Sunday, 10 May 2015

Placental stem cells are relatively safe inMS

Lublin FD, Bowen JD, Huddlestone J, Kremenchutzky M, Carpenter A, Corboy JR, Freedman MS, Krupp L, Paulo C, Hariri RJ, Fischkoff SA. Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: A randomized, placebo-controlled, multiple-dose study.Mult Scler Relat Disord. 2014 3:696-704.

BACKGROUND: Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis.
OBJECTIVE:This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis.
METHODS:This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse.
RESULTS: Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score >0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection.
CONCLUSION:PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosispatients. No paradoxical worsening of lesion counts was noted with either dose.


So this is a safety study of a stem cell and based on the data it did not make MS worse but it did not provide enough information to determine whether it made things better. This cell comes from someone elses placenta and so if it became a useful cell in the future it may been to protected against tissue rejection that could happen. There will be a number of papers surfacing about stem cells notably mesenchymal-stem cells. What will happen? I am not sure but I have a concern. Based on animal studies these mesenchymal cells induce no or marginal immunosuppressive activity. It this is all they do it will be an expensive way to cause immunosuppression and in the majority of cases you can achieve much better results with current DMT. However what we want from these cells is the re-creation of myelination and even regrowth of nerves. To date in animals this has been marginal and is problematic due to poor penetration of the cells to get into the CNS if administered systemically. Then they have to differentiate into myelinating cells, which the oligodendrocyte precursors already present in the CNS are not doing. 

So whilst stem cells hold much promise, we have to be realistic about what we are likely to achieve and not get our hopes too high  

3 comments:

  1. mouse,

    There seems to be lots of these mesenchymal stem cell trials kicking off - Tisch MS centre, Canadian MS society are funding a trial.... I thought Prof Scolding in Bristol was running one (seems to have gone quiet). Is Team G doing any work in this field? I'm assuming the hope of these trials is remyelination or nerve repair. What's your view on their potential? If a phase 3 trial showed potential, would the therapy need to be licensed like a drug?

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  2. The hope has to be remyelination but if the cells have difficulty getting there then this will be a problem. Other people aim for immunomodulation, we looked with neural stem cells and terminated the project early which makes me more sceptical. However there are amn increasing number of positive studies and if ghe approach works in phase iii I imagine the approach will need to be licenced. Indeed it will be interesting to see what will happen and how people will be charged for this but i suspect we will see a pharmacological/biological approach that supercedes this, if the biotin trial or other stuff is remyelination and i say if then the days of ttransplanting cells will be numbered.

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  3. This is very unlikely to work in the manner that we hope it could. The work by Pluchino, Aguzzi, Einstein and others has suggested that in mouse, stem cells improve EAE, probably by a paracrine, immunomodulation rather than cell replacement effect. There is still tremendous hurdles to overcome in humans, phase I studies tell us nothing (if you inject your own cells is unlikely that the cells will be toxic) but increases speculation and "hope" in patients and the press that love to use hyperbole to cover the work.

    If this works via immunomodulation, why then use it when we have 12 immunodulators? What will be the difference and efficacy of autologous stem cells vs., DMTs, how many injections of stem cells you need to have the same effect of natalizumab? or tecfidera? Can you get a brain tumor by injecting multiple times in the CSF, as reported by amariglio et al 2009. I would like to use that clinical trial.!

    If this is remyelination, how do you know that you are achieving that in humans? Not even the work of Reich in NIH is that advanced to evaluate remyelination in a clinical trial. Of course the research must go on, but since 1992 where Reynolds and Snyder published their seminal independent work in stem cells, we have not cure anybody YET!

    We hope that this research will shed light on mechanisms for newer drugs that can activate and protect endogenous remyelination and maybe there will be some diseases or even few MS patient, where exogenous direct transplantation of stem cells could very promising like macular degeneration with tissue derived from pluripotent stem cells.

    In reality, this kind of news that unfiltered will give more impetus to "stem cell" clinics and programs, popping out around the world and even doctors, (mostly surgeons) profiting from the hope and misery of MS patients offering, extraction of stem cells in dubious clinic in many countries, making 20K euros for therapy.

    I am very hopeful in the research but, just giving the reader a shot of reality.

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