Allogeneic Human Umbilical Cord Mesenchymal Stem Cells for the Treatment of Autism Spectrum Disorder in Children: Safety Profile and Effect on Cytokine Levels

Neil H Riordan, Maria Luisa Hincapié, Isabela Morales, Giselle Fernández, Nicole Allen, Cindy Leu, Marialaura Madrigal, Jorge Paz Rodríguez, Nelson Novarro, Neil H Riordan, Maria Luisa Hincapié, Isabela Morales, Giselle Fernández, Nicole Allen, Cindy Leu, Marialaura Madrigal, Jorge Paz Rodríguez, Nelson Novarro

Abstract

Individuals with autism spectrum disorder (ASD) suffer from developmental disabilities that impact communication, behavior, and social interaction. Immune dysregulation and inflammation have been linked to children with ASD, the latter manifesting in serum levels of macrophage-derived chemokine (MDC) and thymus, and activation-regulated chemokine (TARC). Mesenchymal stem cells derived from umbilical cord tissue (UC-MSCs) have immune-modulatory and anti-inflammatory properties, and have been safely used to treat a variety of conditions. This study investigated the safety and efficacy of UC-MSCs administered to children diagnosed with ASD. Efficacy was evaluated with the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS), and with measurements of MDC and TARC serum levels. Twenty subjects received a dose of 36 million intravenous UC-MSCs every 12 weeks (four times over a 9-month period), and were followed up at 3 and 12 months after treatment completion. Adverse events related to treatment were mild or moderate and short in duration. The CARS and ATEC scores of eight subjects decreased over the course of treatment, placing them in a lower ASD symptom category when compared with baseline. MDC and TARC inflammatory cytokine levels also decreased for five of these eight subjects. The mean MDC, TARC, ATEC, and CARS values attained their lowest levels 3 months after the last administration. UC-MSC administration in children with ASD was therefore determined to be safe. Although some signals of efficacy were observed in a small group of children, possible links between inflammation levels and ASD symptoms should be further investigated. Stem Cells Translational Medicine 2019;8:1008-1016.

Keywords: Autism; Cytokines; Mesenchymal stem cells; Safety; Umbilical cord mesenchymal stem cells.

Conflict of interest statement

N.H.R. and J.P.R. declared leadership position, patent holder, and shareholders of MediStem Panama and the Stem Cell Institute. M.L.H. declared research funding as subinvestigator for Stem Cell Institute. I.M., N.A. declared leadership position with MediStem Panama. G.F., C.L. declared leadership position with Stem Cell Institute. M.M. declared leadership position and stock ownership with MediStem Panama. N.N. declared research funding from MediStem Panama.

© 2019 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Figures

Figure 1
Figure 1
(A): Mean serum macrophage‐derived chemokine levels at the four treatment points and the 12‐month and 21‐month visits (n = 20, 20, 18, 16, 13, and 10, respectively). (B): Mean serum thymus and activation‐regulated chemokine levels at the four treatment points and the 12‐month and 21‐month visits (n = 20, 20, 18, 16, 13, and 10, respectively).
Figure 2
Figure 2
(A): Mean Autism Treatment Evaluation Checklist scores at the four treatment points and the 12‐month and 21‐month visits (n = 20, 20, 18, 17, 14, and 14, respectively). (B): Mean Childhood Autism Rating Scale scores at the four treatment points and the 12‐month and 21‐month visits (n = 20, 20, 18, 17, 15, and 14, respectively).
Figure 3
Figure 3
Improvements in Childhood Autism Rating Scale (CARS) scores for eight participants between baseline and the 12‐month visit. Each bar represents the individual CARS score of one participant. Dotted lines correspond to the CARS thresholds for severity (severe at >37 in red, mild between 30 and 36.5 in green, and below autism threshold

