Compositions and methods for cell conditioning

Abstract

Compositions and methods for non-genotoxic monoclonal antibody (mAb) conditioning, where the methods involve altering a cluster of differentiation 117 (CD117; c-KIT) polynucleotide sequence in a hematopoietic stem cell (HSC) or progenitor thereof to encode a CD117 polypeptide with reduced binding to the antibody. In various embodiments, the methods further include introducing a therapeutic alteration to a gene of the HSC or progenitor thereof for treatment of a hemoglobinopathy.

Description

[0001]ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 COMPOSITIONS AND METHODS FOR CELL CONDITIONING CROSS REFERENCE TO RELATED APPLICATIONS The present application claims priority to U.S. Provisional Application No.63 / 641,097 filed May 1, 2024, the entire contents of which are hereby incorporated by reference in its entirety. SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The Sequence Listing XML file, created on April 15, 2025, is named 180802-047301PCT_SL.xml and is 2,423,003 bytes in size. BACKGROUND Busulfan is a DNA alkylating reagent that induces bone marrow immunosuppression and is widely used for conditioning prior to allogenic hematopoietic stem cell transplantation and administration of autologous cell therapies. Notably, a prerequisite for ex vivo treatment of sickle cell disease (SCD), the most common single gene inherited hemoglobinopathy, is conditioning of the patient prior to infusion of an autologous cell therapy. While busulfan is the current standard of care for patients in need of allogenic or autologous transplants and engraftment of cell therapies, the use of this potent cytotoxic agent has associated risks including genotoxicity, primary or secondary malignancy, and organ toxicities including infertility. These risks present barriers to patients who would otherwise seek treatment. Accordingly, there is a need for improved methods for conditioning prior to allogeneic hematopoietic stem cell transplantation. SUMMARY As described below, the present disclosure features compositions and methods for non- genotoxic monoclonal antibody (mAb) conditioning, where the methods involve altering a cluster of differentiation 117 (CD117; c-KIT) polynucleotide sequence in a hematopoietic stem cell (HSC) or progenitor thereof to encode a CD117 polypeptide with reduced binding to the antibody. In various embodiments, the methods further include introducing a therapeutic alteration to a gene of the HSC or progenitor thereof for treatment of a hemoglobinopathy (e.g., sickle cell disease). In one aspect, the disclosure features a method for hematopoietic stem cell transplantation in a subject. The method involves (a) contacting an isolated hematopoietic stem cell or progenitor thereof with a prime editor guide polynucleotide and a prime editor containing ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, or a polynucleotide encoding the prime editor, thereby generating an edited cell. The prime editor guide polynucleotide targets a nucleic acid molecule encoding a CD117 polypeptide and contains an editing template containing an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide. The method further involves (b) administering the edited cell to the subject. The method also involves (c) administering to the subject an antibody or antigen binding fragment thereof, where the antibody is selected from one or more of ABTx135, ABTx052, ABTx196, ABTx198, ABTx202, ABTx203, ABTx205, ABTx206, ABTx248, ABTx250, ABTx251, ABTx253, ABTx254, ABTx255, ABTx256, ABTx265, ABTx268, ABTx270, ABTx271, ABTx272, ABTx273, ABTx274, ABTx307, ABTx308, ABTx309, and ABTx313. In another aspect, the disclosure features a method for hematopoietic stem cell transplantation in a subject. The method involves (a) contacting an isolated hematopoietic stem cell or progenitor thereof with a prime editor guide polynucleotide and a prime editor containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, or a polynucleotide encoding the prime editor, where the prime editor guide polynucleotide targets a nucleic acid molecule encoding a CD117 polypeptide and contains an editing template containing an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, thereby generating an edited cell. The contacting results in i) introducing an intended nucleotide edit in a codon encoding a tyrosine at amino acid position 259, where the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 259 results in the codon expressing a cytosine, or in identical edits at corresponding positions in another CD117 polypeptide, and / or ii) introducing an intended nucleotide edit in a codon encoding an asparagine at amino acid position 260, where the alteration of the nucleobase encoding the tyrosine at amino acid position 260 results in the codon expressing an aspartate, or in identical edits at corresponding positions in another CD117 polypeptide. The method further involves (b) administering the edited cell to the subject. The method also involves (c) administering to the subject an antibody or antigen binding fragment thereof, antibody drug conjugate, or a chimeric antigen receptor T (CAR-T) cell, each of which selectively binds a wild type CD117 polypeptide. In another aspect, the disclosure features a method for treating a hemoglobinopathy in a subject. The method involves (a) contacting an isolated hematopoietic stem cell or progenitor thereof with two or more prime editor guide polynucleotides