"Autologous Umbilical Cord Blood Stem Cells to Improve Symptoms in Children with Autism" safe but...

On a recent visit to the local aquarium with some of my brood, I listened to an interesting talk given by one of the staff. It concerned starfish and, among other things, how these creatures possess the fantastic ability to grow new limbs as and when one or more are 'given' to predators. The mechanism behind such fabulous regenerative power is down to stem cells I was told; those marvels of biological engineering that have the potential to "develop into many different cell types in the body during early life and growth." From what I understand, most, if not all animals have stem cells, although us human folk aren't quite Curt Connors just yet...

Anyhow, stem cells as well as allowing some animals to regrow limbs, have been touted as being potentially *useful* for all manner of other conditions/diseases/ailments (see here). You probably won't be surprised to hear that autism has been mentioned with stem cells in mind (see here for example), with various potential modes of action being discussed. Some of the peer-reviewed research talking about various types of stem cell use in the context of some autism has been quite *hopeful* in terms of observed effects (see here and see here) but not all...

The findings reported by Michael Chez and colleagues [1] (open-access available here) probably fall into that 'but not all' category. Reporting results based on a clinical trial listing (see here), authors concluded that: "autologous umbilical cord infusions are safe for children with ASD [autism spectrum disorder]" but "no statistically significant differences for any endpoints" were detected in their "randomized, blinded, placebo-controlled, crossover trial." I'm not entirely sure therefore as to how at least one press release on the Chez study was able to arrive at some of the text that they did (see here)...

OK, a few descriptions might be useful. Autologous basically means 'obtained from the same individual'. Indeed this was one of the inclusion criteria for the study: "Participants were required to have AUCB [autologous umbilical cord blood] cryopreserved at Cord Blood Registry (CBR, South San Francisco, CA) processed on the AutoXpress (AXP) Platform (Cesca Therapeutics, Rancho Cordova, CA)." That means that stem cell rich blood taken from the umbilical cord that united infant with their placenta had to be available for this study use. The "randomized, blinded, placebo-controlled, crossover trial" bit basically means that this study followed a gold-standard scientific methodology; participants were randomly allocated to receive a cord blood infusion or a placebo, none of the investigators who administered the various tests knew who was receiving which (cord blood or placebo), and at some point in the study, participants switched from cord blood to placebo or vice-versa continuing with the not-knowing status. As for those 'various tests', the primary outcome was scores on the "Expressive One Word Picture Vocabulary Test, 4th edition (EOWPVT-4) and Receptive One Word Picture Vocabulary Test, 4th edition (ROWPVT-4)" alongside some other secondary outcomes looking at behaviour "at baseline 12, and 24 weeks after infusion of each product." Safety of the product was also a key part of this study.

Results: bearing in mind the loss of one participant (to the study results, not anything else!), there are a few noteworthy findings. First, it looks like over the course of the study period at least, this was a fairly safe intervention. Out of a total of 86 adverse events reported, only 3 were eventually thought to be 'probably' related to the autologous umbilical cord blood infusion. Importantly: "No adverse events required treatment" so there is a potential tick for the tenet 'first, do no harm' at least in the short-term. When however it came to looking at those language and behaviour outcomes, the authors note that: "There were also no statistically significant differences between scores on the two primary or secondary endpoints after infusion with AUCB versus infusion of placebo." The authors do talk about "trends in improvement on the Socialization Subscale of the Vineland" but a trend is not the same as a statistically significant result...

The authors opine as to the possible reasons for the lack of statistically significant changes following the use of the cord blood infusion. Dose is mentioned as one possibility, and specifically: "participants varied widely in percentage and number of CD34+ cells in samples infused." Although no expert on CD34+ cells, from what I gather the numbers of these cells present in cord blood samples provides some potential important information on the 'quality' of the infusion as a function of their connection to hematopoietic progenitor cells. The authors also talk about the 'reticence' of parents of participants to "use the entire banked sample on an investigational treatment" given the finite material available.

So, where next for stem cells 'for autism'? Well, given the data showing such an intervention to be safe at least in the short-term, this research area is still ripe for further study alongside chatter about modelling autism via stem cells [2] and beyond [3]. I know there are varied opinions out there about the 'usefulness', long-term safety and acceptability of this class of intervention [4], but like any other area of the autism research landscape, issues such as potential best and non-responders need to be considered before baby and bathwater are thrown out completely...

To close, that (recent) feeling when, at the birthday party of one of your brood, a song by Loded Diper is introduced as the song of the day for the birthday child. Cue the curious looks from other mums and dads and the embarrassed smiles from yours truly...

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[1] Chez M. et al. Safety and Observations from a Placebo-Controlled, Crossover Study to Assess Use of Autologous Umbilical Cord Blood Stem Cells to Improve Symptoms in Children with Autism. Stem Cells Transl Med. 2018 Feb 6.

[2] Ilieva M. et al. Psychiatry in a Dish: Stem Cells and Brain Organoids Modeling Autism Spectrum Disorders. Biol Psychiatry. 2017 Nov 16. pii: S0006-3223(17)32197-2.

[3] Donegan JJ. et al. Embryonic stem cell transplants as a therapeutic strategy in a rodent model of autism. Neuropsychopharmacology. 2018. Feb 7.

[4] Simberlund J. et al. Mesenchymal stem cells in autism spectrum and neurodevelopmental disorders: pitfalls and potential promises. World J Biol Psychiatry. 2015 Jul 31:1-8.

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"a single intravenous infusion of autologous umbilical cord blood" and autism

'Could stem cells offer hope for autism?' went one media headline referencing the very preliminary "phase I, open-label trial" published by Geraldine Dawson and colleagues [1] (open-access) detailing the experiences of a single intravenous infusion of autologous umbilical cord blood in 25 children with "a confirmed diagnosis of ASD [autism spectrum disorder]."

Well, the results were promising in respect of important issues such as safety in light of the tenet 'first do no harm': "Assessment of adverse events across the 12-month period indicated that the treatment was safe and well tolerated" and some potentially interesting effects were noted when it came to behaviour "across a wide range of outcome measures in this study." But much like another quite innovative study with a similar research design published quite recently (see here) one needs to be a little cautious about the limitations of this current study. Not least that: "As an uncontrolled open-label study, it is not possible to determine whether the observed behavioral changes were due to the treatment or reflect the natural course of development during the preschool period." I might add that any study mentioning the words 'stem cells and autism' in the same sentence is going to be subject to significant scrutiny (see here for example).

Although the Dawson paper is open-access, here are a few choice details:

• "All participants had to have an available autologous umbilical cord blood unit banked at a family or public cord blood bank."  This was a study using the participants own stored cord blood - blood 'left over' from the umbilical cord and/or placenta at birth - which was initially screened to make sure it was both viable and safe: "negative maternal infectious disease markers tested on the maternal donor or cord blood product (minimally including hepatitis B, hepatitis C, human immunodeficiency virus [HIV], human T-lymphotrophic virus [HTLV], and syphilis)." Cord blood contains stem cells; cells that have significant [mighty] morphing capabilities in terms of turning into different cell types. In amongst the various peer-reviewed research (and research hype) surrounding stem cells, their use with autism in mind has been slowly creeping into the public consciousness (see here for example) with appropriate caveats.
• Participants were given one infusion of their cord blood samples. They were fairly closely monitored over the study duration to ensure that any adverse effects (AEs) were catalogued. Researchers reported: "A total of 92 AEs were reported in 23 participants... with a median of three events per participant. All events were graded as Mild (71 events) or Moderate (21 events)." Further: "Twelve events (13%) were considered related to the infusion, with the most common being allergic reaction, manifested by urticartia and or/cough occurring on the day of infusion (5 events in 4 participants; all Mild; 2 requiring an additional dose of IV Benadryl). The most common unrelated AEs were agitation, skin changes, and typical childhood infections, reported between 2 days and 1 year post-infusion."
• Alongside looking for AEs, authors also reported some changes to the various behavioural schedules included for study. Looking at scores at baseline (pre-infusion) and then at 6 and 12 months, a pattern started to emerge based on group results. So: "Most of the observed behavioral changes occurred during the first 6 months and were sustained between 6 and 12 months post-infusion." The direction of the behavioural change were all positive (i.e. behavioural measures indicated improvement) and were spread out across both parent-reported and clinician-reported schedules. Interestingly too, eye gaze measurements for some 21 participants who were scanned also showed changes: "a 20% increase in odds of gazing at the actress’ eyes over time." Researchers also noted that: "children's nonverbal IQ was correlated with change for the majority of outcomes measures, with higher nonverbal IQ being associated with greater improvements in behavior." Such a finding might also tie into some other research looking at a group termed 'optimal outcome' (see here).

There is a scheme of research required to follow this preliminary study, of that there is no doubt. We don't for example, know exactly how any behavioural changes were tied into the infusion (or not) because among other things, no other physiological measurements were made over the course of the Dawson study pointing to possible mechanisms. This is not entirely unexpected given the preliminary nature of the study. I will also stress again that these results were based on participants' own stored cord blood samples not other donor samples just in case any incorrect generalisation of results is made. As an aside, I was quite interested to see the use of IV (intravenous) Benadryl in relation to some of those AEs. Benadryl is an antihistamine used to manage allergy symptoms. I've talked before on this blog about how treating allergy issues in relation to some individual cases of autism might have some interesting effects on the presentation of autistic symptoms too (see here). I wonder...

I am assuming that there will be more to talk about in this area of autism research as a consequence of a concluding sentence made by the authors: "we have also included the clinician-rated CGI and additional measures as secondary endpoints in our next study, a phase II, double-blind randomized clinical trial designed to formally evaluate the efficacy of umbilical cord blood infusion in improving core symptoms of ASD." Accepting that there is still some PR to be done with regards to the issue of cord blood and stem cell use in relation to autism [2] (that also includes work related to modelling conditions like autism too [3]), I'll be interested to see whether the current Dawson results survive more rigorous scientific study...

To close, skin problems in Hollywood villains. No really, someone has actually studied this... 

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[1] Dawson G. et al. Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial. Stem Cells Translational Medicine. 2017. April 5.

[2] Sharpe K. et al. In the Know and in the News: How Science and the Media Communicate About Stem Cells, Autism and Cerebral Palsy. Stem Cell Rev. 2016 Feb;12(1):1-7.

[3] Wen Z. Modeling neurodevelopmental and psychiatric diseases with human iPSCs. J Neurosci Res. 2017 May;95(5):1097-1109.

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Geraldine Dawson, Jessica M. Sun, Katherine S. Davlantis, Michael Murias,, Lauren Franz, Jesse Troy, Ryan Simmons, Maura Sabatos-DeVito, Rebecca Durham, & Joanne Kurtzberg (2017). Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial. Stem Cells Translational Medicine : 10.1002/sctm.16-0474

"Androgens were not associated with autistic traits at 12 months of age"

EARLI - the Early Autism Risk Longitudinal Investigation study - has been mentioned on this blog before (see here) with the aim of the initiative to "examine possible environmental risk factors for autism and study whether there is any interplay between environmental factors and genetic susceptibility."

In this post I'm bringing the paper by Bo Park and colleagues [1] (open-access) to your attention and the observation(s) that umbilical cord blood levels of testosterone and other related androgens were seemingly not associated with autistic traits at 12 and 36 months of age in their cohort. Such findings represent yet another biological research blow (see here) to facets of the Extreme Male Brain (EMB) theory of autism and the suggestion that "ASD [autism spectrum disorder] is an extreme presentation of a typical male cognitive profile where the drive to “systemize” is stronger than the drive to empathize."

So, looking at cord blood samples from 137 children recruited on to EARLI - "a high autism-risk cohort following pregnant mothers with an older child diagnosed with an ASD (autistic disorder, Asperger syndrome, or pervasive developmental disorder not otherwise specified)" - researchers looked at whether measures of various androgens might correlate with scores on the Autism Observation Scales for Infants (AOSI) and Social Responsiveness Scale (SRS). Said schedules were administered at 12 months and 36 months respectively and various potentially confounding variables were taken into account when it came to looking at any associations. It's also worth pointing out that the technology of choice when it came to those measures of cord blood levels of androgens was an old favourite of this blog: liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results: well as per the title of this post, and after adjustment for potentially confounding variables - "maternal age, gestational age, and cesarean delivery" - there wasn't a great deal to see in terms of levels of androgens and the presence of autistic traits. Indeed, the title of this post only tells half the story as testosterone was also found not to be associated with the SRS scores at 36 months too. The authors do note that: "Male infants (n=75) showed significantly higher umbilical cord testosterone levels and greater social deficits at 36 months of age" than females, but after adjustment for confounders this observation was left wanting. They also talk about some interesting observations about when a child had an older female sibling diagnosed with autism - "androgen levels and autistic traits may depend on sex of the older affected sibling" - but I'm not so sure about the strength of such findings and whether other mechanisms might also be at work. I might reiterate that autistic traits were the name of the research game in this study not a diagnosis of autism.

As mentioned, the Park findings represent another setback for the generalisability of the role of androgens (prenatal and beyond) in relation to autism and/or autistic traits. I guess that in these days of the plural 'autisms' (see here) it's perhaps not entirely unexpected that grand theories of autism seem doomed to fail when put up to scientific scrutiny. Indeed someone recently has talked about this [2]. I still however remain interested in the discussions around the EMB theory of autism, and although this and other research has not been entirely kind to the hypothesis, it is still perhaps deserving of further study in order to see who it may be most relevant to in these days of plural autisms and subgroupings...

To close, isn't this why Twitter was invented?

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[1] Park BY. et al. Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study. Molecular Autism. 2017; 8: 3.

[2] Müller R-A. & Amaral DG. Editorial: Time to give up on Autism Spectrum Disorder? Autism Res. 2017. Jan 27.

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Park, B., Lee, B., Burstyn, I., Tabb, L., Keelan, J., Whitehouse, A., Croen, L., Fallin, M., Hertz-Picciotto, I., Montgomery, O., & Newschaffer, C. (2017). Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study Molecular Autism, 8 (1) DOI: 10.1186/s13229-017-0118-z