Gene-Editing Technologies Paired With Viral Vectors for Translational Research Into Neurodegenerative Diseases

Abstract

AAV-AS Derived from AAV9 CNS-transduction improved 6-15x vs. AAV9 AAV-BR1 Derived from AAV2 Brain endothelium Olig001 Derived from AAVs1, 2, 6, 8, and 9 Oligodendrocytes TM6 Derived from AAV6 Microglia AAV-DJ Derived from AAVs 2, 4, 5, 8, and 9 Liver AAV-DJ/8 Derived from AAV-DJ Liver, CNS rAAV2retro Derived from AAV2 CNS-efficient retrograde transduction PHP.B Derived from AAV9 CNS-transduction improved ∼40x vs. AAV9 PHP.S Derived from PHP.B Peripheral nervous system PHP.eB Derived from PHP.B CNS-transduction rate further improved vs. PHP.B

Lentiviral Vectors for Delivery of Gene-Editing Systems Based on CRISPR/Cas: Current State and Perspectives

“…For the above considerations, over the last three decades a significant effort has been devoted to developing AAV into one of the gold-standard delivery systems for broad range of gene-therapy applications [ 40 ]. Notwithstanding these advances, impressive and rapidly diversifying array of AAV-CRISPR/Cas-derived tools predominantly have been used in vitro (reviewed in [ 41 ]). Efficient delivery in vivo using AAV vectors is a significantly more challenging task.…”

“…The resulting AAVs are then co-delivered, and the complete protein is reassembled in situ by a split intein—a pair of domains which “splice themselves out”, thus re-joining two peptides in the end-to-end configuration [ 42 ]. Nevertheless, further improvement of this and other systems (reviewed in [ 41 ]) would be necessary to achieve the desired therapeutic efficacy.…”

“…Overall, prime editing substantially expands the scope and capabilities of genome editing, and in principle could correct up to 89% of known genetic variants associated with human diseases [ 57 ]. A good summary expanding on the diversity of dCas9-effector tools and systems could be also found in Rittiner et al [ 41 ].…”

Non-codon Optimized PiggyBac Transposase Induces Developmental Brain Aberrations: A Call for in vivo Analysis

“…For translational therapeutic approaches, adeno-associated virus (AAV) is better suited due to the limited immune response (see e.g., Mattugini et al, 2019 ; Rittiner et al, 2020 ). A multitude of serotypes allow targeting specific cell types even via non-invasive, e.g., intravenous, application routes ( Haggerty et al, 2020 ; Nectow and Nestler, 2020 ; Rittiner et al, 2020 ).…”

“…For translational therapeutic approaches, adeno-associated virus (AAV) is better suited due to the limited immune response (see e.g., Mattugini et al, 2019 ; Rittiner et al, 2020 ). A multitude of serotypes allow targeting specific cell types even via non-invasive, e.g., intravenous, application routes ( Haggerty et al, 2020 ; Nectow and Nestler, 2020 ; Rittiner et al, 2020 ). While allowing long-term stable gene expression depending on the cell type, these vectors stay episomal, i.e., do not integrate into the host genome, but may be used to deliver constructs that are themselves able to integrate (such as transposon systems) or to permanently edit the host genome (e.g., CRISPR/Cas9).…”