The Use of Stem Cells in Autism

By Dr Stacy-Lee Sigamoney 8 months ago
Home  /  Next Biosciences Articles  /  The Use of Stem Cells in Autism

Autism Spectrum Disorder (ASD) is not well-understood as there are no defined mechanisms of aetiology or pathogenesis and presents as varied neurodevelopmental conditions [1; 2].

It is characterized by early-onset challenges in reciprocal social interaction, cognition and perception; and communication. Additionally, there may be unusually restricted, repetitive behaviours and interests [1; 2]. Those individuals who fall within the ASD-spectrum, may also present with executive dysfunction and atypical information processing [1].

The aetiology and pathogenesis of ASD may be attributed to multifaceted interactions between genetic and non-genetic risk factors.

Introduction

In 1943, psychiatrist Leo Kanner, described eight boys and three girls with the above-described presentation. In 1944, paediatrician Hans Asperger, also described four boys with a distinctive type of behaviour, which included a 6-year-old boy Fritz, who learnt to talk very quickly, but whose social interaction was limited to adults. These reports arose into what we recognize today as ASD. Awareness and understanding of ASD has grown substantially in the last 70 years. [1]

The latest revision of the DSM (Diagnostic and Statistical Manual of Mental Disorders): the DSM-V, which was last updated in May 2013, adopted the broad term of ASD without specifying subtypes. ASD was reorganized from a triad into a dyad, with atypical language development being removed from the criteria which is now considered an affiliated condition, with variations thereof.

Please see table 1 for features of ASD:

A constant network of brain areas which include the medial prefrontal cortex, superior temporal sulcus, temporoparietal junction, amygdala, and fusiform gyrus have been found to be hypoactive in ASD across all fields in which social perception and cognition are used. [1]

Genetic factors

Some genetic factors are distinct-in-nature such as Mendelian single-gene mutations that present as syndromic autism occurring in 5% in all individuals with ASD, as well as chromosomal abnormalities (approximately 5%), rare copy number variations (5-10%) and de novo and transmitted mutations. Large-scale epidemiological studies have shown a male predominance (autism seems to affect 4-5 times more males than females), which could imply a sex-linked aetiological load and susceptibility. [1]

Twin studies have suggested that there may be a prominent inheritance of autism more than 80%. [1] This heritability does show the presence of a gene-environment relationship, as monozygotic concordance rates are never 100%. [1]

The genetic structural design, in itself is both intricate and diverse as shown by cytogenetic studies of whole-genome linkage and association. Many genetic variations are linked to autism with a high occurrence of pleiotropy (this means that one gene affects more than one phenotype). Additionally, there is a high level of locus heterogeneity with theories that suggest up to 100 genes are involved. [1]

Non-genetic factors

Epidemiological studies have identified certain environmental risk factors but these were identified more as associations than causalities.

Advanced maternal or paternal age could account for the germline mutation, particularly if paternal-in-origin. [1]

Gestational factors could include complications during pregnancy and chemical-exposure. Alternatively, folic acid supplements before conception and during early gestation seem to be protective.

Vaccines such as thiomersal-containing, MMR (Mumps, Measles and Rubella) or repeated vaccines do not seem to cause autism according to the article entitled “Autism” from Lancet by Lai, et al (2014).

Interventions

Individualized and multidisciplinary approaches which are principally classified into behavioural, educational, medical and allied health exist. [2] Experimental drugs targeting various systems such as oxytocin, cholinergic and glutamatergic agents are underway. Antipsychotic drugs such as Serotonin Reuptake Inhibitors (SSRI’s) have been shown to reduce repetitive behaviours in children with autism. Risks for adverse events from these drugs are concerning. [1]

Additionally, complementary and alternative medicine may be considered. [1] These include melatonin, vitamins, a gluten-casein-free diet and omega-3 fatty acids but their effectiveness have not been established. [1]

With emerging therapies, the use of stem cells is increasingly being used in clinical trials to prove safety and efficacy.

