posted on 2024-01-15, 06:06authored byNegar Mahmoudi, Yi Wang, Niamh Moriarty, Noorya Y. Ahmed, Nathalie Dehorter, Leszek Lisowski, Alan R. Harvey, Clare L. Parish, Richard J. Williams, David R. Nisbet
The central nervous system’s limited capacity
for regeneration
often leads to permanent neuronal loss following injury. Reprogramming
resident reactive astrocytes into induced neurons at the site of injury
is a promising strategy for neural repair, but challenges persist
in stabilizing and accurately targeting viral vectors for transgene
expression. In this study, we employed a bioinspired self-assembling
peptide (SAP) hydrogel for the precise and controlled release of a
hybrid adeno-associated virus (AAV) vector, AAVDJ, carrying the NeuroD1
neural reprogramming transgene. This method effectively mitigates
the issues of high viral dosage at the target site, off-target delivery,
and immunogenic reactions, enhancing the vector’s targeting
and reprogramming efficiency. In vitro, this vector
successfully induced neuron formation, as confirmed by morphological,
histochemical, and electrophysiological analyses. In vivo, SAP-mediated delivery of AAVDJ-NeuroD1 facilitated the trans-differentiation
of reactive host astrocytes into induced neurons, concurrently reducing
glial scarring. Our findings introduce a safe and effective method
for treating central nervous system injuries, marking a significant
advancement in regenerative neuroscience.