# Renovating Neural Networks With Viral‐Mediated Gene Transfer From A Tissue Contacting Matrix Mimic

## TL;DR

This study shows that combining gene therapy with a smart hydrogel improves brain cell protection in Huntington's disease.

## Contribution

A self-assembling peptide hydrogel enhances AAV gene delivery for sustained BDNF production in the brain.

## Key findings

- AAVDJ-BDNF delivered via hydrogel provides better neuroprotection than injection alone in a mouse model.
- The hydrogel system improves BDNF presentation and slows neurodegenerative disease progression.
- Engineered biomaterials enhance gene therapy efficacy for conditions like Huntington's disease.

## Abstract

Neurodegenerative diseases such as Huntington's Disease (HD) have a significant impact on healthcare accessibility and costs. A fatal genetic condition, characterized by the progressive loss of striatal neurons, HD is hindered by the lack of endogenous repair in the adult brain. Recent efforts toward protecting neural circuits through neurotrophic support using brain‐derived neurotrophic factor (BDNF) have been suboptimal due to the protein's short half‐life and limited diffusion. Addressing this, adeno‐associated viral vectors (AAV) can be employed as a delivery tool to spatially transduce cells, enabling the localised production of BDNF with consequential neuron protection and/or plasticity, yet present their own constraints. To overcome these known challenges of AAV gene delivery, an injectable, physiologically stable hydrogel‐mimic of the brain's extracellular matrix was fabricated to encapsulate the AAVs. This smart system both shielded and constrained the AAV; optimising transfection and therefore elevated and sustained BDNF presentation at the target site. Here, we achieved high neuroprotection using AAVDJ‐BDNF delivered through a hydrogel formed via self‐assembling peptide nanoscaffolds. These findings support the notion that the spatiotemporal release of BDNF to striatal neurons, facilitated by engineered biomaterial delivery systems, demonstrates tremendous promise by enhancing the efficacy of gene therapy targeted at slowing neurodegenerative disease progression.

Fmoc‐DDIKVAV self‐assembling peptidemediated delivery of AAV‐BDNF significantly enhances neuroprotection in the striatum of a mouse model compared with AAV‐BDNF injection alone. This synergistic integration of biomaterial scaffolding and gene therapy holds substantial promise for slowing the progression of neurodegenerative diseases such as Huntington's disease (HD).