Autologous bone marrow mononuclear cell therapy for autism: an open label proof of concept study

Alok Sharma, Nandini Gokulchandran, Hemangi Sane, Anjana Nagrajan, Amruta Paranjape, Pooja Kulkarni, Akshata Shetty, Priti Mishra, Mrudula Kali, Hema Biju, Prerna Badhe, Alok Sharma, Nandini Gokulchandran, Hemangi Sane, Anjana Nagrajan, Amruta Paranjape, Pooja Kulkarni, Akshata Shetty, Priti Mishra, Mrudula Kali, Hema Biju, Prerna Badhe

Abstract

Cellular therapy is an emerging therapeutic modality with a great potential for the treatment of autism. Recent findings show that the major underlying pathogenetic mechanisms of autism are hypoperfusion and immune alterations in the brain. So conceptually, cellular therapy which facilitates counteractive processes of improving perfusion by angiogenesis and balancing inflammation by immune regulation would exhibit beneficial clinical effects in patients with autism. This is an open label proof of concept study of autologous bone marrow mononuclear cells (BMMNCs) intrathecal transplantation in 32 patients with autism followed by multidisciplinary therapies. All patients were followed up for 26 months (mean 12.7). Outcome measures used were ISAA, CGI, and FIM/Wee-FIM scales. Positron Emission Tomography-Computed Tomography (PET-CT) scan recorded objective changes. Out of 32 patients, a total of 29 (91%) patients improved on total ISAA scores and 20 patients (62%) showed decreased severity on CGI-I. The difference between pre- and postscores was statistically significant (P < 0.001) on Wilcoxon matched-pairs signed rank test. On CGI-II 96% of patients showed global improvement. The efficacy was measured on CGI-III efficacy index. Few adverse events including seizures in three patients were controlled with medications. The encouraging results of this leading clinical study provide future directions for application of cellular therapy in autism.

Figures

Figure 1
Figure 1
Frequency distribution of participants on CGI-II scale. This figure shows the percentage of people showing varying degrees of improvement after cellular transplantation.
Figure 2
Figure 2
Frequency distribution of the participants on the CGI-III scale. This figure demonstrates the percentage of people on varying degrees of efficacy of the intervention. This takes into consideration the side effects and the benefits observed.
Figure 3
Figure 3
Schematic representation of clinical improvements after cellular therapy. This figure shows proposed theoretical outline of observed changes after cellular therapy.
Figure 4
Figure 4
Findings in PET-CT scan before and after cellular therapy. (a) PET-CT scan before intervention showing reduced FDG uptake in the areas of frontal lobe, cerebellum, amygdala, hippocampus, parahippocampus, and mesial temporal lobe. (b) PET-CT scan six months after intervention comparison shows increased FDG uptake in the areas of frontal lobe, cerebellum, amygdala, hippocampus, parahippocampus, and mesial temporal lobe.

