Autism is derived from the word “Autos”, which in Greek means “self”, as a person affected with autism is the one who lives in a world of their own, with least or no social interaction and interplay.
The autism spectrum or autistic spectrum describes a range of conditions classified as neuro-developmental disorders in the fifth revision of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5). The Diagnostic and Statistical Manual-5, published in 2013, redefined the autism spectrum to encompass the previous (Diagnostic and Statistical Manual-IV-TR) diagnoses of Autism. As per syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), and childhood disintegrative disorder. These disorders are characterised by social deficits and communication difficulties, stereotyped or repetitive behaviours and interests, sensory issues, and in some cases, cognitive delays.
Burden of disorder
According to Autism and Developmental Disabilities Monitoring Network, 11 sites in the United States in 2010, reported the overall prevalence of ASD among the Autism and Developmental Disabilities Monitoring sites was 14.7 per 1000 in children aged 8 years and below, i. e., 1 in 68. In more current statistics, according to the National Health Statistics report 2011–2012, the prevalence among children aged 6 to 12 was 2 per cent, a significant increase from 2007, when it was 1.16 per cent, among children of the same age. In India, it has been reported in the Journal of Social Sciences 2012, as 1 in 250. This disorder in boys are four times more affected than girls.
Symptomatology
Children with autism seem normal at birth, but within 36 months the symptoms start appearing. One course of development follows a gradual course of onset in which parents report concerns in development over the first two years of life and diagnosis is made around 3 to 4 years of age. Some of the early signs of ASDs in this course include decreased looking at faces, failure to turn when name is called, failure to show interests by showing or pointing, and delayed pretend play. A second course of development is characterized by normal or near-normal development followed by loss of skills or regression in the first 2 to 3 years. Regression may occur in a variety of domains, including communication, social, cognitive, and self-help skills; however, the most common regression is loss of language. There continues to be a debate over the differential outcomes based on these two developmental courses. Some studies suggest that regression is associated with poorer outcomes and others report no differences between those with early gradual onset and those who experience a regression period. Overall, the prognosis is poor for persons with classical (Kanner-type) autism with respect to academic achievement and poor to below-average for persons across the autism spectrum with respect to independent living abilities; in each case, a lack of early intervention exacerbates the odds against success.
Cause and pathology
The cause of this disorder is largely unknown, research suggests that autism can be precipitated by a variety of conditions and combinations of genetic and inflammatory factors triggered by environmental factors and sometimes physical or psychological trauma. It may also be due to intra-uterine predisposition, hypoxia, autoimmunity, etc. Ultimately leading to: Neuronal degeneration and loss vs underdevelopment; loss of inter neuronal connections; release of pro-inflammatory cytokines causing collateral damage; de-vascularization due to capillary destruction; T4 cells and NK cells would be stimulated, leading to release of TNFa, IL 1a, etc, to cause internal immune intolerance and dysregulation causing damage.
Diagnosis
There is no a single test to detect autism disorder, instead, health professionals use physical examination, personal histories, clinical assessment tools, and possibly genetic testing for diagnosis. So it is basically a diagnosis of exclusion, based on Indian Autism Detection Scale.
Current management
Currently there are no specific treatment options available. Pharmacotherapy is directed towards controlling of symptoms, like convulsions, agitation, etc. Other therapies like behavioral, nutritional, immunological modulation have been tried, but have not been effective with certainty. Hyperbaric oxygen therapy with or without erythropoietin (hormone enhancing red cell production) have been the first attempt to correct hypoxia, i. e., trying to supply more oxygen to the oxygen deprived tissues, but just increasing the oxygen tension in blood and not its ultimate delivery to tissues, has made very little predictable difference.
This has paved way to the correction of the actual pathology by means of cell therapy.
Rational of using cytotherapy
There are two major problems responsible for causing autistic spectrum disorder, namely, hypo-perfusion of specific areas of the brain and immunological abnormalities leading to cellular insult and death. In addition, chemicals are secreted from dying or dead cells, called Cytokines, Interleukins, etc, lead to collateral damage and death of more cells in the periphery, clogs capillaries and their death (endarteritis). The harmful chemicals and capillary destruction per petuatesdysregulation of the immune thermostat, leading to faulty perception of one’s own cells as foreign and leading to their destruction as well (auto-immunity). So, if both the primary problems could be corrected, the entire pathology behind autism could be reversed.
Why would stem cells work?