References

    1. Sanchack KE, Thomas CA. Autism spectrum disorder: Primary care principles. Am Fam Phys 2016;94:972–979.
    1. Rice CE, Rosanoff M, Dawson G et al. Evaluating changes in the prevalence of the autism spectrum disorders (ASDs). Public Health Rev 2012;34:1–22.
    1. Lavelle TA, Weinstein MC, Newhouse JP et al. Economic burden of childhood autism spectrum disorders. Pediatrics 2014;133:e520–e529.
    1. Buescher AV, Cidav Z, Knapp M et al. Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr 2014;168:721–728.
    1. Bhat S, Acharya UR, Adeli H et al. Autism: Cause factors, early diagnosis and therapies. Rev Neurosci 2014;25:841–850.
    1. Park SY, Cervesi C, Galling B et al. Antipsychotic use trends in youth with autism spectrum disorder and/or intellectual disability: A meta‐analysis. J Am Acad Child Adolesc Psychiatry 2016;55:456.e454–468.e454.
    1. Sharma SR, Gonda X, Tarazi FI. Autism spectrum disorder: Classification, diagnosis and therapy. Pharmacol Ther 2018;190:91–104.
    1. Golnik AE, Ireland M. Complementary alternative medicine for children with autism: A physician survey. J Autism Dev Disord 2009;39:996–1005.
    1. Ashwood P, Krakowiak P, Hertz‐Picciotto I et al. Altered T cell responses in children with autism. Brain Behav Immun 2011;25:840–849.
    1. Ashwood P, Krakowiak P, Hertz‐Picciotto I et al. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun 2011;25:40–45.
    1. Ashwood P, Enstrom A, Krakowiak P et al. Decreased transforming growth factor beta1 in autism: A potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol 2008;204:149–153.
    1. Ashwood P, Wills S, Van de Water J. The immune response in autism: A new frontier for autism research. J Leukoc Biol 2006;80:1–15.
    1. Careaga M, Van de Water J, Ashwood P. Immune dysfunction in autism: A pathway to treatment. Neurotherapeutics 2010;7:283–292.
    1. Ashwood P, Anthony A, Pellicer AA et al. Intestinal lymphocyte populations in children with regressive autism: Evidence for extensive mucosal immunopathology. J Clin Immunol 2003;23:504–517.
    1. Adams JB, Johansen LJ, Powell LD et al. Gastrointestinal flora and gastrointestinal status in children with autism—Comparisons to typical children and correlation with autism severity. BMC Gastroenterol 2011;11:22.
    1. Buie T, Campbell DB, Fuchs GJ 3rd et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: A consensus report. Pediatrics 2010;125:S1–S18.
    1. Horvath K, Perman JA. Autism and gastrointestinal symptoms. Curr Gastroenterol Rep 2002;4:251–258.
    1. Molloy CA, Manning‐Courtney P. Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders. Autism Int J Res Pract 2003;7:165–171.
    1. Nikolov RN, Bearss KE, Lettinga J et al. Gastrointestinal symptoms in a sample of children with pervasive developmental disorders. J Autism Dev Disord 2009;39:405–413.
    1. Theoharides TC, Asadi S, Patel AB. Focal brain inflammation and autism. J Neuroinflammation 2013;10:46.
    1. Bode MK, Mattila ML, Kiviniemi V et al. White matter in autism spectrum disorders—Evidence of impaired fiber formation. Acta Radiol 2011;52:1169–1174.
    1. Essa MM, Guillemin GJ, Waly MI et al. Increased markers of oxidative stress in autistic children of the Sultanate of Oman. Biol Trace Elem Res 2012;147:25–27.
    1. Dong D, Zielke HR, Yeh D et al. Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder. Autism Res 2018;11:1076–1090.
    1. Ray B, Long JM, Sokol DK et al. Increased secreted amyloid precursor protein‐alpha (sAPPalpha) in severe autism: Proposal of a specific, anabolic pathway and putative biomarker. PLoS One 2011;6:e20405.
    1. Al‐Ayadhi LY, Mostafa GA. Elevated serum levels of macrophage‐derived chemokine and thymus and activation‐regulated chemokine in autistic children. J Neuroinflammation 2013;10:72.
    1. Shi Y, Wang Y, Li Q et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol 2018;14:493–507.
    1. Hu J, Yu X, Wang Z et al. Long term effects of the implantation of Wharton's jelly‐derived mesenchymal stem cells from the umbilical cord for newly‐onset type 1 diabetes mellitus. Endocr J 2013;60:347–357.
    1. Liang J, Zhang H, Hua B et al. Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis. Mult Scler 2009;15:644–646.
    1. Ma L, Zhou Z, Zhang D et al. Immunosuppressive function of mesenchymal stem cells from human umbilical cord matrix in immune thrombocytopenia patients. Thromb Haemost 2012;107:937–950.
