A non-naturally occurring or engineered composition and a repair template for use in therapy, by manipulation of first and second target sequence on opposite strands of a DNA duplex in a genomic locus of interest in a cell by promoting homology directed repair, wherein the composition comprises: I. a first CRISPR-Cas system chimeric RNA (chiRNA) polynucleotide sequence, wherein the first polynucleotide sequence comprises: (a) a first guide sequence capable of hybridizing to the first target sequence, (b) a first tracr mate sequence, and (c) a first tracr sequence, II. a second CRISPR-Cas system chiRNA polynucleotide sequence, wherein the second polynucleotide sequence comprises: (a) a second guide sequence capable of hybridizing to the second target sequence, (b) a second tracr mate sequence, and (c) a second tracr sequence, and III. a Type II Cas9 enzyme or a polynucleotide sequence encoding it, wherein the Cas9 enzyme is a SpCas9 protein comprising the mutation N863A, or an ortholog thereof, having a mutation corresponding to SpCas9N863A, and comprising zero, or at least one or two or more nuclear localization sequences, wherein (a), (b) and (c) are arranged in a 5' to 3' orientation; wherein the polynucleotide sequence encoding said Cas9 enzyme is DNA or RNA wherein the first guide sequence directs cleavage of one strand of the DNA duplex near the first target sequence and the second guide sequence directs cleavage of the other strand near the second target sequence result in 3' overhangs; and wherein the composition further comprises the repair template or wherein the repair template is an exogenous template. I. a first CRISPR-Cas system chimeric RNA (chiRNA) polynucleotide sequence, wherein the first polynucleotide sequence comprises: (a) a first guide sequence capable of hybridizing to the first target sequence, (b) a first tracr mate sequence, and (c) a first tracr sequence, (a) a first guide sequence capable of hybridizing to the first target sequence, (b) a first tracr mate sequence, and (c) a first tracr sequence, II. a second CRISPR-Cas system chiRNA polynucleotide sequence, wherein the second polynucleotide sequence comprises: (a) a second guide sequence capable of hybridizing to the second target sequence, (b) a second tracr mate sequence, and (c) a second tracr sequence, and (a) a second guide sequence capable of hybridizing to the second target sequence, (b) a second tracr mate sequence, and (c) a second tracr sequence, and III. a Type II Cas9 enzyme or a polynucleotide sequence encoding it, wherein the Cas9 enzyme is a SpCas9 protein comprising the mutation N863A, or an ortholog thereof, having a mutation corresponding to SpCas9N863A, and comprising zero, or at least one or two or more nuclear localization sequences, wherein (a), (b) and (c) are arranged in a 5' to 3' orientation; wherein the polynucleotide sequence encoding said Cas9 enzyme is DNA or RNA wherein the first guide sequence directs cleavage of one strand of the DNA duplex near the first target sequence and the second guide sequence directs cleavage of the other strand near the second target sequence result in 3' overhangs; and wherein the composition further comprises the repair template or wherein the repair template is an exogenous template. wherein (a), (b) and (c) are arranged in a 5' to 3' orientation; wherein the polynucleotide sequence encoding said Cas9 enzyme is DNA or RNA wherein the first guide sequence directs cleavage of one strand of the DNA duplex near the first target sequence and the second guide sequence directs cleavage of the other strand near the second target sequence result in 3' overhangs; and wherein the composition further comprises the repair template or wherein the repair template is an exogenous template. <EOS>