and a prime editor containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 domain, or a polynucleotide encoding the prime editor, thereby generating an edited cell. One prime editor guide polynucleotide targets a nucleic acid molecule encoding a CD117 polypeptide and contains an editing template containing an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, and another prime editor guide polynucleotide that targets a nucleic acid molecule encoding a beta globin (HBB) polypeptide and contains an editing template containing an intended nucleotide edit to the nucleic acid molecule encoding the HBB polypeptide. The method also involves (b) administering the edited cell to the subject. The method further involves (c) administering to the subject an antibody or antigen binding fragment thereof, where the antibody is selected from one or more of ABTx135, ABTx052, ABTx196, ABTx198, ABTx202, ABTx203, ABTx205, ABTx206, ABTx248, ABTx250, ABTx251, ABTx253, ABTx254, ABTx255, ABTx256, ABTx265, ABTx268, ABTx270, ABTx271, ABTx272, ABTx273, ABTx274, ABTx307, ABTx308, ABTx309, and ABTx313. In another aspect, the disclosure features a method for treating a hemoglobinopathy in a subject. The method involves (a) contacting an isolated hematopoietic stem cell or progenitor thereof with two or more prime editor guide polynucleotides and a prime editor containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, or a polynucleotide encoding the prime editor, thereby generating an edited cell. One prime editor guide polynucleotide targets a nucleic acid molecule encoding a CD117 polypeptide and contains an editing template containing an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, thereby i) introducing an intended nucleotide edit in a codon encoding a tyrosine at amino acid position 259, where the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 259 results in the codon expressing a cytosine, or results in an identical edit at corresponding positions in another CD117 polypeptide, and / or ii) introducing intended nucleotide edit in a codon encoding an asparagine at amino acid position 260, where the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 260 results in the codon expressing an aspartate, or results in identical edits at corresponding positions in another CD117 polypeptide. Another prime editor guide polynucleotide targets a nucleic acid molecule encoding a beta globin (HBB) polypeptide and containing an editing template containing an intended nucleotide edit to the nucleic acid molecule encoding the HBB polypeptide, thereby introducing an amino acid alteration from a valine to a glutamate at position 6 of the HBB polypeptide. The method further involves (b) administering the edited cell to the subject. The method also involves (c) administering to the subject an antibody or antigen binding fragment thereof, antibody drug conjugate, or a chimeric ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 antigen receptor T (CAR-T) cell, each of which selectively binds a wild type CD117 polypeptide. In another aspect, the disclosure features a method of altering a nucleobase of a CD117 polynucleotide. The method involves contacting the CD117 polynucleotide with a prime editor polypeptide containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, and a prime editor guide polynucleotide that targets a nucleic acid molecule encoding a CD117 polypeptide and contains an editing template containing an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide. The contacting results in i) introducing an intended nucleotide edit in a codon encoding a tyrosine at amino acid position 259, where the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 259 results in the codon expressing a cytosine, or results in identical edits at corresponding positions in another CD117 polypeptide, and / or ii) introducing an intended nucleotide edit in a codon encoding an asparagine at amino acid position 260, where the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 260 results in the codon expressing an aspartate, or corresponding positions in another CD117 polypeptide. The prime editor guide polynucleotide contains a spacer containing the sequence AAACCAGCAGACUAAACUAC (SEQ ID NO: 1049) and a sequence selected from one or more of AUUACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1050); UAUUACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1051); UAUCACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1052); and UAUCACAUUUCUCCUGUAGUUUAGUCUG (SEQ ID NO: 1053). In another aspect, the disclosure features a method for preparing an altered hematopoietic stem cell. The method involves (a) contacting an isolated hematopoietic stem cell or progenitor thereof with two or more prime editor guide polynucleotides and a prime editor containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, or a polynucleotide encoding the prime editor, thereby generating the altered hematopoietic stem cell. One prime editor guide polynucleotide targets a nucleic acid molecule encoding a CD117 polypeptide and contains an editing template containing an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, thereby i) introducing an an intended nucleotide edit in a codon encoding a tyrosine at amino acid position 259, where the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 259 results in the codon expressing a cytosine, or results in identical edits at corresponding positions in another CD117 polypeptide, and / or ii) introducing an intended nucleotide edit in a codon encoding an asparagine at amino acid position 260, where the intended nucleotide edit in ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 the codon encoding the tyrosine at amino acid position 260 results in the codon expressing an aspartate, or results in identical edits at corresponding positions in another CD117 polypeptide. The prime editor guide polynucleotide contains a sequence selected from one or more of: gRNA 7206 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUmU*mU*mU*U (SEQ ID NO: 1057); gRNA7207 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUGmU*mU*mU*U (SEQ ID NO: 935); gRNA 7209 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1058); gRNA7210 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 936); gRNA 7248 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1059); gRNA7249 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 937); and gRNA7260 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCCUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 938). The symbol “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O-methyl nucleotide alteration. Another prime editor guide polynucleotide targets a nucleic acid molecule encoding a beta globin (HBB) polypeptide and contains an editing template containing an intended nucleotide edit to the ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 nucleic acid molecule encoding the HBB polypeptide, thereby introducing an amino acid alteration from a valine to a glutamate at position 6 of the HBB polypeptide. In another aspect, the disclosure features a cell produced by the method of any aspect of the disclosure, or embodiments thereof. In another aspect, the disclosure features a pharmaceutical composition containing an effective amount of the cell of any aspect of the disclosure, or embodiments thereof. In another aspect, the disclosure features a prime editor system containing a prime editor containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase, or a polynucleotide encoding the prime editor, and a prime editor guide polynucleotide that targets a nucleic acid molecule encoding a CD117 polypeptide and contains an editing template containing an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide. The method results in i) introducing an intended nucleotide edit in a codon encoding a tyrosine at amino acid position 259, where the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 259 results in the codon expressing a cytosine, or results in identical edits at corresponding positions in another CD117 polypeptide, and / or ii) introducing intended nucleotide edit in a codon encoding an asparagine at amino acid position 260, where the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 260 results in the codon expressing an aspartate, or results in identical edits at corresponding positions in another CD117 polypeptide. The prime editor guide polynucleotide contains a sequence selected from one or more of: gRNA 7206 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUmU*mU*mU*U (SEQ ID NO: 1057); gRNA7207 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUGmU*mU*mU*U (SEQ ID NO: 935); gRNA 7209 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1058); gRNA7210 ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 936); gRNA 7248 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1059); gRNA7249 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 937); and gRNA7260 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCCUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 938). The symbol “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O-methyl nucleotide alteration. In another aspect, the disclosure features a polynucleotide encoding the prime editor system of any aspect of the disclosure, or embodiments thereof. In another aspect, the disclosure features a prime editor guide polynucleotide containing a nucleotide sequence selected from one or more of: gRNA 7206 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUmU*mU*mU*U (SEQ ID NO: 1057); gRNA7207 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUGmU*mU*mU*U (SEQ ID NO: 935); gRNA 7209 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1058); gRNA7210 ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 936); gRNA 7248 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1059); gRNA7249 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 937); and gRNA7260 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCCUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 938). The symbol “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O-methyl nucleotide alteration. In another aspect, the disclosure features a nicking RNA for use in prime editing containing a nucleotide sequence selected from one or more of: ngRNA 7195 mU*mA*mG*UCUGCUGGUUUCAGAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1060); and ngRNA 7196 mU*mC*mU*CCUGUAGUUUAGUCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1061). The symbol “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O- methyl nucleotide alteration. In another aspect, the disclosure features a kit containing the cell, base editor system, polynucleotide, or pharmaceutical composition of any aspect of the disclosure, or embodiments thereof, and a container. In any aspect of the disclosure, or embodiments thereof, the DNA polymerase domain is a reverse transcriptase. In any aspect of the disclosure, or embodiments thereof, the reverse transcriptase is a Moloney murine leukemia virus reverse transcriptase. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 In any aspect of the disclosure, or embodiments thereof, the napDNAbp domain is a Cas9. In any aspect of the disclosure, or embodiments thereof, the Cas9 is a Cas9 nickase. In any aspect of the disclosure, or embodiments thereof, the Cas9 is a Streptococcus pyogenes Cas9, a P. lavamentivorans Cas9, a C. diphtheriae Cas9, an N. cinerea Cas9, a S. aureus Cas9, a staphylococcus lugdunensis Cas9, or an A. lari Cas9. In any aspect of the disclosure, or embodiments thereof, the prime editor contains an amino acid sequence having at least about 85% identity to the following sequence: MKRTADGSEFESPKKKRKVDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKN LIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEED KKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDL NPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLF GNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILL SDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGG ASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFY PFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIER MTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLT LTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSD GFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKV MGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLY YLQNGRDMYVDQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKK MKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTK YDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLES EFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETG EIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGF DSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKL PKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQH KHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKY FDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGDSGGSEAAAKEAAAKEAAAKEAA AKSGGSTLNIEDEYRLHETSKEPDVSLGSTWLSDFPQAWAETGGMGLAVRQAPLIIPLKATSTP VSIKQYPMSQEARLGIKPHIQRLLDQGILVPCQSPWNTPLLPVKKPGTNDYRPVQDLREVNKRV EDIHPTVPNPYNLLSGLPPSHQWYTVLDLKDAFFCLRLHPTSQPLFAFEWRDPEMGISGQLTWT RLPQGFKNSPTLFNEALHRDLADFRIQHPDLILLQYVDDLLLAATSELDCQQGTRALLQTLGNL GYRASAKKAQICQKQVKYLGYLLKEGQRWLTEARKETVMGQPTPKTPRQLREFLGKAGFCRLFI PGFAEMAAPLYPLTKPGTLFNWGPDQQKAYQEIKQALLTAPALGLPDLTKPFELFVDEKQGYAK ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 GVLTQKLGPWRRPVAYLSKKLDPVAAGWPPCLRMVAAIAVLTKDAGKLTMGQPLVILAPHAVEA LVKQPPDRWLSNARMTHYQALLLDTDRVQFGPVVALNPATLLPLPEEGLQHNCLDILAEAHGGG SKRTADGSEFEPKKKRKV (SEQ ID NO: 1065). In any aspect of the disclosure, or embodiments thereof, the prime editor guide polynucleotide contains a spacer containing the following nucleotide sequence: AAACCAGCAGACUAAACUAC (SEQ ID NO: 1049). In any aspect of the disclosure, or embodiments thereof, the prime editor guide polynucleotide contains a scaffold containing the following nucleotide sequence: GUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCA CCGAGUCGGUGC (SEQ ID NO: 1054). In any aspect of the disclosure, or embodiments thereof, the prime editor guide polynucleotide contains a sequence selected from one or more of: AUUACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1050); UAUUACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1051); UAUCACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1052); and UAUCACAUUUCUCCUGUAGUUUAGUCUG (SEQ ID NO: 1053). In any aspect of the disclosure, or embodiments thereof, the prime editor guide polynucleotide contains a nucleotide sequence selected from one or more of: gRNA 7206 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUmU*mU*mU*U (SEQ ID NO: 1057); gRNA7207 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUGmU*mU*mU*U (SEQ ID NO: 935); gRNA 7209 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1058); gRNA7210 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 936); gRNA 7248 ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1059); gRNA7249 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 937); and gRNA7260 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCCUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 938). The symbol “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O-methyl nucleotide alteration. In any aspect of the disclosure, or embodiments thereof, the method further involves administering to the cell a nicking guide RNA. In any aspect of the disclosure, or embodiments thereof, the nicking guide RNA contains a spacer containing a nucleotide sequence selected from one or more of: UAGUCUGCUGGUUUCAGAAA (SEQ ID NO: 1062); an UCUCCUGUAGUUUAGUCUGC (SEQ ID NO: 1063). In any aspect of the disclosure, or embodiments thereof, the nicking guide RNA contains a nucleotide sequence selected from one or more of: ngRNA 7195 mU*mA*mG*UCUGCUGGUUUCAGAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1060); and ngRNA 7196 mU*mC*mU*CCUGUAGUUUAGUCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1061). The symbol “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O- methyl nucleotide alteration. In any aspect of the disclosure, or embodiments thereof, the method further involves altering a protospacer adjacent motif capable of being bound by the napDNAbp. In any aspect of the disclosure, or embodiments thereof, the subject has a hemoglobinopathy selected from one or more of sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 In any aspect of the disclosure, or