Stem cells would potentially solve the major problems, by giving rise to new blood vessels hence not only remove the cellular debris but also wash away the harmful chemicals (Neo-vascularization). It would thus decrease the inflammation and accelerate healing and increase the delivery of oxygen to the end organ and tissues, participating in rejuvenation and regeneration. For these functions to happen two types of cells are required, CD34+ cells or Haematopoietic progenitor cells and Mesenchymal progenitor cells. Attracted by this possibility of patho-physiological level correction of autistic spectrum disorder, many clinical trials were undertaken. All interventions were done in human subjects using stem cells from bone marrow, embryonic tissue and fetal tissues, as there was and still, is no animal model of Autism. The first publication was way back in 2002, two academic publications were available in Cell and Neurology, in 2004 – one paper in Archives of Neurology, 2005 – two papers in Current Neurology and Brain and in 2006 one paper in Neurosciences. None of them could exhibit clear cut improvement in the global symptomatology of ASD. This was addressed by Dr Thomas Ichim in his review publication in the Journal of Translational Medicine, in June 2007 “ Stem cell therapy for autism and later emphasized by Sinisalco D, et al in his review publication titled – Autistic Spectrum Disorder: Is mesenchymal stem cell personalized therapy of the future? The Journal of Biomedicine and Biotechnology, in February 2012. All the publications dealt with embryonic stem cells, endogenous stem cells and cells in their individuality, not realizing the importance of the multi-cellular niche, which is most vital for the whole renewal process, not only rejuvenate but also to regenerate when the mature cells die as part of natural cycle.
Umbilical cord blood derived stem cells were possibly the only ethical source of naïve stem cells, Regulatory and naïve T cells, CD34+ and Mesenchymal Progenitor cells, all in the same basket. CD34+ Progenitor cells, commonly known as Haematopoietic stem cells, which has been proved that ontogenically is the mother of both the blood vessels and blood cells – more aptly called “haemangiogenic stem cells” – helps in neovascularization, building up of new capillary network, which propagates the newly formed blood cells, not only enhancing the oxygenation, but also carries with it the Regulatory and naïve T cells, which resets the dysregulated immune thermostat, such that the old and new cells are tolerated. As stem cells home to the site of injury, so even when injected intravenously are able to home to the injured sites of the brain and heal the damaged neuronal tissue. The Mesenchymal Progenitor cells, which are known as stromal cells in the umbilical cord blood, also home to the site of injury, and actively reduces the pathological immune response additionally provides the matrix of the niche (immediate micro-environment), integrating within which not only the new cells grow (neo-neuronalization by cell fusion and/or differentiation) and establish the inter-neuronal connections or synapses.
Related current studies
Based on these findings from different experiments, safety and efficacy of stem cell therapy in patients with Autism was submitted for study in April 2011, at the Shandong Jiantong Hospital, Jinan, Shandong, China. Where four doses of intravenous and intrathecal injections of umbilical cord blood derived mono nuclear cells (UCB MNCs) were administered. Results were published as: LvYT, et al. Transplantation of human cord blood mono nuclear cells and human cord derived mesenchymal stem cells in autism. J Trans Med, 2013 Aug 27; 11: 196, which concluded that transplantation of umbilical cord blood derived mono nuclear cells demonstrated efficacy compared to control group. This was followed by intervention using autologous cord blood stem cells for autism. It was conceived as a randomized, interventional, double blind, placebo controlled, cross-over, efficacy study. This was being done at Sutter Pediatric Neurology, Sacramento, California, US, under Dr Michael Chez, where efficacy of single IV infusion of autologous UCB would be studied over a period of 6 months. The final outcome would be judged based ondifferences in expressive and receptive language and changes in levels of TNFa, TNF ß, IL-1a, IL-1ß, IL-6, IL-10 and IL-13. The results of the phase I study has been published in 2015, which is extremely encouraging.
Based on this a mixed Phase I and Phase II study has been started in March 2015, by Dr JoAnne Kurtzberg at the Duke’s Medical Centre, California, USA.
Conclusion
Modern medicine rests on three pillars: pharmacotherapy, devices and biological, but futuristic medicine would be having four, the most current and valued addition would be cellular therapy. Regenerative medicine is that branch of medicine which would be practicing regeneration, rejuvenation and healing through the use of “stem cells”. The naïve population, waiting to be transformed by appropriate cues into cells required for healing. Umbilical cord and cord blood, being fetal remnants are the richest and ethically and socially most accepted source of stem cells. Given the plasticity and the naivety of such cells it is the best, and when being used for the same person (autologous use), there is absolute acceptance of the cells for regenerative therapy without the slightest chance for rejection. Once the results of the above mentioned studies are available, we would definitely know the direction, where pharmacotherapy ends, paving way for cytotherapy, for such hitherto incurable disorders, using stem cells derived from umbilical cord blood. Personalized and genomic medicine is the next logical step and the right direction to go ahead. This would pave way for management of diseases and disorders by correction of pathology and restoration of physiology and answer plenty unanswered questions. Cordlife, being the largest umbilical cord bank, boasts of the highest inventory, in South East Asia. In its endeavor to mitigate sufferings of the mass, Cordlife has invited Dr. Chez, to conduct multi-centric study on the safety and efficacy of autologous umbilical cord blood in autistic spectrum disorders, which he has graciously accepted. This study would be beginning very soon under his supervision.
(Author is technical director, Cordlife Sciences India Pvt. Ltd.)