"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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Can a bone marrow transplant really affect psychotic symptoms in schizophrenia?

"Though BMT [bone marrow transplantation] may not be a cure for all cases of schizophrenia, it definitely possesses the potential to manage overall disease severity and improve the quality of life, and this case report is a preliminary demonstration of the safety and efficacy of BMT in treatment-resistant schizophrenia."

So said the findings reported by Tsuyoshi Miyaoka and colleagues [1] (open-access available here) discussing a case report of a young man initially diagnosed with paranoid schizophrenia which was eventually deemed 'treatment-resistant' on the basis of his lack of [positive] response to anti-psychotic medication(s) given for "his auditory hallucinations, suspiciousness, active social avoidance, persecutory delusion, and deterioration in the level of social functioning."

Things unfortunately got worse for this young man we are told, as he was subsequently diagnosed with acute myeloid leukemia - cancer of the white blood cells - setting in motion the initially daunting task of treatment via a bone marrow transplant. As the name suggests, BMT involves the transplantation of bone marrow where stem cells are made. Stem cells are those wonderful cells that give rise to the various types of blood cells we all have among other things. The idea being that a kinda of reboot of white blood cells in this case could potentially treat his leukemia.

Although Miyaoka et al don't actually say how successful the BMT was for his leukemia (the patient was alive 8 years after BMT so I assume successful), they do talk about what happened to his psychotic symptoms following the BMT. So: "Thirty days later, his psychotic symptom had almost disappeared. He was sustained without any neuroleptic treatment and need for any other administration." Indeed, this didn't appear to be any short-term effect neither as "8 years after BMT, the improvements of somatic and psychiatric symptoms are continued, and the patient is very well and there are no residual psychiatric symptoms." In short, things were still going well for this young man both in terms of his past leukemia diagnosis and also psychotic symptoms.

There is always the possibility of "spontaneous improvement without any treatment" as accounting for the psychiatric results presented by the authors. Indeed, I also note that various immunosuppressive medicines were also administered around the time of the BMT to "avoid graft versus host disease (GVHD)" which might also have played some role in light of other research suggestions [2]. One has to be careful not to jump to too many conclusions particularly on the basis of single case reports.

But... it is a potentially important coincidence that use of a BMT came at the same time as the symptom changes noted. I'll also draw your attention to a 'call for case histories' on the topic of "BMT in patients with coincident schizophrenia" made by Sommer and van Bekkum [3] on the back of other work from these authors in relation to "the possibility that schizophrenia may be transmitted" where "a patient... developed severe psychosis after receiving a BM transplant from his schizophrenic brother" [4]. It seems that there may be a two-way process potentially at work when it comes to immune function and schizophrenia.

This is interesting stuff. Framed alongside the idea that schizophrenia might not be a homogeneous condition - think 'the schizophrenias' -  and that at least one 'type' of schizophrenia might have a significant 'immune' component to it (see here for example), one could envisage further investigations on the potential use of BMT in certain cases. I do have to mention safety and the possible side-effects of BMT outside of just GVHD (see here) as being important considerations; added to the invasiveness of BMT.

And whilst we're on this topic, I'd also direct you to some chatter about mice and bone marrow transplants in the context of autism some years back (see here) minus any sweeping generalisations but again, interesting...

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[1] Miyaoka T. et al. Remission of Psychosis in Treatment-Resistant Schizophrenia following Bone Marrow Transplantation: A Case Report. Front Psychiatry. 2017 Sep 21;8:174.

[2] Knight JG. et al. Rationale for a trial of immunosuppressive therapy in acute schizophrenia. Mol Psychiatry. 2007 May;12(5):424-31.

[3] Sommer IE, van Bekkum DW. Call for case histories of BMT in patients with coincident schizophrenia. Bone Marrow Transplantation. 2013;48(6):880.

[4] Sommer IE. et al. Severe chronic psychosis after allogeneic SCT from a schizophrenic sibling. Bone Marrow Transplantation. 2015;50(1):153-154.

