TY - JOUR
T1 - Electrostatic coating of viral particles for gene delivery applications in muscular dystrophies
T2 - influence of size on stability and antibody protection
AU - Guerra-Rebollo, Marta
AU - Stampa, María
AU - Lázaro, Miguel Ángel
AU - Cascante, Anna
AU - Fornaguera, Cristina
AU - Borrós, Salvador
N1 - Funding Information:
Financial support from MINECO/FEDER (grant RTI2018-094734-B-C22) is acknowledged. The Support of Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) from Generalitat de Catalunya for their support trough SGR 2017 1559 grant is acknowledged. Duchenne Parent Project España (DPPE) is also acknowledged for their financial support. Authors acknowledge Elena García and Irene Porcar for their kind support in polymer synthesis and some experiments performance.
Publisher Copyright:
© 2021-IOS Press. All rights reserved.
Marta Guerra-Rebollo, María Stampa, Miguel Ángel Lázaro, Anna Cascante, Cristina Fornaguera, Salvador Borrós.
PY - 2021/9/14
Y1 - 2021/9/14
N2 - Background: Duchenne Muscular Dystrophy (DMD) is one of the most common muscular dystrophies, caused by mutated forms of the dystrophin gene. Currently, the only treatment available is symptoms management. Novel approximations are trying to treat these patients with gene therapy, namely, using viral vectors. However, these vectors can be recognized by the immune system decreasing their therapeutic activity and making impossible a multidose treatment due to the induction of the humoral immunity following the first dose. Objective: Our objective is to demonstrate the feasibility of using a hybrid vector to avoid immune clearance, based on the electrostatic coating of adeno-associated virus (AAVs) vectors with our proprietary polymers. Methods: We coated model adeno-associated virus vectors by electrostatic interaction of our cationic poly (beta aminoester) polymers with the viral anionic capsid and characterized biophysical properties. Once the nanoformulations were designed, we studied their in vivo biodistribution by bioluminescence analysis and we finally studied the capacity of the polymers as potential coatings to avoid antibody neutralization. Results: We tested two polymer combinations and we demonstrated the need for poly(ethylene glycol) addition to avoid vector aggregation after coating. In vivo biodistribution studies demonstrated that viral particles are located in the liver (short times) and also in muscles (long times), the target organ. However, we did not achieve complete antibody neutralization shielding using this electrostatic coating. Conclusions: The null hypothesis stands: although it is feasible to coat viral particles by electrostatic interaction with a proprietary polymer, this strategy is not appropriate for AAVs due to their small size, so other alternatives are required as a novel treatment for DMD patients.
AB - Background: Duchenne Muscular Dystrophy (DMD) is one of the most common muscular dystrophies, caused by mutated forms of the dystrophin gene. Currently, the only treatment available is symptoms management. Novel approximations are trying to treat these patients with gene therapy, namely, using viral vectors. However, these vectors can be recognized by the immune system decreasing their therapeutic activity and making impossible a multidose treatment due to the induction of the humoral immunity following the first dose. Objective: Our objective is to demonstrate the feasibility of using a hybrid vector to avoid immune clearance, based on the electrostatic coating of adeno-associated virus (AAVs) vectors with our proprietary polymers. Methods: We coated model adeno-associated virus vectors by electrostatic interaction of our cationic poly (beta aminoester) polymers with the viral anionic capsid and characterized biophysical properties. Once the nanoformulations were designed, we studied their in vivo biodistribution by bioluminescence analysis and we finally studied the capacity of the polymers as potential coatings to avoid antibody neutralization. Results: We tested two polymer combinations and we demonstrated the need for poly(ethylene glycol) addition to avoid vector aggregation after coating. In vivo biodistribution studies demonstrated that viral particles are located in the liver (short times) and also in muscles (long times), the target organ. However, we did not achieve complete antibody neutralization shielding using this electrostatic coating. Conclusions: The null hypothesis stands: although it is feasible to coat viral particles by electrostatic interaction with a proprietary polymer, this strategy is not appropriate for AAVs due to their small size, so other alternatives are required as a novel treatment for DMD patients.
KW - adeno-associated viruses
KW - antibody neutralization
KW - biodistribution studies
KW - duchenne Muscular dystrophy
KW - hybrid vectors
KW - pBAE nanoparticles
KW - viral coating
UR - http://www.scopus.com/inward/record.url?scp=85115120454&partnerID=8YFLogxK
UR - https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS&DestLinkType=FullRecord;KeyUT=000696382400006
UR - https://pubmed.ncbi.nlm.nih.gov/34366365/
UR - http://hdl.handle.net/20.500.14342/4155
U2 - 10.3233/JND-210662
DO - 10.3233/JND-210662
M3 - Article
C2 - 34366365
AN - SCOPUS:85115120454
SN - 2214-3599
VL - 8
SP - 815
EP - 825
JO - Journal of neuromuscular diseases
JF - Journal of neuromuscular diseases
IS - 5
ER -