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.

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