Monday, 31 March 2014

ALV003 glutenase and more

Today's post is a bit of mash-up but hopefully containing some common threads. If you're also reading the title of this post and wondering what it might have to do with autism research, stay with me...
For mash get smash... @ Wikpedia 

The chopping up duties of ALV003
To start, we have the paper by Lähdeaho and colleagues [1] who reported results based on the "ability of ALV003, a mixture of 2 recombinant gluten-specific proteases given orally, to protect patients with celiac disease from gluten-induced mucosal injury". Those with their ear to the coeliac (celiac) disease research ground will probably have heard something about ALV003 from Alvine Pharmaceuticals before. This glutenase mix - a protease compound designed to degrade gluten - comprising cysteine endoprotease B-isoform 2 and prolyl endopeptidase has already started to make some scientific waves following the results of a couple of studies reporting tolerability [2] and initial efficacy [3] in cases of coeliac disease (CD). The theory behind it being that chopping up those dastardly gluten proteins/peptides might break an important link in the chain of biological events observed in coeliac disease.

The data from Lähdeaho et al suggest that "the glutenase ALV003 appears to attenuate gluten-induced small intestinal mucosal injury in patients with celiac disease in the context of an everyday gluten-free diet containing daily up to 2 g gluten". In other words, taking ALV003 together with a gluten-supplemented meal seemed to have some protective effect on the state of the gut mucosa compared to the effects of a placebo.

With my autism research hat on, and particularly the green beret marked gluten and casein-free (GFCF) diets, I did wonder whether there may be something to be potentially learned from these results. I'm not for one minute implying that ALV003 should be indicated for autism nor am I suggesting that autism is coeliac disease despite some potential overlap. But I did wonder in light of something like the opioid-excess theory of autism [4] and some continued interest in all-things digestive enzymes and autism (see here), whether there may be some investigations to do in this area.

IgA deficiency and autoimmunity
Next up is the paper by Ludvigsson and colleagues [5] who observed that: "Individuals with IgA deficiency have a higher prevalence of several other autoimmune disorders". IgA deficiency is something that has cropped up on this blog before, again with an autism slant (see here). Harking back to some potentially important work by the late Reed Warren [6] suggestive that some on the autism spectrum may present with an IgA deficiency, extrapolating the results from Ludvigsson (yes, he of the 'not quite coeliac disease but something close in cases of autism' study) might have some important implications.

In particular, Ludvigsson et al  report quite a dazzling connection between IgA deficiency and the risk of various autoimmune conditions, such that there was: "a 35-fold higher PR [prevalence ratio] for celiac disease and 10-fold higher for type 1 diabetes". I'm only an amateur statistician but even I understand that a frequency of CD in IgA deficient vs. non-deficient population controls amounting to 6.7% and 0.2% respectively, is something potentially very important. Outside of the fact that IgA deficiency can affect the serological diagnosis of CD [7] I find these results to be interesting. That some people on the autism spectrum presenting with IgA deficiency may similarly find themselves in the cycle of greater risk of autoimmune conditions potentially offers some important lessons for screening and management of such issues. Also noted in a fairly recent presentation from one Alessio Fasano (see here for the video), science could do a lot worse than look to something like gluten as also being one of the important [modifiable] drivers in this autoimmunity relationship too.

I've probably bored you enough with this post and the speculations contained within. As per my recent ramblings on disappearing anti-gliadin antibodies following use of a gluten-free diet (see here) the important point to get across is that alongside a diagnosis of autism (and other comorbidity) there may be some important biochemistry that needs to be examined at least for some on the autism spectrum. Looking past the presented behavioural symptoms to see the person first and the autism label second is a pretty important part of this strategy so as to ensure that such health issues if present for some on the autism spectrum, don't disadvantage individuals further.

Now, how about some light reading paralleling pathogens and gluten peptides in CD [8] with suitable musical accompaniment by Sheryl Crow. Have some fun!

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[1] Lähdeaho ML. et al. The Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients with Celiac Disease. Gastroenterology. 2014 Feb 25. pii: S0016-5085(14)00242-X.

[2] Siegel M. et al. Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials. Dig Dis Sci. 2012 Feb;57(2):440-50.

[3] Tye-Din JA. et al. The effects of ALV003 pre-digestion of gluten on immune response and symptoms in celiac disease in vivo. Clin Immunol. 2010 Mar;134(3):289-95.

[4] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[5] Ludvigsson JF. et al. Association Between IgA Deficiency & Other Autoimmune Conditions: A Population-Based Matched Cohort Study. J Clin Immunol. 2014 Mar 2.

[6] Warren RP. et al. Brief report: immunoglobulin A deficiency in a subset of autistic subjects. J Autism Dev Disord. 1997 Apr;27(2):187-92.

[7] Shahnaz A. et al. Tissue transglutaminase antibody levels predict IgA deficiency. Arch Dis Child. 2013 Nov;98(11):873-6.

[8] Bethune MT. & Khosla C. Parallels between Pathogens and Gluten Peptides in Celiac Sprue. PLoS Pathog 2008; 4(2): e34.

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ResearchBlogging.org Lähdeaho ML, Kaukinen K, Laurila K, Vuotikka P, Koivurova OP, Kärjä-Lahdensuu T, Marcantonio A, Adelman DC, & Mäki M (2014). The Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients with Celiac Disease. Gastroenterology PMID: 24583059



ResearchBlogging.org Ludvigsson JF, Neovius M, & Hammarström L (2014). Association Between IgA Deficiency & Other Autoimmune Conditions: A Population-Based Matched Cohort Study. Journal of clinical immunology PMID: 24584841