embodiments thereof, the method further involves contacting the hematopoietic stem cell or progenitor thereof with a prime editor guide polynucleotide that targets a nucleic acid molecule encoding a beta globin (HBB) polypeptide and contains an editing template containing an intended nucleotide edit to the nucleic acid molecule encoding the HBB polypeptide, thereby introducing an amino acid alteration from a valine to a glutamate at position 6 of the HBB polypeptide. In any aspect of the disclosure, or embodiments thereof, the hematopoietic stem cell or progenitor thereof is autologous or allogeneic to the subject. In any aspect of the disclosure, or embodiments thereof, the subject is a mammal. In any aspect of the disclosure, or embodiments thereof, the method further involves contacting the isolated hematopoietic stem cell or progenitor thereof with a nicking guide RNA containing a nucleotide sequence selected from one or more of: ngRNA 7195 mU*mA*mG*UCUGCUGGUUUCAGAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1060); and ngRNA 7196 mU*mC*mU*CCUGUAGUUUAGUCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1061); where, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O-methyl nucleotide alteration. In any aspect of the disclosure, or embodiments thereof, the prime editor system further contains a nicking guide RNA containing a nucleotide sequence selected from one or more of: ngRNA 7195 mU*mA*mG*UCUGCUGGUUUCAGAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1060); and ngRNA 7196 mU*mC*mU*CCUGUAGUUUAGUCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1061); where, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O-methyl nucleotide alteration. In any aspect provided herein, or embodiments thereof, the method is not a process for modifying the germline genetic identity of human beings. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise. By “ABTx052 polypeptide” is meant an antibody or antigen binding fragment thereof having at least about 85% amino acid sequence identity to an antibody sequence of antibody ABTx052, wherein the antibody or antigen binding fragment thereof specifically binds to a wild type CD117 polypeptide, but fails to detectably bind or has only reduced binding to an altered CD117 polypeptide. In embodiments, the ABTx052 polypeptide comprises VH and / or VL CDRs 1-3 of ABTx052, wherein the VH and / or VL CDRs, and antigen binding fragments thereof, specifically bind to a wild type CD117 polypeptide, but fail to detectably bind or have only reduced binding to an altered CD117 polypeptide. In embodiments, the antibody or antigen binding fragment thereof has at least 90%, 93%, 95%, 98%, 99% or 100% amino acid sequence identity to an antibody sequence of antibody ABTx052. Exemplary heavy chain and light chain sequences for antibody ABTx052 are provided below, where the variable regions are in plain text, the constant domains are in bold, and complementarity determining regions (CDRs), i.e., CDR1, CDR2, and CDR2, are underlined: ABTx052 heavy chain (HC): QVQLVQSGAAVKKPGESLKISCKGSGYRFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSF QGQVTISAGKSISTAYLQWSSLKASDTAMYYCARHGRGYNGYEGAFDIWGQGTMVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG (SEQ ID NO: 962) ABTx052 light chain (LC): ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 963). The three CDRs of the ABTx052 antibody VH region are as follows: VH CDR1: GYRFTSYW (SEQ ID NO: 964); VH CDR2: IYPGDSDT (SEQ ID NO: 965) orIYPGDSDTR (SEQ ID NO: 946); and VH CDR3: ARHGRGYNGYEGAFDI (SEQ ID NO: 966) . The three CDRs of the ABTx052 antibody VL region are as follows: VL CDR1: QGISSA (SEQ ID NO: 967); VL CDR2: DAS; and VL CDR3: QQFNSYPLT (SEQ ID NO: 968). The four framework (FR) regions, i.e., FR1, FR2, FR3, and FR4, of the ABTx052 antibody are located on either side of each of the CDRs in VH and VL region sequences shown supra. In particular, the four FRs of the ABTx052 antibody VH region are as follows: VH FR1:QVQLVQSGAAVKKPGESLKISCKGS (SEQ ID NO: 969); VH FR2:IGWVRQMPGKGLEWMGI (SEQ ID NO: 970); and VH FR3:RYSPSFQGQVTISAGKSISTAYLQWSSLKASDTAMYYC (SEQ ID NO: 971) or YSPSFQGQVTISAGKSISTAYLQWSSLKASDTAMYYC (SEQ ID NO: 948); VH FR4:WGQGTMVTVSS (SEQ ID NO: 949). The four FRs of the ABTx052 antibody VL region are as follows: VL FR1:AIQLTQSPSSLSASVGDRVTITCRAS (SEQ ID NO: 950); VL FR2:LAWYQQKPGKAPKLLIY (SEQ ID NO: 951); VL FR3:SLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 952); and VL FR4:FGGGTKVEIKRTV (SEQ ID NO: 953). By “ABTx052 polynucleotide” is meant a nucleic acid molecule encoding at least a fragment of an ABTx052 antibody. In an embodiment, the ABTx052 polynucleotide is DNA, RNA, or a hybrid thereof. By “ABTx135 polypeptide” is meant an antibody or antigen binding fragment thereof having at least about 85% amino acid sequence identity to an antibody sequence of antibody ABTx135, wherein the antibody or antigen binding fragment thereof specifically binds to a wild type CD117 polypeptide, but fails to detectably bind or has only reduced binding to an altered CD117 polypeptide. In embodiments, the ABTx135 polypeptide comprises VH and / or VL ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 thereof, specifically bind to a wild type CD117 polypeptide, but fail to detectably bind or have only reduced binding to an altered CD117 polypeptide. In embodiments, the antibody or antigen binding fragment thereof has at least 90%, 93%, 95%, 98%, 99% or 100% amino acid sequence identity to an antibody