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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

Mesenchymal stem cell transplantation and a mouse model of autism

I once again tread carefully in this brief post talking about stem cells and autism on the back of what seems to be some growing research interest in this area (see here).

The paper by Hadar Segal-Gavish and colleagues [1] adds to this increasing interest with their efforts detailing what happened to a mouse model of autism (the BTBR mouse) following "intracerebroventricular MSC [mesenchymal stem cells] transplantation."

Looking at what happened when MSC transplantation was used, the authors highlight various behavioural and biological effects including: "a reduction of stereotypical behaviors, a decrease in cognitive rigidity and an improvement in social behavior." BDNF (brain-derived neurotrophic factor) was also reported to show changes following transplantation: "elevated BDNF protein levels in the hippocampus accompanied by increased hippocampal neurogenesis in the MSC-transplanted mice compared with sham treated mice."

The authors conclude: "Our study suggests a novel therapeutic approach which may be translatable to ASD [autism spectrum disorder] patients in the future."

Acknowledging that stem cells and autism is still a little bit of a hot potato in terms of the limited available research and more ethical questions about its use, these are interesting results. A recent opinion paper from Simberlund and colleagues [2] on the topic of MSC and autism highlighted the 'pitfalls and potential promises' of this line of investigation, and how despite almost universal scientific approval in terms of 'success' of this type of intervention so far, "substantial methodological and theoretical challenges and pitfalls remain before this can be considered a viable therapeutic option."

I'm gonna leave it at that for now.

Music: Aerosmith - Walk This Way.

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[1] Segal-Gavish H. et al. Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice. Autism Res. 2015 Aug 10.

[2] 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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Segal-Gavish H, Karvat G, Barak N, Barzilay R, Ganz J, Edry L, Aharony I, Offen D, & Kimchi T (2015). Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice. Autism research : official journal of the International Society for Autism Research PMID: 26257137

MOCOS: a new candidate for autism research

I'll freely admit that until reading the paper by François Féron and colleagues [1] (open-access available here) I had never heard of MOCOS (MOlybdenum COfactor Sulfurase) before.

Described as "an enzyme of the purine metabolism that sulfurates the molybdenum cofactor, thus allowing the two downstream enzymes—xanthine dehydrogenase (XDH) and aldehyde oxidase (AOX1)—to be active", researchers reported that in nasal stem cells provided by a small group of adults diagnosed with an autism spectrum disorder (ASD), MOCOS was down-regulated compared with analyses of similar cells from asymptomatic controls. They concluded that differences related to MOCOS might be important: "likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders."

I'm intrigued.

The Féron paper is open-access but a few details might be useful:

• Eleven participants diagnosed with autism (autism spectrum disorder, ASD) were included for study. Interestingly, DSM-5 diagnostic criteria were used to confirm the presence of ASD. Age and gender matched asymptomatic (for autism) controls were also used. As per the supplementary information included with the main article (see here), the authors characterised their participant group pretty well from various different angles.
• A nasal biopsy was performed on participants in order to extract "nasal olfactory stem cells" based on a previously published technique [2]. Again, it's new news to me that you can get stem cells from the nose but apparently the "olfactory epithelium is also a nervous tissue that produces new neurons every day to replace those that are damaged by pollution, bacterial of viral infections. This permanent neurogenesis is sustained by progenitors but also stem cells residing within both compartments of the mucosa, namely the neuroepithelium and the underlying lamina propria."
• Based on a "non-hypothesis-driven approach" Féron et al set about looking for "transcriptome anomalies" between the groups. Alongside other potentially important differences they stumbled across MOCOS in relation to their autism cohort and decided to look-see whether this might have some impact on cerebral functions using a classical worm model - Caenorhabditis elegans (C. elegans). A "genetic ablation of mocs-1 (the MOCOS ortholog)" engineered into the worm induced "an alteration of the response to oxidative stress and is responsible for abnormal neurotransmission phenotypes." Human cell studies confirmed this data.