    1. Shi M, Zhang Z, Xu R et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute‐on‐chronic liver failure patients. Stem Cells Translational Medicine 2012;1:725–731.
    1. Wu KH, Sheu JN, Wu HP et al. Cotransplantation of umbilical cord‐derived mesenchymal stem cells promote hematopoietic engraftment in cord blood transplantation: A pilot study. Transplantation 2013;95:773–777.
    1. Wu KH, Tsai C, Wu HP et al. Human application of ex vivo expanded umbilical cord‐derived mesenchymal stem cells: Enhance hematopoiesis after cord blood transplantation. Cell Transplant 2013;22:2041–2051.
    1. Zhang Z, Lin H, Shi M et al. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J Gastroenterol Hepatol 2012;27:112–120.
    1. Kim JH, Jo CH, Kim HR et al. Comparison of immunological characteristics of mesenchymal stem cells from the periodontal ligament, umbilical cord, and adipose tissue. Stem Cells Int 2018;2018:8429042.
    1. Najar M, Raicevic G, Boufker HI et al. Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: Combined comparison of adipose tissue, Wharton's jelly and bone marrow sources. Cell Immunol 2010;264:171–179.
    1. Arutyunyan I, Elchaninov A, Makarov A et al. Umbilical cord as prospective source for mesenchymal stem cell‐based therapy. Stem Cells Int 2016;2016:6901286.
    1. Siniscalco D, Bradstreet JJ, Sych N et al. Mesenchymal stem cells in treating autism: Novel insights. World J Stem Cells 2014;6:173–178.
    1. Liu Q, Chen MX, Sun L et al. Rational use of mesenchymal stem cells in the treatment of autism spectrum disorders. World J Stem Cells 2019;11:55–72.
    1. Ichim TE, Solano F, Glenn E et al. Stem cell therapy for autism. J Transl Med 2007;5:30.
    1. Siniscalco D, Kannan S, Semprun‐Hernandez N et al. Stem cell therapy in autism: Recent insights. Stem Cells Cloning Adv Appl 2018;11:55–67.
    1. 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;2013:623875.
    1. Lv YT, 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;11:196.
    1. Dominici M, Le Blanc K, Mueller I et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315–317.
    1. Geier DA, Kern JK, Geier MR. A comparison of the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS) for the quantitative evaluation of autism. J Mental Health Res Intell Disab 2013;6:255–267.
    1. Lalu MM, McIntyre L, Pugliese C et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): A systematic review and meta‐analysis of clinical trials. PLoS One 2012;7:e47559.
    1. Karussis D, Karageorgiou C, Vaknin‐Dembinsky A et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 2010;67:1187–1194.
    1. Roberts W, Weaver L, Brian J et al. Repeated doses of porcine secretin in the treatment of autism: A randomized, placebo‐controlled trial. Pediatrics 2001;107:E71.
    1. Handen BL, Johnson CR, Lubetsky M. Efficacy of methylphenidate among children with autism and symptoms of attention‐deficit hyperactivity disorder. J Autism Dev Disord 2000;30:245–255.
    1. Krupa P, Vackova I, Ruzicka J et al. The effect of human mesenchymal stem cells derived from Wharton's jelly in spinal cord injury treatment is dose‐dependent and can be facilitated by repeated application. Int J Mol Sci 2018;19:1503.
    1. Richardson JD, Psaltis PJ, Frost L et al. Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction. Cytotherapy 2014;16:460–470.
    1. Guo Y, Wysoczynski M, Nong Y et al. Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Basic Res Cardiol 2017;112:18.
    1. Bolli R. Repeated cell therapy: A paradigm shift whose time has come. Circ Res 2017;120:1072–1074.
    1. Wysoczynski M, Khan A, Bolli R. New paradigms in cell therapy: Repeated dosing, intravenous delivery, immunomodulatory actions, and new cell types. Circ Res 2018;123:138–158.
    1. Jarocha D, Milczarek O, Wedrychowicz A et al. Continuous improvement after multiple mesenchymal stem cell transplantations in a patient with complete spinal cord injury. Cell Transplant 2015;24:661–672.
    1. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: Immune evasive, not immune privileged. Nat Biotechnol 2014;32:252–260.
    1. Masi A, Lampit A, Glozier N et al. Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: A meta‐analysis. Transl Psychiatry 2015;5:e640.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren