Abstract This supplement proposal focuses on investigating if CRISPR Cas9 ribonucleoproteins (RNPs) complexed to cell-penetrating peptides (CPPs) can rescue mice from Huntington’s disease, using the R6/2 mouse model. These experiments are based upon our recent studies demonstrating that CPPs can efficiently transfect CRISPR Cas9-RNPs neurons in the striatum after an intracranial injection using convection enhanced delivery (CED). We have selected the 2/6 mouse model for these studies because this model has recently been rescued with Cas9 based genome editing, using AAV delivered SaCas9. In this proposal we will build on our Preliminary Studies and will inject Cas9-RNP complexed to CPPs into the striatum and thalamus, via CED, and will investigate if we can edit the huntingtin (HTT) gene to rescue mice from Huntington’s disease. If successful, these experiments will identify the levels of genome editing needed in the brain to generate therapeutic outcomes in the Huntington’s animal model.