sequence of antibody ABTx135. In various embodiments, the ABTx135 polypeptide contains an Fc domain having the amino acid alterations L234A, L235A, and D265A (LALADA) referenced to SEQ ID NO: 922. Exemplary heavy chain and light chain sequences for antibody ABTx135 are provided below, where the variable regions are in plain text, the constant domains (e.g., the region of the heavy chain containing an Fc domain) are in bold, and complementarity determining regions (CDRs), i.e., CDR1, CDR2, and CDR2, are underlined: ABTx135 heavy chain (HC): QVQLVQSGAAVKKPGESLKISCKGSGYRFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSF QGQVTISAGKSISTAYLQWSSLKASDTAMYYCARHGRGYNGYEGAFDIWGQGTMVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT LMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK (SEQ ID NO: 1066) ABTx135 light chain (LC): AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 963). The three CDRs of the ABTx135 antibody VH region are as follows: VH CDR1: GYRFTSYW (SEQ ID NO: 964); VH CDR2: IYPGDSDT (SEQ ID NO: 965) orIYPGDSDTR (SEQ ID NO: 946); and VH CDR3: ARHGRGYNGYEGAFDI (SEQ ID NO: 966) . The three CDRs of the ABTx135 antibody VL region are as follows: VL CDR1: QGISSA (SEQ ID NO: 967); VL CDR2: DAS; and VL CDR3: QQFNSYPLT (SEQ ID NO: 968). ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 The four framework (FR) regions, i.e., FR1, FR2, FR3, and FR4, of the ABTx135 antibody are located on either side of each of the CDRs in VH and VL region sequences shown supra. In particular, the four FRs of the ABTx135 antibody VH region are as follows: VH FR1:QVQLVQSGAAVKKPGESLKISCKGS (SEQ ID NO: 969); VH FR2:IGWVRQMPGKGLEWMGI (SEQ ID NO: 970); and VH FR3:RYSPSFQGQVTISAGKSISTAYLQWSSLKASDTAMYYC (SEQ ID NO: 971) or YSPSFQGQVTISAGKSISTAYLQWSSLKASDTAMYYC (SEQ ID NO: 948); VH FR4:WGQGTMVTVSS (SEQ ID NO: 949). The four FRs of the ABTx135 antibody VL region are as follows: VL FR1:AIQLTQSPSSLSASVGDRVTITCRAS (SEQ ID NO: 950); VL FR2:LAWYQQKPGKAPKLLIY (SEQ ID NO: 951); VL FR3:SLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 952); and VL FR4:FGGGTKVEIKRTV (SEQ ID NO: 953). By “ABTx135 polynucleotide” is meant a nucleic acid molecule encoding at least a fragment of an ABTx135 antibody. In an embodiment, the ABTx135 polynucleotide is DNA, RNA, or a hybrid thereof. By “ABTxN polypeptide,” where N is 196, 198, 202, 203, 205, 206, any number from 248 to 273, 307, 308, 309, or 313, is meant an antibody or antigen binding fragment thereof having at least about 85% amino acid sequence identity to an antibody sequence of antibody ABTxN listed in Tables 1 and 2, wherein the antibody or antigen binding fragment thereof specifically binds to a wild type CD117 polypeptide, but fails to detectably bind or has only reduced binding to an altered CD117 polypeptide. In embodiments, the ABTxN polypeptide comprises VH and / or VL CDRs 1-3 of ABTxN, wherein the VH and / or VL CDRs, and antigen binding fragments thereof, specifically bind to a wild type CD117 polypeptide, but fail to detectably bind or have only reduced binding to an altered CD117 polypeptide. In embodiments, the antibody or antigen binding fragment thereof has at least 90%, 93%, 95%, 98%, 99% or 100% amino acid sequence identity to an antibody sequence of antibody ABTxN. Exemplary heavy chain and light chain sequences for antibody ABTxN are provided in Tables 1. Exemplary VL and VH CDR sequences for antibody ABTxN are provided in Table 1. The four framework (FR) regions, i.e., FR1, FR2, FR3, and FR4, of the ABTxN antibody are located on either side of each of the CDRs in VH and VL region sequences listed in Table 2. Exemplary VH and VL FR regions for ABTxN are provided in Table 2. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 Table 1. Antibody Sequences Table 2. Antibody Sequences ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 By “ABTxN polynucleotide,” where N is 196, 198, 202, 203, 205, 206, any number from 248 to 273, 307, 308, 309, or 313, is meant a nucleic acid molecule encoding at least a fragment of an ABTxN antibody. In an embodiment, the ABTxN polynucleotide is DNA, RNA, or a hybrid thereof. Non-limiting examples of antibodies and antibody sequences suitable for use in various aspects and embodiments of the present disclosure include those disclosed in International Patent Application No. PCT / US2023 / 069189, the disclosure of which is hereby incorporated by reference in its entirety for all purposes. “Administering” is referred to herein as providing one or more agents or compositions described herein to a patient or a subject. By way of example and without limitation, composition administration (e.g., injection) can be performed by intravenous (i.v.) injection, sub- ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 cutaneous (s.c.) injection, intradermal (i.d.) injection, intraperitoneal (i.p.) injection, or intramuscular (i.m.) injection. One or more such routes can be employed. Parenteral administration can be, for example, by bolus injection or by gradual perfusion over time. In some embodiments, parenteral administration includes infusing or injecting intravascularly, intravenously, intramuscularly, intraarterially, intrathecally, intratumorally, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidly and intrasternally. Alternatively, or concurrently, administration can be by the oral route. By “agent” is meant any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof. “Allogeneic,” as used herein, refers to cells of the same species that differ genetically to the cell in comparison. “Autologous,” as used herein, refers to cells from the same subject. By “alteration” is meant a change in the level, structure, or activity of an analyte, gene or polypeptide as detected by standard art known methods such as those described herein. As used herein, an alteration includes a change (e.g., increase or reduction) in expression levels. In embodiments, the increase or reduction in expression levels is by 10%, 25%, 40%, 50% or greater. In some embodiments, an alteration includes an insertion, deletion, or substitution of a nucleobase or amino acid (by, e.g., genetic engineering). By “ameliorate” is meant reduce, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease. By “analog” is meant a molecule that is not identical but has analogous functional or structural features. For example, a polypeptide analog retains the biological activity of a corresponding naturally-occurring polypeptide, while having certain biochemical modifications that enhance the analog’s function relative to a naturally occurring polypeptide. Such biochemical modifications could increase the analog’s protease resistance, membrane permeability, or half-life, without altering, for example, ligand binding. An analog may include an unnatural amino acid. As used herein, the term “antibody” refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive with, a particular antigen, and includes polyclonal, monoclonal, genetically engineered, and otherwise modified forms of antibodies, including but not limited to chimeric antibodies, humanized antibodies, heteroconjugate antibodies (e.g., bi- tri- and quad-specific antibodies, diabodies, triabodies, and tetrabodies), and antigen binding fragments of antibodies, including, for example, Fab’, F(ab’)2, Fab, Fv, rlgG, ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 and scFv fragments. Further non-limiting examples of antibodies include VHH domains. Unless otherwise indicated, the term “monoclonal antibody” (mAb) is meant to include both intact molecules, as well as antibody fragments (including, for example, Fab and F(ab’)2 fragments) that are capable of specifically binding to a target protein. As used herein, the Fab and F(ab’)2 fragments refer to antibody fragments that lack the Fc fragment of an intact antibody. Antibodies (immunoglobulins) comprise two heavy chains linked together by disulfide bonds, and two light chains, with each light chain being linked to a respective heavy chain by disulfide bonds in a “Y” shaped configuration. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains (CH). Each light chain has a variable domain (VL) at one end and a constant domain (CL) at its other end. The variable domain of the light chain (VL) is aligned with the variable domain of the heavy chain (VL), and the light chain constant domain (CL) is aligned with the first constant domain of the heavy chain (CH1). The variable domains of each pair of light and heavy chains form the antigen binding site. The isotype of the heavy chain (gamma, alpha, delta, epsilon or mu) determines the immunoglobulin class (IgG, IgA, IgD, IgE or IgM, respectively). The light chain is either of two isotypes (kappa (κ) or lambda (λ)) found in all antibody classes. The terms “antibody” or “antibodies” include intact antibodies, such as polyclonal antibodies or monoclonal antibodies (mAbs), as well as proteolytic portions or fragments thereof, such as the Fab or F(ab')2 fragments, that are capable of specifically binding to a target protein. Antibodies may include chimeric antibodies; recombinant and engineered antibodies, and antigen binding fragments thereof. Exemplary functional antibody fragments comprising whole or essentially whole variable regions of both the light and heavy chains are defined as follows: (i) Fv, defined as a genetically engineered fragment consisting of the variable region of the light chain and the variable region of the heavy chain expressed as two chains; (ii) single-chain Fv (“scFv”), a genetically engineered single- chain molecule including the variable region of the light chain and the variable region of the heavy chain, linked by a suitable polypeptide linker; (iii) Fab, a fragment of an antibody molecule containing a monovalent antigen-binding portion of an antibody molecule, obtained by treating an intact antibody with the enzyme papain to yield the intact light chain and the Fd fragment of the heavy chain, which consists of the variable and CH1 domains thereof; (iv) Fab', a fragment of an antibody molecule containing a monovalent antigen-binding portion of an antibody molecule, obtained by treating an intact antibody with the enzyme pepsin, followed by reduction (two Fab' fragments are generated per antibody molecule); and (v) F(ab')2, a fragment of an antibody molecule containing a monovalent antigen-binding portion of an antibody ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 molecule, obtained by treating an intact antibody with the enzyme pepsin (i.e., a dimer of Fab' fragments held together by two disulfide bonds). According to some aspects and embodiments herein, antibody fragments are understood as meaning functional parts of antibodies, such as Fc, Fab, Fab', Fv, F(ab')2, scFv. According to some aspects and embodiments herein, corresponding biologically active fragments are to be understood as meaning those parts of antibodies which are capable of binding to an antigen, such as