SPLICER: A Highly Efficient Base Editing Toolbox That Enables In Vivo Therapeutic Exon Skipping

A method of treating Alzheimer's disease comprising delivering to a patient in need thereof one or more vectors or proteins comprising:

• (i) a nucleic acid molecule encoding one or more PAM-less or nearly PAM-less Cas nickases and one or more cytosine or adenosine deaminases or one or more PAM-less or nearly PAM-less Cas proteins and one or more cytosine or adenosine deaminase proteins;
• and
• (ii) a nucleic acid molecule encoding one or more single guide RNA (sgRNA) molecules targeting a splice acceptor site, a splice donor site, or both a splice acceptor site and a splice donor site of a target amyloid precursor protein gene (APP),
• wherein one or more exons or one or more portions of an exon of the target amyloid precursor protein gene (APP) are excluded during RNA splicing.

A method of treating Huntington's disease comprising delivering one or more vectors or proteins to a patient in need thereof:

• (i) a nucleic acid molecule encoding one or more PAM-less or nearly PAM-less Cas nickases and one or more cytosine or adenosine deaminases or one or more PAM-less or nearly PAM-less Cas proteins and one or more cytosine or adenosine deaminase proteins;
• and
• (ii) a nucleic acid molecule encoding one or more single guide RNA (sgRNA) molecules targeting a splice acceptor site, a splice donor site, or both a splice acceptor site and splice donor site of a target huntingtin gene (HTT);
• wherein one or more exons or one or more portions of an exon of the huntingtin gene (HTT) are excluded during RNA splicing.