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Mesenchymal Stem Cells Therapy at Swiss Medica Clinic for Autism

What is Autism Disorder?

Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. Autism is the most prevalent ASD which is characterized by dysfunctions in social interactions, abnormal to absent verbal communication, restricted interests, and repetitive stereotypic verbal and non-verbal behaviors influencing the ability to relate to and communicate[1]. The dramatic rise in the number of children affected with autism has been noticed according to recent reports[2].

It is necessary to emphasize that the exact etiology of autism remains unclear. Immune dysregulation is considered to be one of the potential etiologic factors that may be involved in the development of autism.  An imbalance in the production of pro-inflammatory and anti-inflammatory factors takes place in autistic patients[3]. The obtained data showed that an ongoing neuroinflammatory process with marked activation of microglia and astroglia in the cerebral cortex, white matter and cerebellum take place in individuals with autism[4,5]. Also, different autoantibodies responding to the proteins in central nervous system have been detected in the children with autism indicating to autoimmune genesis of this disease[6]. Thus, according to available data immune dysfunction represents an underlying pathophysiological process in autism and therefore the treatment has to be targeted at modifying neuroimmune reactions.

It is necessary to mention that generalized brain hypoperfusion was detected in children with autism. Several studies confirmed that cerebral hypoperfusion is associated with many core symptoms in autism. Inadequate perfusion leads to brain tissue hypoxia which results in neuronal apoptosis as well as abnormal brain tissue metabolism[7,8]. Thus, the therapy has to be also targeted at attenuation of cerebral ischemia.

To date the therapy of autism is mainly symptomatic. Unfortunately, all prescribed drugs fail to address the autism core symptoms as well as they have a lot of adverse effects[9]. Also, there is no defined standard treatment for children with autism. Therapy is mostly limited to behavioral and developmental interventions as well as nutritional approach[10].

Mesenchymal Stem Cells Therapy for Autism

To date mesenchymal stem cells(MSCs) therapy represents a promising novel treatment strategy for autism which promotes to the recovery of the damaged neural tissue at molecular, structural, and functional levels. Due to potent immunomodulatory properties as well as proangiogenetic activity MSCs affect a key pathogenic processes which occur in autistic patients. MSCs exert strong neuroprotective action through production of growth and trophic factors, stimulation of endogenous neurogenesis, angiogenesis and synaptogenesis as well as modulation of neuroinflammation. More specifically, they promote to functional recovery by improving local blood perfusion to damaged areas through stimulation of new blood vessels formation (angiogenesis). MSCs limit the local inflammatory response due to inhibition of microglia and macrophages activation. They impair T-lymphocyte maturation[11]. Indeed, in the presence of MSCs immature or partially immature antigen presenting cells was showed to be produced. These cells turn off T cells leading to down-regulation of activated immune cell reactivity and thus reducing tissue damage[12]. Moreover, it was showed that MSCs can scavenge reactive oxygen species and reactive nitrogen species effectively attenuating of oxidative stress and promoting to tissue regeneration[13]. The microenvironment of damaged tissues produces factors that attract stem cells to the site of injury and enhance their differentiation into desired cells which were lost as a result of autoimmune attack[14].

In 2013 Lv Y.T. et al. reported the results of non-randomized, open-label, single center clinical trial in which children with autism were treated by MSCs. Thirty seven patients with confirmed autism were enrolled in the study. The treatment course included four stem cells infusions once a week. No allergic, immunological reactions or other serious adverse events associated with stem cells therapy were observed during the whole follow-up period. Objective functional and subjective improvements in visual, emotional and intellectual responses, body use, adaption to change, fear or nervousness, nonverbal communication and activity level assessed by Childhood Autism Rating Scale(CARS), as well as in lethargy/social withdrawal, stereotypic behavior, hyperactivity and inappropriate speech evaluated by Aberrant behavior checklist(ABC) were observed after stem cells therapy. Also, the Clinical global impression scale that measures illness severity, global improvement and therapeutic effects showed significant improvements in patients after received treatment. Thus, the obtained results have demonstrated that using of MSCs in the treatment of autistic patients is safe and efficacious[15].

