WORMS for MS

W

This study has been sometime coming and was I think probably originally based on the idea that a worm infection can drive a TH2 (anti-inflammatory) from a TH1 (pro-inflammatory) response. I think there were a number of studies planned, but this study from Nottingham passed the finish line.

In this study people were infected with the hookworm parasite and I guess became biobombs as the worms would infest the intestines. This has been some time coming and TH2 have fallen out of favour. Tregs had become the favoured immunological mechanism of action for MS DMT.

If I open my time capsule from when the study was planned, I would have to say my prediction would be that this study would fail. I was never a fan of TH1 and TH2 yin and yang as I think they are both bad and the story really didn’t hold up when you looked at human cells. Importantly, I remember the 1980s and 1990s when animal houses around the World were fizzing with pinworms and viruses. I can remember loads of wiggly worms on feacal pellets of mice with EAE. So it was clear to me that this was not likely to be an answer. Likewise I remember sitting in a meeting in Boston, USA in 2012 listening with surprise to a guy would supported this approach and telling us that pinworms stopped EAE. I thought and said yeah right. If that were true there would have been no EAE studies in the 1980s-1990s. But who knows humans are different from mice.

So what did we get, well a reduction of MRI lesions by over 60%, so not really in the range of beta interferon and nowhere near a highly active DMT, which reduces lesions by over 80-95%. The relapses dropped by about a half again not in the league of the most potent of DMT. At the end of the day there was no significant effect. So a well conducted trial that again rather questions the T cell immunologists world view. So another T cell immunotherapy bites the dust. There was an increase in the T regulatory cells, but not a good enough effect on MS. Again questions dogma.

Hookworm

This paper is being reviewed at the moment, so get an early look.

Worms for Immune Regulation of Multiple Sclerosis (WIRMS): A Randomised Double-Blinded Placebo Controlled Trial Radu TanasescuChristopher R. TenchCris ConstantinescuGary TelfordSonika SinghNanci FrakichDavid OnionDorothee P. AuerBruno GranNikos EvangelouYasser FalahColin RanshawCinzia CantacessiTimothy P. Jenkins and David I. Pritchard Available at SSRN: https://ssrn.com/abstract=3463311

Background: Studies suggest gut worms induce immune responses that can protect against MS. We tested hookworm treatment in MS.

Methods: We performed a 9-month double-blind, randomised, placebo-controlled trial in patients aged 18-60 years with relapsing MS. Patients were randomised (1:1) to either 25 Necator americanus larvae transcutaneously (HW), or placebo. MRI scans were performed monthly during months 3-9, and 3-months post-treatment. The primary endpoint was the cumulative number of new or enlarging T2 or new enhancing T1 lesions at month 9. The secondary endpoint was the percentage of CD4+CD25highCD127negTreg cells.

Findings: Between September 2012 and March 2015, 71 patients (35 HW;36 placebo) were recruited. 66 patients completed the trial to endpoint. 51% of HW subjects vs 28% placebo had no detectable MRI activity. Median cumulative numbers of new/enlarging/enhancing lesions were not significantly different between the groups. In patients with no missing scans (N=54;28 HW;26 placebo), the OR of MRI activity HW vs placebo was 0.36 (0.14-0.97 95%CI). The percentage of CD4+CD25highCD127negT cells increased at month 9 in the HW group (p=0.013). There were no differences in adverse events between the groups, besides more application-site skin discomfort in the HW group (82% vs 28%). There were five relapses in the HW group vs 11 on placebo.

Interpretation: HW was safe and well-tolerated. The unexpectedly high number of subjects with no MRI activity in the HW group reduced the power of the primary outcome test, which was not statistically significant. HW infection increased Treg cells. Together the data suggests a possible therapeutic effect of HW infection. The potential of HW as immune-modulatory living drug in MS deserves further investigation.

Trial Registration: (ClinicalTrials.gov NCT01470521).

Funding Statement: UK MS Society; Bayer; Forman Hardy Charitable Trust via the University of Nottingham.

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