BIOCHEMISTRY, BIOMEDICINE & PHARMACEUTICS

AAV5 mediated delivery of micro-RNA for treatment of ALS and FTD with C9orf72 G4C2 expansion Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons, leading to muscle atrophy and paralysis. A significant number of ALS patients also develop frontal temporal dementia (FTD) caused by progressive degeneration of frontal and temporal lobes. There are no disease-modifying drug and most patients die within 3-5 years after the onset of the disease. The most common genetic cause of ALS and FTD is an expansion of G4C2 repeats (> one hundred repeats) in the first intronic site of the  c9orf72 gene present on chromosome 9.   The two underlying pathogenic mechanisms have been proposed for c9orf72 related neurotoxicity. First, the loss of function of c9orf72 caused by G4C2 expansion disrupts mRNA splicing and decreased protein expression resulting in neurotoxicity. But t...

CRISPR is a gene editing tool that are being explored as a potential gene therapy candidate for gene deletions, corrections etc. The high efficiency and specificity of the CRISPR enable its global use in basic research and drug discovery research. The CRISPR consists of two components a) Cas9, a protein that has a nuclease activity b) Guide RNA that recognizes the target sequence, and enables cleavage of target sequence catalyzed by Cas9. Cas9 is a protein that is originally isolated from bacteria Staphylococcus aureus and Streptococcus pyogenes. Because Cas9 is originated from human pathogenic bacteria, the prior exposure to the protein may result in pre-existing antibodies and T cell response against Cas9. The pre-existing immunogenicity against the Cas9 poses a risk impacting the safety and efficacy of CRISPR mediated gene therapy. Recent studies have reported that the prevalence of pre-existing antibodies against Cas9 proteins. Simhari et al. 2018 reported the prevalence of a...