Therapeutic Potential of AAV1-Rheb(S16H) Transduction against Neurodegenerative Diseases

Abstract

Neurotrophic factors (NTFs) are essential for cell growth, survival, synaptic plasticity, and maintenance of specific neuronal population in the central nervous system. Multiple studies have demonstrated that alterations in the levels and activities of NTFs are related to the pathology and symptoms of neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease. Hence, the key molecule that can regulate the expression of NTFs is an important target for gene therapy coupling adeno-associated virus vector (AAV) gene. We have previously reported that the Ras homolog protein enriched in brain (Rheb)–mammalian target of rapamycin complex 1 (mTORC1) axis plays a vital role in preventing neuronal death in the brain of AD and PD patients. AAV transduction using a constitutively active form of Rheb exerts a neuroprotective effect through the upregulation of NTFs, thereby promoting the neurotrophic interaction between astrocytes and neurons in AD conditions. These findings suggest the role of Rheb as an important regulator of the regulatory system of NTFs to treat neurodegenerative diseases. In this review, we present an overview of the role of Rheb in neurodegenerative diseases and summarize the therapeutic potential of AAV serotype 1 (AAV1)-Rheb(S16H) transduction in the treatment of neurodegenerative disorders, focusing on diseases, such as AD and PD.

Gene therapy of yeast NDI1 on mitochondrial complex I dysfunction in rotenone-induced Parkinson’s disease models in vitro and vivo

“…Potential molecular and cellular therapies have been tested for the treatment of PD, including stem cell transplantation therapy with embryonic stem (ES) cells and induced pluripotent stem (iPS) cells (Ge et al 2018 ; Muñoz et al 2019 ), immunotherapy with antibodies, and gene therapy using viral vector-mediated gene delivery, RNA interference, CRISPR-Cas9 gene editing, and et al (Jamebozorgi et al 2019 ; Lin et al 2017 ). Gene therapy for PD offers a promising strategy (Choong and Mochizuki 2017 ), including delivery of genes encoding proteins that can protect dopaminergic neurons from damage, such as neurotropic factors, anti-apoptotic and anti-free radical proteins (Lin et al 2017 ; Valdés and Schneider 2016 ; Nam et al 2021 ), and delivery of genes encoding enzymes involving in dopamine synthesis, for example, aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), GTP cyclohydrolase (GCH) (Jamebozorgi et al 2019 ; Lin et al 2017 ; Christine et al 2019 ; Ciesielska et al 2017 ). To date, gene therapy for PD has shown encouraging results in preclinical animal models, but few are being investigated in clinical trials.…”