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Mimimally invasive retrograde targeting of aCAR lentiviral vector to non-human primate motor neurons

Objective

Lentiviral vectors pseudotyped with the rabies-G envelope have been used for the delivery of therapeutic transgenes via the peripheral intamuscular route, increasing lifespan and reducing neuromuscular deficits in mouse models of both amyotrophic lateral sclerosis and spinal muscular atrophy. Despite these successes clinical translation of gene therapy for ALS with these and other vectors with retrograde transport such as AAV2 has been hampered as a result of limitations experienced with gene transfer in non-human primates (NHPs). In order to overcome these limitations, and to design a safe, efficient and a minimally invasive therapeutic strategy, we have developed as part of the ERC Advanced investigator’s grant: IRLVGTMND, a novel new generation of surface engineered lentiviral vectors with tropism to motor neurons (MNs) via the neuromuscular junction (NMJ). These vectors are targeted with antibodies against NMJ presynaptic terminal receptors, such as the CAR (coxsackievirus and adenovirus receptor). We found that these vectors can recognise, bind and enter target cells with high specificity determined by the antibody incorporated on their surface. They have specificity for MNs and have retrograde transport as demonstrated in vitro in compartmentalised primary motor cultures and in vivo upon intramuscular (i.m.) delivery in leg muscles leading to transduction of lumbar spinal cord MNs. All data to date indicate that the targeted lentiviral vectors we have constructed have superior transduction and specificity for MNs than previously used lentiviral vectors, making them thus good candidates for minimally invasive neuroprotective gene therapy of ALS. We therefore with this PoC grant want to investigate the transduction of NHP MNs via i.m. injections. We aim to have an indication within 12 months whether these vectors can achieve sufficient transduction in this model which will open up the way for their preclinical development, clinical testing and commercialisa

Call for proposal

ERC-2013-PoC
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Funding Scheme

CSA-SA(POC) - Supporting action (Proof of Concept)

Host institution

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Address
South Kensington Campus Exhibition Road
SW7 2AZ London
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 110 302,98
Administrative Contact
Tatjana Palalic (Ms.)

Beneficiaries (2)

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
United Kingdom
EU contribution
€ 110 302,98
Address
South Kensington Campus Exhibition Road
SW7 2AZ London
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Tatjana Palalic (Ms.)
ASSISTANCE PUBLIQUE HOPITAUX DE PARIS
France
EU contribution
€ 39 223
Address
3 Avenue Victoria
75000 Paris
Activity type
Research Organisations
Administrative Contact
Alix Pillot (Ms.)