References

    1. Kopetz P, Endowed E. Autism worldwide: prevalence, perceptions, acceptance, action. Journal of Social Sciences. 2012;8(2):196–201.
    1. Myers S, Johnson C. American academy of pediatrics council on children with disabilities. Management of children with autism spectrum disorders. Pediatrics. 2007;120(5):1162–1182.
    1. Gray S. Gene therapy and neurodevelopmental disorders. Neuropharmacology. 2012;68:136–142.
    1. Ichim TE, Solano F, Glenn E, et al. Stem cell therapy for autism. Journal of Translational Medicine. 2007;5:p. 30.
    1. Siniscalco D. Stem cell research: an opportunity for autism spectrum disorders treatment. Autism. 2012;2:p. 2.
    1. Fujita Y, Ihara M, Ushiki T, et al. Early protective effect of bone marrow mononuclear cells against ischemic white matter damage through augmentation of cerebral blood flow. Stroke. 2010;41(12):2938–2943.
    1. Prasad K, Mohanty S, Bhatia R, et al. Autologous intravenous bone marrow mononuclear cell therapy for patients with subacute ischemic stroke: a pilot study. Indian Journal of Medical Research. 2012;136(2):221–228.
    1. Geffner LF, Santacruz P, Izurieta M, et al. Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplantation. 2008;17(12):1277–1293.
    1. Sharma A, Gokulchandran N, Chopra G, et al. Administration of autologous bone marrow-derived mononuclear cells in children with incurable neurological disorders and injury is safe and improves their quality of life. Cell Transplantation. 2012;21(supplement 1):S79–S90.
    1. Chen G, Wang Y, Xu Z, et al. Neural stem cell-like cells derived from autologous bone mesenchymal stem cells for the treatment of patients with cerebral palsy. Journal of Translational Medicine. 2013;26(11):p. 21.
    1. Khan AA, Parveen N, Mahaboob VS, et al. Safety and efficacy of autologous bone marrow stem cell transplantation through hepatic artery for the treatment of chronic liver failure: a preliminary study. Transplantation Proceedings. 2008;40(4):1140–1144.
    1. Prabhakar S, Marwaha N, Lal V, Sharma R, Rajan R, Khandelwal N. Autologous bone marrow-derived stem cells in amyotrophic lateral sclerosis: a pilot study. Neurology India. 2012;60(5):465–469.
    1. Kishk NA, Gabr H, Hamdy S, et al. Case control series of intrathecal autologous bone marrow mesenchymal stem cell therapy for chronic spinal cord injury. Neurorehabilitation and Neural Repair. 2010;24(8):702–708.
    1. Carlson RV, Boyd KM, Webb DJ. The revision of the declaration of Helsinki: past, present and future. British Journal of Clinical Pharmacology. 2004;57(6):695–713.
    1. Petit I, Szyper-Kravitz M, Nagler A, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nature Immunology. 2002;3(7):687–694.
    1. Zhu B, Murthy S. Stem cell separation technologies. Current Opinion in Chemical Engineering. 2013;2(1):3–7.
    1. Khan A, Khan SR, Shankles EB, Polissar NL. Relative sensitivity of the Montgomery-Asberg depression rating scale, the Hamilton depression rating scale and the clinical global impressions rating scale in antidepressant clinical trials. International Clinical Psychopharmacology. 2002;17(6):281–285.
    1. Kadouri A, Corruble E, Falissard B. The improved Clinical Global Impression Scale (iCGI): development and validation in depression. BMC Psychiatry. 2007;7:p. 7.
    1. Leucht S, Engel RR. The relative sensitivity of the clinical global impressions scale and the brief psychiatric rating scale in antipsychotic drug trials. Neuropsychopharmacology. 2006;31(2):406–412.
    1. Stigler KA, Mullett JE, Erickson CA, Posey DJ, McDougle CJ. Paliperidone for irritability in adolescents and young adults with autistic disorder. Psychopharmacology. 2012;223(2):237–245.
    1. Jordan I, Robertson D, Catani M, Craig M, Murphy D. Aripiprazole in the treatment of challenging behaviour in adults with autism spectrum disorder. Psychopharmacology. 2012;223(3):357–360.
    1. Hollander E, Soorya L, Chaplin W, et al. A double-blind placebo-controlled trial of fluoxetine for repetitive behaviors and global severity in adult autism spectrum disorders. American Journal of Psychiatry. 2012;169(3):292–299.
    1. Natrajan P, Kumar A, Goyal H, et al. Scientific report on research project for development of Indian Scale for assessment of autism. , 2008.
    1. Gerrard P, Goldstein R, Divit M, et al. Validity and reliability of the FUM instrument in the inpatient burn rehabilitation population. Archives of Physical Medicine and Rehabilitation. 2013
    1. Bradstreet JJ, Smith S, Baral M, Rossignol DA. Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder. Alternative Medicine Review. 2010;15(1):15–32.
    1. Herbert MR. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Current Opinion in Neurology. 2010;23(2):103–110.
    1. Gatto L, Broadie K. Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models. Frontline Synaptic Neurosciences. 2010;7:2–4.
    1. Johnson C, Meyers S. Council on children with disabilities, identification and evaluation of children with autism spectrum disorders. Pediatrics. 2007;120(5):1183–1215.
    1. Frith U, Frith C. The social brain: allowing humans to boldly go where no other species has been. Philosophical Transactions of the Royal Society B. 2010;365(1537):165–175.
