Proteins, compositions, and methods for treating Farber disease are provided.

The disclosure provides methods, base editors, vectors encoding base editors and cognate gRNAs, and compositions and kits comprise said components, for installing nucleobase edits to the SMN2 locus to increase the activity and/or amount and/or stability of SMN2 protein in a cell, thereby treating Spinal Muscular Atrophy. In certain aspect, the disclosure provides compositions and methods to edit C840T of exon 7 of the SMN2 gene, or installing another one or more nucleobase edits which have the effect of removing or inactivating a degron, such as the C-terminal portion of the region encoded by exon 6 or the 4-amino acid region encoded by exon 8 (i.e., the EMLA (SEQ ID NO: 466)-tail) so as to remove or limit their degron activity to reduce, mitigate, or eliminate the intracellular degradation of the SMN2 protein.

The disclosure provides methods, base editors, vectors encoding base editors and cognate gRNAs, and compositions and kits comprise said components, for installing nucleobase edits to the SMN2 locus to increase the activity and/or amount and/or stability of SMN2 protein in a cell, thereby treating Spinal Muscular Atrophy. In certain aspect, the disclosure provides compositions and methods to edit C840T of exon 7 of the SMN2 gene, or installing another one or more nucleobase edits which have the effect of removing or inactivating a degron, such as the C-terminal portion of the region encoded by exon 6 or the 4-amino acid region encoded by exon 8 (i.e., the EMLA (SEQ ID NO: 466)-tail) so as to remove or limit their degron activity to reduce, mitigate, or eliminate the intracellular degradation of the SMN2 protein.

Provided are methods of using an anti-cancer agent's cell cycle-related, cell-killing activity to identify it as an effective combination with YM155 monobromide for treating MYC-associated cancers, and related kits, compositions, methods of screening, and methods for treating cancer in a subject in need thereof.

Provided are methods of using an anti-cancer agent's cell cycle-related, cell-killing activity to identify it as an effective combination with YM155 monobromide for treating MYC-associated cancers, and related kits, compositions, methods of screening, and methods for treating cancer in a subject in need thereof.

The present disclosure provides improved adenosine base editors (ABE) that have an expanded range of PAM sequence recognition capability (i.e., recognition of non-canonical ′5-NGG-′3 PAM sequence). In addition, the present disclosure provides improved cytidine base editors (CBE) and adenosine base editors (ABE) comprising circular permutant variants of Cas9 (CP-Cas9) with an increased window of base editing within the protospacer sequence (e.g., from about 4-5 nucleotides to up to about 8-9 nucleotides) and even outside of the protospacer sequence.

The present disclosure provides improved adenosine base editors (ABE) that have an expanded range of PAM sequence recognition capability (i.e., recognition of non-canonical ′5-NGG-′3 PAM sequence). In addition, the present disclosure provides improved cytidine base editors (CBE) and adenosine base editors (ABE) comprising circular permutant variants of Cas9 (CP-Cas9) with an increased window of base editing within the protospacer sequence (e.g., from about 4-5 nucleotides to up to about 8-9 nucleotides) and even outside of the protospacer sequence.

The present invention features compositions and methods for editing a gene associated with Shwachman Diamond Syndrome (SDS) using a programmable nucleobase editor, such that the gene is permissive for transcription and generates a functional gene product (e.g., providing a splice site and/or altering a nonsense mutation).

The present invention features compositions and methods for editing a gene associated with Shwachman Diamond Syndrome (SDS) using a programmable nucleobase editor, such that the gene is permissive for transcription and generates a functional gene product (e.g., providing a splice site and/or altering a nonsense mutation).

The present invention provides compositions and methods for treating a disease treatable by asparagine depletion in a human subject comprising dosing a human subject with L-asparaginase.