Despite the small participant group, the MOCOS findings might carry some weight in view of some of the other 'dysregulated' genes that turned up with the ASD group in mind. So: "9 out of these 156 genes—ADAM23, CADM1, FOS, FOSB, JAG1, MEST, OXTR, SFRP1 and XIST—have been previously associated with ASD." You might note the mention of OXTR in that list, denoting the oxytocin receptor gene bearing in mind the cautious history in that area. That also pathway analysis of the genes differentially regulated in the autism group "identified developmental disorders and gastrointestinal diseases as two of the most represented categories associated with these genes" adds to the interest, bearing in mind the term 'over-represented' when it comes to bowel issues and autism (see here).

The suggestion that "MOCOS misexpression increases sensitivity to oxidative stress" is also an important part of the Féron findings. Oxidative stress and autism has quite a bit of peer-reviewed research history (see here for example) particularly in areas such as glutathione metabolism (see here) albeit not universally [3]. It's not beyond the realms of possibility that MOCOS may indeed be a contributory factor to such issues being present in some cases.

Further work is required in this area to corroborate the Féron data using larger participant numbers for example. With that in mind, I'll be keeping my eye open for more work on MOCOS and autism and whether it lives up to its 'new player' status...

Music: Weezer and Undone.

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[1] Féron F. et al. Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. Mol Psychiatry. 2015 Aug 4.

[2] Girard SD. et al. Isolating nasal olfactory stem cells from rodents or humans. J Vis Exp. 2011 Aug 22;(54). pii: 2762.

[3] Durieux AM. et al. Cortical and subcortical glutathione levels in adults with autism spectrum disorder. Autism Res. 2015 Aug 20.

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Féron F, Gepner B, Lacassagne E, Stephan D, Mesnage B, Blanchard MP, Boulanger N, Tardif C, Devèze A, Rousseau S, Suzuki K, Izpisua Belmonte JC, Khrestchatisky M, Nivet E, & Erard-Garcia M (2015). Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. Molecular psychiatry PMID: 26239292

Efficacy of foetal stem cell transplantation in autism...

The recent news that researchers might be one step closer to 'curing' type 1 diabetes following the publication of the paper by Pagliuca and colleagues [1] brought back into focus how stem cell therapy might hold some promise for all manner of conditions. The idea that researchers could generate "hundreds of millions of glucose-responsive β cells from hPSC [human pluripotent stem cells] in vitro" still faces a few challenges, including overcoming the immune assault central to the autoimmune condition that is type 1 diabetes. I have but one comment to make about the immune system and autoimmunity in this context: worm pills (see here)...

The question of whether an advance has been similarly made following the publication of the paper by Jeff Bradstreet and colleagues [2] (open-access available here) is perhaps open to some discussion with their observations that: "Statistically significant differences (p<0.05) were shown on ATEC/ABC scores for the domains of speech, sociability, sensory and overall health, as well as reductions in the total scores when compared to pre-treatment values" based on the use of foetal stem cells (FSCs) "in treating children diagnosed with ASDs [autism spectrum disorders]". Further details about the study can also be found in the latter slides of the presentation shown here.

Stem cell therapy in the context of autism is still a scientific hot potato. I've covered previous, very preliminary, forays into this research area before on this blog (see here). It is with the same cautions and caveats that I discuss the latest paper from Bradstreet et al.

So:

• This was a study of some 45 children diagnosed with an autism spectrum disorder (ASD) (mean age = 6-7 years). Diagnosis was confirmed by some of the gold-standard assessment instruments including ADOS and ADI. There were quite a few exclusion criteria applied to study entrants such that those with epilepsy, or "a neurological or co-morbid psychiatric disorder" were not examined. Learning disability without autism was also "considered exclusion criteria" as was a diagnosis of Asperger syndrome.
• The study was based in Kiev in the Ukraine where "stem cells harvested from 5-9 weeks old human fetuses following voluntarily – elective pregnancy terminations (legally available in the Ukraine)" were used. I don't doubt that there may be some who have strong views about this practice as per commentary from other authors (see here). Hematopoietic stem cells (HSCs) after harvesting were tested for various bacterial, fungal and viral infections as were the women who previously carried.
• Long quote coming up... "Stem cell transplantation of suspensions containing cryopreserved fetal stem cells were preceded by pre-medication of the subject via intravenous slow infusion of diphenylhydramine (Darnitsa, Ukraine) 10 mg and prednisone (Darnitsa, Ukraine) 15 mg on Day 1 and diphenhydramine (Darnitsa, Ukraine) 10 mg on Day 2". At this point, I'll draw your attention to some other work previously discussed on this blog on a possible role for corticosteroid therapy for some types of autism (see here) which included the use of prednisolone, the active metabolite of prednisone. After which the stem cells were administered...
• Results: "Early post-transplantation effects were reported in 78% of children: 26% of these children became calmer; eye contact was improved in 9%, while 29% had better appetite and 23% had an improved affect". Importantly, the authors report that no adverse effects were initially noted and "No transmittable diseases were noted during the 12 month follow-up". They also make mention of how initial effects may well have been [partly] as a consequence of the corticosteroid and other medication initially administered.
• Scores on the ATEC and ABC bore out the positive group changes noted between baseline (before stem cell therapy) and at 6 and 12 month follow-up which were also accompanied by various immunological changes "indicative of improved cell-mediated immunity in children".

OK. Despite these results the authors themselves are still cautious about their findings and stress: "future research studies are urgently needed and larger randomized -placebo controlled trials are needed to further characterize potential FSC-associated improvements in ASDs". This was a straight forward observational trial (before and after) which lacked control groups and in particular a placebo-controlled element so one has to be slightly hesitant about the strength of any findings. For those however who might be pulling on this study because of the use of something like the ATEC to measure autistic presentation, I'll draw your attention to some work suggesting that this instrument might be rather useful for monitoring intervention options for autism (see here).

As previously described, feelings run deep about the use or not of stem cells when it comes to autism not least because of the lack of data on long-term safety (and efficacy) in this context, the source 'material' for stem cells and the lack of information on just what might be going on in biological terms consequent to the behavioural results described. Examining this research from a cold, dispassionate, scientific point of view, I have to say that I'm becoming rather interested in what might be potentially going on during this and other studies [3] if not just as a function of other work by the late Paul Patterson and colleagues overlapping with this area [4] (discussed in a previous post). 

That being said, I'd like to see a lot more research done in this area before this kind of intervention enters anything like mainstream autism practice...

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[1] Pagliuca FW. et al. Generation of Functional Human Pancreatic β Cells In Vitro. Cell. 2014 Oct 9;159(2):428-439.

[2] Bradstreet JJ. et al. Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell Transplant. 2014 Oct 9.

[3] Lv YT. et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med. 2013 Aug 27;11:196.

[4] Hsiao EY. et al. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12776-81.

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Bradstreet JJ, Sych N, Antonucci N, Klunnik M, Ivankova O, Matyashchuk I, Demchuk M, & Siniscalco D (2014). Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell transplantation PMID: 25302490

Stem cell transplantation and autism: early days

My attention was recently caught by the publication of the study by Yong-Tao Lv and colleagues* (open-access) reporting results based on the use of stem cell transplantation in a small group of children diagnosed with an autism spectrum disorder (ASD).

I know that this research area is still a little bit of a hot potato when it comes to a heterogeneous, behaviourally-defined condition like autism (sorry, the autisms). As I intimated in a previous article about some related study in this area (see the ClinicalTrials.gov entry here) there are still quite a lot of unanswered questions about whether stem cell therapy is 'right' for autism or not; the progress of which is not helped by the historical propagation of the therapy via all those Google ads for specialist clinics offering stem cell services.

The new paper is open-access and includes a notable addition to the authorship group - one Paul Ashwood from UC Davis who has appeared more than once on this blog - and basically reports the results of a trial investigating "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". Without trying to rehash the authors findings, they basically suggested that (a) aside from some cases of transient fever, stem cell therapy was relatively 'safe' when it came to the monitoring of various measures, at least over the course of the investigative period and (b) compared with a control group who only received "professional sensory integration and behavioral rehabilitation therapy", two other groups of children who received CBNMC and CBMC + UCMSC transplantation in addition to behavioural intervention showed various "improvements" according to the behavioural measures used over the course of the 24 week trial. Indeed, the combination therapies CBMC + UCMSC transplantation "showed larger therapeutic effects than the CBMNC transplantation alone". That being said, this was quite a small trial and the trial was non-blinded and non-randomised.

I'm going to reiterate my oft-cited caveat about this blog not giving medical or clinical advice particularly when it comes to something as 'new' as stem cell therapy being suggested for autism. I am inclined to point you towards another archive post where stem cell transplants were mentioned with autism (or at least mouse models of autism) in mind, based on the impressive work coming out of Paul Patterson's laboratory (see here) and how immune function, development and behaviour might be players at the same table for some cases of autism. The more recent paper has gone beyond mouse models....

Every therapeutic option which is put forward for 'managing' the characteristics of autism needs to start somewhere when it comes to testing for safety and efficacy and stem cell therapy is no exception. Whilst questions still remain about the long-term safety and effects of such transplantations and indeed, whether there is any appetite for such an intervention, the research toe has well and truly been dipped into the experimental waters.

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* Yong-Tao Lv. 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

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Yong-Tao Lv (2013). Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism Journal of Translational Medicine DOI: 10.1186/1479-5876-11-196

Lenalidomide and autism?

Lenalidomide @ Wikipedia

Of the thousands of medicines which have been or are currently in use, a few really enter the mainstream public consciousness for a variety of different reasons.

That little blue pill which now graces many a man's medicine cabinet worldwide is probably the best example, as any email spam folder can readily confirm.

One drug, suggested to treat morning sickness during pregnancy in the late 1950s, is however synonymous with the darker side of pharmaceutics; illustrative of the failings of appropriate medicines testing: thalidomide.

If you don't know the story of thalidomide this article offers quite a succinct timeline, and how only recently the company responsible for the invention of thalidomide has formally apologised to all those affected by this medicine.

You would perhaps think that after such a torrid history, this drug would and should be consigned to the annals of history, never to be used in medical practice again. You might however want to think again; as thalidomide is re-emerging as a medicine for various conditions including certain cancers, inflammatory diseases and even persistent cough, albeit with a few tweaks and heaps more pharmacovigilance particularly when administered to females of reproductive age.

OK so what's all this got to do with autism? Well, my attention was grabbed by the publication of this proof-of-concept study by Michael Chez and colleagues* (open-access) and the suggestion that lenalidomide, an analogue of thalidomide, might (might) show some promise in cases of autism. I had seen mention of this study, or something like this study, in a previous abstract from IMFAR 2010 (see here). The ClinicalTrials.gov entry for the study can also be seen here.

The keen eyes out there might recognise the name Dr Michael Chez and the Sutter Institute for some other recent publicity regarding the first FDA-approved stem cell trial for autism (see trial details here) which has created some column inches among mainstream media and bloggers alike (including me). It seems that this research group is intent on creating scientific waves.

Back to the paper, which is open-access, for a summary and few comments:

• The basic premise of the trial was the recognition of quite a bit of research which has indicated the immune system and various features of immune function might correlate with the presence of autism in some cases. Mention for example of that dastardly cytokine, interleukin-6 (IL-6) is made, but the main protagonist in this particular study is tumor necrosis factor - alpha (TNF-α), another inflammatory cytokine, and a target for lenalidomide (see here). The authors cite the focus of TNF-α as an outcome measure "because other cytokines were not always available in all patients" referring to tested parameters.
• A daily dose (2.5mgs) of lenalidomide was given for 12 weeks to 7 males (aged 6-12 years) diagnosed with autism and with parental report of regression being associated with symptom onset. Autoimmune "dysfunction" (I assume this means autoimmune disease) was reported in first-degree relatives of all participants, although prospective participants with various diagnosed autoimmune conditions were excluded from the present study.
• Various measures of behaviour and cognitive functioning were used during the study (baseline - 6 weeks - 12 weeks) including ADOS, CARS and the Receptive and Expressive One-Word Picture Vocabulary Test. This accompanied measurement of both serum and CSF levels of TNF-α (CSF levels collected via that most invasive of methods, lumbar puncture - don't click on this link if you are squeamish). 
• To ascertain the pharmacokinetics of the drug (drug metabolism), blood draws at 1, 2, 4 and 8 hours after the first dose of the lenalidomide were administered. 
• Results: well, mixed is probably the best description. Safety-wise, two participants were withdrawn from the study following their developing a rash. Another participant discontinued when their neutrophil count (white blood cells) dipped; albeit transiently. 
• Four participants registered a drop in TNF-α levels in both serum and CSF at study end. Whilst on the surface of things this might be considered an interesting finding, one has to bear in mind that analysis of CSF levels of the cytokine were accepted anywhere up to 8 months before the baseline testing started.
• Behaviourally, there was some suggestion of improvement on the various measures included for study, particularly at 6 weeks, but alas none of these changes were statistically significant. Indeed with the attrition (drop-out) rate (n=3) mentioned at study end, I'm not really surprised that nothing was found to be significantly improved. It would have to be an almost spectacular change in behaviour for 4 participants to register a significant change from baseline to study end.
• Conclusion: some interesting trends from the various data but nothing concrete probably as a function of the small participant group.

The science-y types out there may very well look at this trial and its results and focus on its failings and weaknesses. Whilst not trying to defend the study, I would draw your attention to several keywords in the title like 'pilot study' as a clue to the very preliminary nature of this investigation. Indeed, the authors do mention that this was not a randomised trial (i.e. participants randomly allocated to treatment or not), did not include a placebo group and neither was it double-blind; everyone knew that participants were taking lenalidomide and nothing else. It's more of case series description than a scientific trial.

Before any chatter arises about me somehow endorsing thalidomide derivatives to 'treat' autism by highlighting this study, I just want to say that I'm not. My mind keeps wandering back to the devastating teratogenic effects that thalidomide bestowed, and still I can't help but wonder if this is indeed one of those drugs which given its history perhaps should have been consigned to the great pharmaceutical rubbish tip, never to be used again.

I'll let you form your own opinion on whether this is an area requiring further research with autism in mind or not. Bear in mind however that for some people with certain conditions, lenalidomide has probably had some real benefit for them (see here) and its adoption reflects, quote "the pressing need to develop molecules with enhanced immunomodulatory and antitumor activity". Not that there may not be alternatives as per this study however.

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* Chez M. et al. Safety and observations in a pilot study of lenalidomide for treatment in autism. Autism Research & Treatment. 2012; 291601.
DOI: 10.1155/2012/291601

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Michael Chez, Renee Low, Carol Parise, & Tammy Donnel (2012). Safety and observations in a pilot study of lenalidomide for treatment in autism Autism Research & Treatment DOI: 10.1155/2012/291601

Mouse modeling, immune function and autism

Contrary to the title of this post and any images that it may conjure up of mice parading down a runway in this season's 'hottest looks' whilst pouting to the clicks and flashes of multiple cameras, I'm back to mouse models and autism again(!) and an interesting piece of research by Hsiao and colleagues*.

I am kinda standing on the shoulders of giants with this paper given that it comes from the laboratory of Paul Patterson who has already run with a short description about it on his blog (see here). Whilst not pinning my colours to any mast, Prof. Patterson's blog is one I enjoy reading, not least because of the various links being made between the immune system and the brain (at least in mice). I assume most people would recognise by now that the brain does not run independent of the rest of the body despite our implicit need to compartmentalise anything and everything (see this post on labels).

Drawing heavily on Prof. Patterson's latest blog entry and the paper in question - hopefully without plagiarising - a few factoids:

• The Patterson team have previously published results based on a mouse model of stimulated immune activation during pregnancy and the resultant behavioural effects on offspring which seemed to overlap with the core symptoms of autism (see this paper by Malkova and colleagues**).
• In the latest study* the authors report on the profile of immune function in offspring mice of immune-stimulated mothers, suggesting some interesting effects in the area of T regulatory cells and cytokine production. I have recently talked about T-cells in this post on pristine cysteine so will perhaps put that to one side for now. Of just as much interest are elevations in that old favourite IL-6 and similar suggestions for IL-17, again the source of some interest recently on the topic of autoimmunity and autism (here). Roads toward inflammation seemed to be a key part of their findings.
• Coincidental to these findings is the report of "altered myeloid lineage potential and differentiation" in offspring. I'm not even going to profess to begin to know what this actually means, aside from referring you to quite a nice overview of hematopoietic stem cells (here) showing the distinction between myeloid and lymphoid progenitors. 
• Then to the big findings and please don't shoot the messenger: irradiating and transplanting "immunologically normal" bone marrow from both affected and non-affected control mice offspring into the offspring of immune stimulated mother mice seemed to correct some of the autism-type behaviours that were exhibited. So repetitive- and anxiety-like behaviours seemed to be reduced bearing in mind that anxiety is not (yet) a core symptom of autism (see here).
• That and some suggestion that timing might be everything when it comes to programming for immune dysfunction as a result of very few effects being seen when transplanting bone marrow from affected offspring to non-affected offspring over being born into a stimulated maternal immune system environment.

I note that on quite a few sites analysing these latest results, the authors have gone to great lengths to stress that (a) these were mouse findings - I'll say again, these were mouse findings, and (b) at the moment, no-one is suggesting that a bone marrow / stem cell transplant is any kind of 'treatment' for autism given questions for example, about whether the 'irradiation' bit of the procedure might have shown any effect alongside the actual bone marrow transplant. I would most definitely support these statements given both the preliminary nature of this research and also the complications and risks attached to bone marrow transplants (see here).

Having said that this is not the first time that bone marrow transplants and conditions like autism have appeared in the research literature. This paper by Akaho and colleagues*** talks about such transplants in cases of autism (and schizophrenia) occurring alongside leukaemia with a specific focus on maintaining treatment regimes and the anxiety related to the treatment process. Sharma and colleagues**** discussed some rather more direct observations following administration of "autologous bone marrow-derived mononuclear cells" in their quite varied patient group including cases of autism, bearing in mind one tree does not a forest make.

Indeed the concept of stem cell therapy, words which still seem to create quite an emotional response in many people, seems to be occurring more and more often in the research literature on autism as per this review by Siniscalco and colleagues***** (full-text) including a familiar name (Anna Sapone). I know many people might read 'stem cells and autism' and think back to those pop-up ads that seem to appear on various search engines offering some kind of James Bond style 'Die Another Day' rearrangement. Again, no endorsement is intended or given but perhaps what the Patterson lab study is suggesting is that a little more focused research is required in this area just before the door is entirely slammed shut. 

The Hsiao findings do represent another very important preliminary step into the immune-behaviour relationship with conditions like autism in mind. Assuming that the whole is greater than the sum of its parts, these moves towards a more whole body analysis of conditions like autism, where immune function, gut and gut bacterial function and brain function are examined in unison, offer the promise of some truly tantalising insights into autism.

And finally... just in case you are not convinced on the potential for an immune-behaviour link, cast your eye over this recent preliminary report on Alzheimer's disease and the use of IVIg as another area ripe for further inquiry.

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* Hsaio EY. et al. Modeling an autism risk factor in mice leads to permanent immune dysregulation. PNAS. July 2012.
DOI: 10.1073/pnas.1202556109

** Malkova NV. et al. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain, Behavior & Immunity. 2012; 26: 607-616.

*** Akaho R. et al. Bone marrow transplantation in subjects with mental disorders. Psychiatry & Clinical Neurosciences. 2003; 57: 311-315.

**** Sharma A. 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: Suppl 1: S79-S90.

***** Siniscalco D. et al. Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? Journal of Biomedicine & Biotechnology. 2012; 480289.

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Hsiao EY, McBride SW, Chow J, Mazmanian SK, & Patterson PH (2012). Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proceedings of the National Academy of Sciences of the United States of America PMID: 22802640