comorbidities, and is accompanied with a significant improvement of motor and cognitive activities in severe CP patients. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

The Role of Macrophages in Damage Recovery of Central Nervous System: New Options for Treatment of Neurological Disorders

“…Пилотные клинические исследования аутологичных М2-клеток при церебральном инсульте и ДЦП показали, что интратекальное введение М2-клеток безопасно и не индуцирует системной воспалительной реакции. Клиниче-ский эффект у пациентов с тяжелыми формами ДЦП проявлялся значимым возрастанием мо-торной активности (в том числе тонкой мотори-ки), улучшением когнитивных функций, сниже-нием спастического синдрома и прекращением или ослаблением судорожного синдрома [9,10].…”

Intranasal delivery of M2 macrophage-derived soluble products reduces neuropsychological deficit in patients with cerebrovascular disease: a pilot study

“…As compared to M1, M2 macrophages generated were characterised by low antigen-presenting and pro-inflammatory activity, while possessing more pronounced regeneration potential due to high production of a variety of growth and neurotrophic factors [13,14]. Pilot studies of M2 intrathecal administrations in ischemic stroke [15] and severe cerebral palsy [16,17] demonstrated the safety and amelioration of motor and cognitive functions. However, the invasiveness of intrathecal injection and the possibility of M2→M1 repolarization in pathological microenvironment were serious factors limiting clinical translation of this treatment.…”

Malectin gene polymorphisms promote cerebral palsy via M2‐like macrophage polarization

“…On the other side, M2 macrophages are not neurotoxic and promote neuron repair by stimulating long-distance axon growth, 9 which will relieve multiple CP symptoms. 10 Malectin (MLEC) is a carbohydrate-binding protein malectin, which is a Type I membrane-anchored endoplasmic reticulum protein, 11,12 and interacts directly with embryonic lethal abnormal vision (ELAV) like RNA binding protein 1 (ELAVL1), 13 a regulator of macrophage polarization. 14 If 2 proteins interact with each other, they may have shared functions.…”