Tuesday, 29 July 2014

lentiviral anti-lingo supports remyelination

Wang CJ, Qu CQ, Zhang J, Fu PC, Guo SG, Tang RH. Lingo-1 Inhibited by RNA Interference Promotes Functional Recovery of Experimental Autoimmune Encephalomyelitis. Anat Rec (Hoboken). 2014 Jul . doi: 10.1002/ar.22988. [Epub ahead of print]

Lingo-1 is a negative regulator of myelination. Repairment of demyelinating diseases, such as multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE), requires activation of the myelination program. In this study, we observed the effect of RNA interference on Lingo-1 expression, and the impact of Lingo-1 suppression on functional recovery and myelination/remyelination in EAE mice. Lentiviral vectors encoding Lingo-1 short hairpin RNA (LV/Lingo-1-shRNA) were constructed to inhibit Lingo-1 expression. LV/Lingo-1-shRNA of different titress were transferred into myelin oligodendrocyte glycoprotein-induced EAE mice by intracerebroventricular (ICV) injection. Meanwhile, lentiviral vectors carrying nonsense gene sequence (LVCON053) were used as negative control. The Lingo-1 expression was detected and locomotor function was evaluated at different time points (on days 1,3,7,14,21, and 30 after ICV injection). Myelination was investigated by luxol fast blue (LFB) staining. LV/Lingo-1-shRNA administration via ICV injection could efficiently down-regulate the Lingo-1 mRNA and protein expression in EAE mice on days 7,14,21, and 30 (P < 0.01), especially in the 5 × 108 TU/mL and 5 × 109 TU/mL LV/Lingo-1-shRNA groups. The locomotor function score in the LV/Lingo-1-shRNA treated groups were significantly lower than the untreated or LVCON053 group from day 7 on. The 5 × 108 TU/mL LV/Lingo-1-shRNA group achieved the best functional improvement (0.87 ± 0.11 vs. 3.05 ± 0.13, P < 0.001). Enhanced myelination/remyelination was observed with 50 million to 5 billion Units of virus/mL LV/Lingo-1-shRNA groups by LFB staining (P < 0.05, P < 0.01, and P < 0.05).The data showed that administering LV/Lingo-1-shRNA by ICV injection could efficiently knockdown Lingo-1 expression in vivo, improve functional recovery and enhance myelination/remyelination. Antagonism of Lingo-1 by RNA interference is, therefore, a promising approach for the treatment of demyelinating diseases, such as MS/EAE.




Anti-Lingo-1 antibody can promote remyelination and is clinical trial. However the problem with antibodies is that they do not readily get into the CNS so about 99.9% of that delivered will probably not get there. In the early trials they gave it intravenously wonder if there would be a better effect of intrathecal delivery so more gets in the brain.


 This study uses gene therapy to deliver the therapy to block Lingo-1 and inject a genetically engineered lentiviral vector. The virus delivers something that blocks message of Lingo-1 and this blocks a non-remyelination signal.


Would you be willing to have a viral particle put into your brain?
This is a perceived problem with this type of therapy.

However it provides additional evidence that Lingo-1 blockage is useful.  In MS how will an anti-Lingo, be used given every few weeks forever or as a pulse therapy. With alemtuzumab you are being introduced to an £50,000 short course of antibody.

The phase II trial will be occurring soon.

6 comments:

  1. This what I want to see on Good News Tuesdays. Well done Prof M. It saves me logging in on other days and seeing all the grim news- dementia, incontinebce etc. Keep up the good work.

    ReplyDelete
  2. Prof M,,

    Do you mean the antilingo phase II will be reporting soon? I thought the phase II trials were ongoing.

    ReplyDelete
    Replies
    1. you are correct they are only ongoing and reporting will not be soon

      Delete
  3. Yep, I am also all for Good News Tuesdays (without exaggerations) - one good news item which is scientifically robust and positive will suffice - so now it's official ;-)

    ReplyDelete
  4. well said Anon 8.44. It's difficult enough dealing with this disease, yet I often visit this blog and get more upset - look at the surveys (are you crying too much? are your passing too much urine at night?). i need a pick up and some hope for the future. Good News Tuesdays is an excellent idea. The sorts of posts I'd like to see on Tuesday are positive trial results, ground breaking research into the cause, remyelination research (where positive) etc. etc.. I do wonder if the researchers get desensitized to the feeligs of those with the disease. Pictures of shrunken brains, graphs showing time to disability progression may be of interest to researchers, but frighten the lives out of us with the disease. And we're not putting our heads in the sand, but we can't do anything about it at the moment. Neuro-protective drugs, drugs that offer some repair are what I'm looking forward to - it gives me hope. Roll on good news Tuesdays. Like anon above, it will stop me from trawling through all the depressing bad news that can be posted on the other six days.

    ReplyDelete
  5. Nope. Keep it real, Prof G. I want the truth about MS. This isn't the Disney Channel, it's a scientific and social conscience blog.

    I veto Good News Tuesdays. It's a nonsense suggestion. Our culture of entitlement has gone crazy. Next they'll be asking for cures. Good grief,.

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.