CRISPR takes on Huntington’s disease

A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo

“…Similarly, an inhibitor of histone deacetylase 3 suppressed somatic CAG expansions through unknown processes 106 . A sequence-specific polyamide directed to the fully paired duplex GAA/TTC repeat that is expanded in Friedreich’s ataxia patients prevented triple-stranded structure formation and suppressed GAA repeat expansions in FRDA cells, but did not induce contractions 107 . The earliest non-enzymatic chemical approaches to target the HD locus aimed to modulate gene regulation using ligands targeted to fully paired duplex DNAs 116 , 125 .…”

“…Targeting DNA repeats to eliminate or correct the expansion in disease cells is of interest 2 , 49 , 101 – 107 , with substantial mechanistic and human data validating somatic instability as a driver of disease age-of-onset, progression and severity 8 , 9 , 19 , 54 , 55 , 108 , 109 . Here we targeted slipped-DNA structures using a small molecule, NA, which induced contractions in vivo in patient cells and in the striatum of HD mice.…”

“…A small molecule approach may overcome some of the in vivo hurdles of enzyme-mediated paths (delivery, editing efficiency, persistent nuclease/off-targets, immune response, haploinsufficiency, etc.) 107 , 119 – 121 . Previous studies using cell models of CAG/CTG instability demonstrated that exogenously added compounds, including DNA damaging agents, can modulate repeat instability 122 .…”

Haplotyping SNPs for allele-specific gene editing of the expanded huntingtin allele using long-read sequencing

“…We 20 , 21 and other groups 22 previously reported allele-specific editing of the mHTT allele in vitro and in vivo , taking advantage of SNPs identified for use with the CRISPR/SpCas9 system. However, these studies mainly screened common SNPs in the normal population and a detailed haplotype map surrounding exon-1 of the HD population is unknown.…”

What Should Clinicians Do to Engage the Public About Gene Editing?

“…8 A CRISPR/Cas9 complex targeting the mutated Huntington gene, for example, could locate the defective DNA sequence and cut it with high accuracy, preventing production of defective Huntingtin protein. 9 This technology has advanced rapidly, and a variety of other genomic modifications are now being introduced by mRNA editing and alternative splicing. 10 Current Applications Today, numerous academic and biotechnology groups are focused on the translation of CRISPR/Cas9 technology to correct a variety of genetic diseases.…”