Gene Therapy Strategies to Restore ER Proteostasis in Disease

Abstract

Proteostasis alterations are proposed as a transversal hallmark of several pathological conditions, including metabolic disorders, mechanical injury, cardiac malfunction, neurodegeneration, and cancer. Strategies to improve proteostasis aim to reduce the accumulation of specific disease-related misfolded proteins or bolster the endogenous mechanisms to fold and degrade abnormal proteins. Endoplasmic reticulum (ER) stress is a common pathological signature of a variety of diseases, which engages the unfolded protein response (UPR) as a cellular reaction to mitigate ER stress. Pharmacological modulation of the UPR is challenging considering the physiological importance of the pathway in various organs. However, local targeting of ER stress responses in the affected tissue using gene therapy is emerging as a possible solution to overcome side effects. The delivery of ER chaperones or active UPR components using adeno-associated virus (AAV) has demonstrated outstanding beneficial effects in several disease models (e.g., neurodegenerative conditions, eye disorders, and metabolic diseases). Here, we discuss current efforts to design and optimize gene therapy strategies to improve ER proteostasis in different disease contexts.

Keywords: AAV; ER stress; UPR; diabetes; gene therapy; neurodegeneration; protein misfolding.

Figure 1

ER Stress and the UPR Left: flowchart showing the hallmarks of the UPR activation under ER stress. Right: principal components and potential targets of the UPR to modulate in disease by AAV-mediated gene therapy approaches. ASK1, apoptosis signal-regulating kinase 1; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; ATF6f, fragmented activating transcription factor 6; BiP, binding immunoglobulin protein; CHOP, C/EBP homologous protein; EDEM1, ER degradation-enhancing alpha-mannosidase-like 1; eIF2α, eukaryotic translation initiation factor-2 alpha; GADD34, growth arrest and DNA damage-inducible 34; Hrd1, hypoxia responsive domain-1; IRE1, inositol-requiring enzyme 1; JNK, c-Jun N-terminal kinase; PERK, protein kinase RNA-like endoplasmic reticulum kinase; PP1, protein phosphatase 1; Rab1, Ras-associated binding protein 1; Sil1, SIL1 nucleotide exchange factor 1; TRAF2, TNF receptor-associated factor 2; Xbp1s, spliced X-box binding protein 1; Xbp1u, unspliced X-box binding protein 1.