Encouraging results were obtained in clinical trial conducted by Sharma A.et al. It was an open label proof of concept study in which patients with autism were treated by autologous bone marrow-derived stem cells. Thirty two patients were enrolled in the clinical trial. The follow-up period was 26 months. Initiation and consistency of eye contact as well as decrease in hyperactivity were observed immediately after the intervention. More specifically, restlessness, rocking, hand flapping, and jumping were seen to reduce early after stem cells treatment. Moreover, arousal and activity levels continued to normalize progressively. The improved attention span that was noticed after received therapy led to facilitation of communication. The patients began to initiate social interaction and engage in play, forming peer relationships. It is necessary to emphasize that significant clinical improvements were observed in emotional responsiveness, speech, language, sensory aspects, and cognition. No major side effects associated with intervention were reported[16].

In conclusion, cell-based therapy for patient with autism represents a highly promising therapeutic approach. According to available data from clinical trials MSCs threatment is safe and possesses the potential to manage overall disease severity and improve the quality of life the autistic patients.

References

  1. Siniscalco D. Current Findings and Research Prospective in Autism Spectrum Disorders. Autism 2013; S2:e001; doi:10.4172/2165-7890.S2-e001
  2. Mitka M. Rising autism rates still pose a mystery. JAMA 2010; 303(7):602
  3. Connolly A. M., Chez M., Streif E. M. et al. Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, LandauKleffner syndrome, and epilepsy. Biological Psychiatry 2006; 59(4):354–363
  4. Onore C., Careaga M., Ashwood P. The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun 2012; 26(3):383–392
  5. Vargas D.L., Nascimbene C., Krishnan C. et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005; 57(1):67–8
  6. Singer H.S., Morris C.M., Williams P.N. et al. Antibrain antibodies in children with autism and their unaffected siblings. J Neuroimmunol 2006; 178(1–2):149–155
  7. Gupta S.K., Ratnam B.V. Cerebral perfusion abnormalities in children with autism and mental retardation: a segmental quantitative SPECT study. Indian Pediatr 2009; 46(2):161–164
  8. Burroni L., Orsi A., Monti L. et al. Regional cerebral blood flow in childhood autism: a SPET study with SPM evaluation. Nucl Med Commun 2008, 29(2):150–156
  9. Doyle C.A., McDougle C.J. Pharmacotherapy to control behavioral symptoms in children with autism. Expert Opin Pharmacother 2012; 13:1615-1629; PMID: 22550944; doi:10.1517/14656566.2012.674110.12
  10. Ospina M.B., Krebs Seida J., Clark B. et al. Behavioural and developmental interventions for autism spectrum disorder: a clinical systematic review. PLoS One 2008; 3(11):e3755
  11. Aggarwal S., Pittenger M.F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105:1815–1822
  12. Beyth S., Borovsky Z., Mevorach D. et al. Human mesenchymal stem cells alter antigenpresenting cell maturation and induce T-cell unresponsiveness. Blood .2005; 105:2214-9
  13. Valle-Prieto A., Conget P.A. Human mesenchymal stem cells efficiently manage oxidative stress. Stem Cells Dev 2010; 19:1885–1893.
  14. Caplan A.I., Dennis J.E. Mesenchymal stem cells as trophic mediators. J Cell Biochem 2006;98:1076-84.
  15. Lv Y.T., Zhang Y., Liu M. et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med. 2013 Aug 27;11:196. doi: 10.1186/1479-5876-11-196
  16. Sharma A., Gokulchandran N., Sane H. et al. Autologous bone marrow mononuclear cell therapy for autism: an open label proof of concept study. Stem Cells Int 2013; 623875;PMID: 24062774; doi:10.1155/2013/623875