    1. Brothers L, Ring B, Kling A. Response of neurons in the macaque amygdala to complex social stimuli. Behavioural Brain Research. 1990;41(3):199–213.
    1. Pelphrey KA, Shultz S, Hudac CM, Vander Wyk BC. Research review: constraining heterogeneity: the social brain and its development in autism spectrum disorder. Journal of Child Psychology and Psychiatry and Allied Disciplines. 2011;52(6):631–644.
    1. Allison T, Puce A, McCarthy G. Social perception from visual cues: role of the STS region. Trends in Cognitive Sciences. 2000;4(7):267–278.
    1. Zilbovicius M, Boddaert N, Belin P, et al. Temporal lobe dysfunction in childhood autism: a PET study. American Journal of Psychiatry. 2000;157(12):1988–1993.
    1. Gotts S, Simmons W, Milbury L, Wallace G, Cox R, Martin A. Fractionation of social brain circuits in autism spectrum disorders. Brain. 2012;135:2711–2725.
    1. Hashimoto T, Sasaki M, Fukumizu M, Hanaoka S, Sugai K, Matsuda H. Single-photon emission computed tomography of the brain in autism: effect of the developmental level. Pediatric Neurology. 2000;23(5):416–420.
    1. Connolly AM, Chez M, Streif EM, et al. Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy. Biological Psychiatry. 2006;59(4):354–363.
    1. Vojdani A, O’Bryan T, Green JA, et al. Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutritional Neuroscience. 2004;7(3):151–161.
    1. Cohly HHP, Panja A. Immunological findings in autism. International Review of Neurobiology. 2005;71:317–341.
    1. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology. 2005;57(1):67–81.
    1. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain, Behavior, and Immunity. 2011;25(1):40–45.
    1. Grove J, Bruscia E, Krause DS. Plasticity of bone marrow-derived stem cells. Stem Cells. 2004;22(4):487–500.
    1. Nakano-Doi A, Nakagomi T, Fujikawa M, et al. Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction. Stem Cells. 2010;28(7):1292–1302.
    1. Sykova E, Hendelova P, Urdzikova L, Lensy P, Hejcl A. Bone marrow stem cells and polymer hydrogels-two strategies for spinal cord injury repair. Cell Molecular Neurobiology. 2006;26(7-8):1113–1129.
    1. Siniscalo D, Bradstreet J, Antonucci N. The promise of regenerative medicine and stem cell research for the treatment of autism. Journal of Regenerative Medicine. 2012;1:p. 1.
    1. Siniscalco D, Sapone A, Cirillo A, Giordano C, Maione S, Antonucci N. Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? Journal of Biomedicine and Biotechnology. 2012;2012:6 pages.480289
    1. Pelacho B, Mazo M, Gavira JJ, Prósper F. Adult stem cells: from new cell sources to changes in methodology. Journal of Cardiovascular Translational Research. 2011;4(2):154–160.
    1. Meng J, Muntoni F, Morgan JE. Stem cells to treat muscular dystrophies-where are we? Neuromuscular Disorders. 2011;21(1):4–12.
    1. Glover LE, Tajiri N, Weinbren NL, et al. A step-up approach for cell therapy in stroke: translational hurdles of bone marrow-derived stem cells. Translational Stroke Research. 2012;3(1):90–98.
    1. Callera F, De Melo CMTP. Magnetic resonance tracking of magnetically labeled autologous bone marrow CD34+ cells transplanted into the spinal cord via lumbar puncture technique in patients with chronic spinal cord injury: CD34+ cells’ migration into the injured site. Stem Cells and Development. 2007;16(3):461–466.
    1. Callera F, Do Nascimento RX. Delivery of autologous bone marrow precursor cells into the spinal cord via lumbar puncture technique in patients with spinal cord injury: a preliminary safety study. Experimental Hematology. 2006;34(2):130–131.
    1. Theoharides TC, Angelidou A, Alysandratos K, et al. Mast cell activation and autism. Biochimica et Biophysica Acta. 2012;1822(1):34–41.
    1. Theoharides TC, Zhang B. Neuro-inflammation, blood-brain barrier, seizures and autism. Journal of Neuroinflammation. 2011;8:p. 168.
    1. Newschaffer CJ, Croen LA, Daniels J, et al. The epidemiology of autism spectrum disorders. Annual Review of Public Health. 2007;28:235–258.
    1. Anagnostou E, Taylor MJ. Review of neuroimaging in autism spectrum disorders: what have we learned and where we go from here. Molecular Autism. 2011;2(1):p. 4.
    1. Verhoeven JS, Cock PD, Lagae L, Sunaert S. Neuroimaging of autism. Neuroradiology. 2010;52(1):3–14.
    1. Schifter T, Hoffman JM, Hatten HP, Jr., Hanson MW, Coleman RE, DeLong GR. Neuroimaging in infantile autism. Journal of Child Neurology. 1994;9(2):155–161.
    1. Zilbovicius M, Meresse I, Boddaert N. Autism: neuroimaging. Revista Brasileira de Psiquiatria. 2006;28(supplement 1):S21–S28.
    1. Chugani DC. Neuroimaging and neurochemistry of autism. Pediatric Clinics of North America. 2012;59(1):63–73.
    1. Galuska L, Szakáll S, Jr., Emri M, et al. PET and SPECT scans in autistic children. Orvosi hetilap. 2002;143(21, supplement 3):1302–1304.
    1. Case-Smith J, Arbesman M. Evidence-based review of interventions for autism used in or of relevance to occupational therapy. American Journal of Occupational Therapy. 2008;62(4):416–429.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する