Gene Therapy for Neurodegenerative Diseases: Slowing Down the Ticking Clock

Abstract

Gene therapy is an emerging and powerful therapeutic tool to deliver functional genetic material to cells in order to correct a defective gene. During the past decades, several studies have demonstrated the potential of AAV-based gene therapies for the treatment of neurodegenerative diseases. While some clinical studies have failed to demonstrate therapeutic efficacy, the use of AAV as a delivery tool has demonstrated to be safe. Here, we discuss the past, current and future perspectives of gene therapies for neurodegenerative diseases. We also discuss the current advances on the newly emerging RNAi-based gene therapies which has been widely studied in preclinical model and recently also made it to the clinic.

Emerging role of RNA interference in immune cells engineering and its therapeutic synergism in immunotherapy

“…however, the clinical development was terminated in 2016 due to several immune-related toxicities (Martier & Konstantinova, 2020 Abbreviations: HBV, hepatitis B virus; hepatitis C virus; HCC, hepatocellular carcinoma; HIV, human immunodeficiency virus; NGF, nerve growth factor myeloma (Tolcher et al, 2015), since MYC activation is a hallmark of cancer and up-regulated in all types of cancer, including hepatocellular carcinoma (Gabay et al, 2014). An appropriate application of DCR-MYC from this study has anticipated soon.…”

“…For instance, to treat liver cancer, delivery systems are being used to deliver miR‐34, a potent tumour suppressor that hinders cancer cell proliferation and survival (Zhang et al, 2019). A Phase I clinical trial (NCT01829971) of MRX34, a mimetic of this miRNA, was the first clinical trial against hepatocellular carcinoma ; however, the clinical development was terminated in 2016 due to several immune‐related toxicities (Martier & Konstantinova, 2020). Moreover, a Phase I dose escalation cohort study (NCT02314052 and NCT02110563) of DCR‐MYC, a Dicer‐based RNAi therapeutic, has been recruited to evaluate the safety, pharmacodynamics, pharmacokinetics and clinical activity in patients with advanced solid tumours, myeloma (Tolcher et al, 2015), since MYC activation is a hallmark of cancer and up‐regulated in all types of cancer, including hepatocellular carcinoma (Gabay et al, 2014).…”

“…For example, most initial in vivo preclinical studies were carried out by adeno‐associated virus‐mediated delivery of anti‐HTT shRNA into Huntington's disease transgenic mice, resulting in significant reductions in the mRNA levels of mutant HTT (Rodriguez‐Lebron et al, 2005). Therefore, FDA has provided clearance for AMT‐130, which is the first adeno‐associated virus‐miRNA‐based gene therapy for the treatment of Huntington's disease to start as a Phase I/II clinical trial (Martier & Konstantinova, 2020). Currently, several RNAi‐based clinical trials are ongoing to harness approaches used for brain diseases and effectively apply them to neurological disorders (Piguet et al, 2017).…”

Toward Development of Neuron Specific Transduction After Systemic Delivery of Viral Vectors

“…Many factors may influence the transduction efficiency and targeting of AAV gene therapy such as route of delivery, use of a self-complementary AAV genome, and serotype ( 3 ). Most preclinical experiments and clinical trials focusing on neurodegeneration deliver AAV gene therapy by intracranial injection into the brain ( 4 , 5 ). In addition to the need for a craniotomy, only a portion of the brain is transduced and there is a gradient of transduction diminishing with distance from the site of injection.…”

What, When and How to Measure—Peripheral Biomarkers in Therapy of Huntington’s Disease

“…RNAi is originally activated by siRNAs but can be also applied in therapeutic approaches using vectors expressing precursors encoding RNA duplexes. Due to their variety in cell- and tissue-specific tropisms, adeno-associated viruses (AAVs) are currently the most attractive delivery vectors for siRNAs, providing long-term expression without genomic integration and relative high safety [ 22 ]. More clinical trials using this system were considered after the first AAV-mediated gene therapy was approved by the FDA in 2017 [ 23 ].…”