ReviewGene therapy to target ER stress in brain diseases

- ER stress operates as a driver of disease progression in neurodegenerative diseases.
- The UPR modulates ER stress to induce cell adaptation or apoptosis.
- AAV-mediated gene therapy is emerging as an alternative to treat diseases.
- Modulating the UPR has protective effects in preclinical models of neurodegeneration.

Gene therapy based on the use of Adeno-associated viruses (AAVs) is emerging as a safe and stable strategy to target molecular pathways involved in a variety of brain diseases. Endoplasmic reticulum (ER) stress is proposed as a transversal feature of most animal models and clinical samples from patients affected with neurodegenerative diseases. Manipulation of the unfolded protein response (UPR), a major homeostatic reaction under ER stress conditions, had proved beneficial in diverse models of neurodegeneration. Although increasing number of drugs are available to target ER stress, the use of small molecules to treat chronic brain diseases is challenging because of poor blood brain barrier permeability and undesirable side effects due to the role of the UPR in the physiology of peripheral organs. Gene therapy is currently considered a possible future alternative to circumvent these problems by the delivery of therapeutic agents to selective regions and cell types of the nervous system. Here we discuss current efforts to design gene therapy strategies to alleviate ER stress on a disease context.This article is part of a Special Issue entitled SI:ER stress.