The Use of Stem Cells in Autism

A non-randomized, open-label, single centre phase I/II trial investigated the safety and efficacy of combined transplantation of human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) in treating children with autism. This study was done in Shandong Jiaotong Hospital and Shandong Rehabilitation Therapy Centre between March and September 2009, after the study protocol and informed consent forms were approved by the Institutional Review Board of Shandong Jiaotong Hospital. [2]

Eligible participants included male and female children of 3 to 12 years of age, who had been diagnosed with ASD, in accordance with the diagnostic criteria for autism in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (which was relevant at the time in the diagnosis of autism); as well as a score of Childhood Autism Rating Scale (CARS) ≥ 30. [2]

Exclusion criteria included the following: prior history of severe allergic reactions; any severe psychiatric disorder or an alternative ASD such as Asperger syndrome, Rett syndrome or undefined pervasive developmental disorders; seizures within the past six months; active epilepsy, cerebrovascular diseases or brain trauma; severity of Illness (SI) of Clinical Global Impression (CGI) scale evaluated as “Normal” or “Borderline mentally ill” or “Mildly ill”; moderate or severe extrapyramidal symptoms or tardive dyskinesia; severe self-injury behaviour; active systemic or severe focal infections including Human Immunodeficiency Virus (HIV), syphilis and hepatitis; autoimmune diseases; severe pulmonary and haematological diseases, malignancy or hypo-immunity; undertaking other treatments that may affect the safety and efficacy evaluation of stem cell therapy; enrolment in other clinical trials in the last three months and lastly  other clinical conditions that the investigators considered not appropriate for enrolment in this study .[2]

37 participants diagnosed with autism were enrolled into this study and divided into three groups: CBMNC group (14 subjects, received CBMNC transplantation and rehabilitation therapy), Combination group (9 subjects, received both CBMNC and UCMSC transplantation and rehabilitation therapy), and Control group (14 subjects, received only rehabilitation therapy). Please see flow chart below. [2]

Transplantations included four stem cell infusions through intravenous and intrathecal injections once a week. Treatment safety was evaluated with laboratory examinations and clinical assessment of adverse effects.

Therapeutic efficacy at baseline (pre-treatment) and post-treatment was assessed using the Childhood Autism Rating Scale (CARS), Clinical Global Impression (CGI) scale and Aberrant Behaviour Checklist (ABC). Please see Tables 3, 4, 5 and 6 below.

Results regarding safety were measured by vital signs: five subjects briefly developed low grade

fever (3 subjects in the CBMNC group and 2 in the Combination group) and recovered without medical interventions. No other adverse events were noted in the 2 transplantation groups.

Therapeutic effects were promising as the study showed statistically significant differences on CARS, ABC scores and CGI evaluation in the two treatment groups compared to the control at 24 weeks post-treatment (p < 0.05). Transplantation of CBMNCs demonstrated efficacy compared to the control group. The combination of CBMNCs and UCMSCs showed larger therapeutic effects than the CBMNC transplantation alone. [2]

These results are quite promising. Having stated that the pathophysiology is poorly understood, several studies have shown that cerebral hypoperfusion is associated with many core symptoms in ASD[2]. Hypoperfusion in the frontal and prefrontal regions, was observed in children with ASD and is associated with cognitive and neuropsychological defects [2]. Hypoperfusion in the temporo-parietal areas could explain the language deficits, impairment of cognitive development and object representation, as well as abnormal perception and responses to sensory stimuli. [2] Targeting cerebral ischemia through therapeutic angiogenesis promoted by systemic administration of cord blood CD34+ stem cells to counteract ischemia has been experimentally established in vitro and animal models. It could account for the improvement shown in this particular study. [2]

The other systems implicated in improving the autistic symptoms might be through augmented regulation of immune dysfunction. Mesenchymal stem cells (MSCs) from umbilical cord tissue have important immunoregulatory properties and are currently being investigated as promising cellular immunomodulatory and anti-inflammatory mediators. Additionally, MSCs can secrete an abundance of growth factors, anti-inflammatory cytokines and immunomodulatory mediators. [2]

In conclusion, umbilical cord blood and tissue cells show a lot of potential in the holistic therapy of improving life for individuals with autism.

 

References:

  1. Lai M, Lombardo M, Baron-Cohen S. Lancet.2014 Mar 8;383(9920):896-910. doi: 10.1016/S0140-6736(13)61539-1. Epub 2013 Sep 26.
  2. Yong-Tao L, Yun Zhang, Min Liu, et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. Journal of Translational Medicine 2013, 11:196 http://www.translational-medicine.com/content/11/1/196
Categories:
  Next Biosciences ArticlesTriScreen
this post was shared 0 times
00
About

 Dr Stacy-Lee Sigamoney

  (2 articles)