Fab, Fab', Fv, F(ab')2, and scFv. The term “antigen-binding fragment,” as used herein, refers to one or more portions or fragments of an antibody that retain the ability to specifically bind to a target antigen. In an embodiment, the target antigen is a CD117 variant polypeptide or peptide. The antigen-binding function of an antibody can be performed by fragments of a full-length antibody. The antibody fragments can be a Fab, F(ab')2, scFv, SMIP, diabody, a triabody, an affibody, a nanobody, an aptamer, or a domain antibody. Examples of binding fragments encompassed by the term “antigen-binding fragment” of an antibody include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VHand CH1domains; (iv) a Fv fragment consisting of the VLand VHdomains of a single arm of an antibody, (v) a dAb including VHand VLdomains; (vi) a dAb fragment (Ward et al., Nature 341:544-546, 1989), which consists of a VH domain; (vii) a dAb which consists of a VH or a VL domain; (viii) an isolated complementarity determining region (CDR); and (ix) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a linker that enables them to be made as a single protein chain in which the VLand VHregions pair to form monovalent molecules (known as single-chain Fv (scFv); see, e.g., Bird et al., Science 242: 423-426, 1988, and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988). Such antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments can be screened for utility in the same manner as intact antibodies. Antigen-binding fragments can be produced by recombinant DNA techniques, enzymatic or chemical cleavage of intact immunoglobulins, or, in some cases, by chemical peptide synthesis procedures known in the art. In some embodiments, antigen-binding fragments (e.g., .g., Fab', F(ab')2, Fab, scFab, Fv, rlgG, and scFv fragments) of an anti-CD117 antibody, which are joined by a synthetic linker, are encompassed herein. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 By “ß-globin (HBB) polypeptide” is meant a polypeptide having at least about 85% amino acid sequence identity to NCBI Accession No. NP_000509, provided below, or a fragment thereof capable of forming a dimer with a HBA1 polypeptide. In particular embodiments, a ß-globin protein comprises one or more alterations relative to the following reference sequence. In one particular embodiment, a ß-globin protein associated with sickle cell disease comprises an E6V (also termed E7V) mutation, where position E6V is shown in bold in the below sequence. MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAH GKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQ AAYQKVVAGVANALAHKYH (SEQ ID NO: 895). By HBB polynucleotide” is meant a nucleic acid molecule that encodes an HBB polypeptide as well as the introns, exons, 3′ untranslated regions, 5′ untranslated regions, and regulatory sequences associated with its expression, or fragments thereof. In embodiments, a HBB polynucleotide is the genomic sequence, cDNA, mRNA, or gene associated with and / or required for HBB expression. Exemplary HBB polynucleotide sequences from Homo sapiens are provided below (NCBI Ref. Seq. Accessions No. NM_000518 and NG_059281). ACATTTGCTTCTGACACAACTGTGTTCACTAGCAACCTCAAACAGACACCATGGTGCATCTGAC TCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGT GAGGCCCTGGGCAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGGGG ATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTGCT CGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGAGT GAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGCTCCTGGGCAACGTGCTGG TCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCAGTGCAGGCTGCCTATCAGAA AGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACTAAGCTCGCTTTCTTGCTGTC CAATTTCTATTAAAGGTTCCTTTGTTCCCTAAGTCCAACTACTAAACTGGGGGATATTATGAAG GGCCTTGAGCATCTGGATTCTGCCTAATAAAAAACATTTATTTTCATTGCAA (SEQ ID NO: 896). >NG_059281.1:5001-6608 Homo sapiens hemoglobin subunit beta (HBB), RefSeqGene (LRG_1232) on chromosome 11; an A altered to T in Sickle cell disease is indicated in bold; the bold-underlined T indicates a SNP that is a C in some sickle cell patients. The underlined ATG is the start codon. ACATTTGCTTCTGACACAACTGTGTTCACTAGCAACCTCAAACAGACACCATGGTGCATCTGAC TCCTGAGGAGAAGTCTGCCGTTACTGCCCTGTGGGGCAAGGTGAACGTGGATGAAGTTGGTGGT GAGGCCCTGGGCAGGTTGGTATCAAGGTTACAAGACAGGTTTAAGGAGACCAATAGAAACTGGG ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 CATGTGGAGACAGAGAAGACTCTTGGGTTTCTGATAGGCACTGACTCTCTCTGCCTATTGGTCT ATTTTCCCACCCTTAGGCTGCTGGTGGTCTACCCTTGGACCCAGAGGTTCTTTGAGTCCTTTGG GGATCTGTCCACTCCTGATGCTGTTATGGGCAACCCTAAGGTGAAGGCTCATGGCAAGAAAGTG CTCGGTGCCTTTAGTGATGGCCTGGCTCACCTGGACAACCTCAAGGGCACCTTTGCCACACTGA GTGAGCTGCACTGTGACAAGCTGCACGTGGATCCTGAGAACTTCAGGGTGAGTCTATGGGACGC TTGATGTTTTCTTTCCCCTTCTTTTCTATGGTTAAGTTCATGTCATAGGAAGGGGATAAGTAAC AGGGTACAGTTTAGAATGGGAAACAGACGAATGATTGCATCAGTGTGGAAGTCTCAGGATCGTT TTAGTTTCTTTTATTTGCTGTTCATAACAATTGTTTTCTTTTGTTTAATTCTTGCTTTCTTTTT TTTTCTTCTCCGCAATTTTTACTATTATACTTAATGCCTTAACATTGTGTATAACAAAAGGAAA TATCTCTGAGATACATTAAGTAACTTAAAAAAAAACTTTACACAGTCTGCCTAGTACATTACTA TTTGGAATATATGTGTGCTTATTTGCATATTCATAATCTCCCTACTTTATTTTCTTTTATTTTT AATTGATACATAATCATTATACATATTTATGGGTTAAAGTGTAATGTTTTAATATGTGTACACA TATTGACCAAATCAGGGTAATTTTGCATTTGTAATTTTAAAAAATGCTTTCTTCTTTTAATATA CTTTTTTGTTTATCTTATTTCTAATACTTTCCCTAATCTCTTTCTTTCAGGGCAATAATGATAC AATGTATCATGCCTCTTTGCACCATTCTAAAGAATAACAGTGATAATTTCTGGGTTAAGGCAAT AGCAATATCTCTGCATATAAATATTTCTGCATATAAATTGTAACTGATGTAAGAGGTTTCATAT TGCTAATAGCAGCTACAATCCAGCTACCATTCTGCTTTTATTTTATGGTTGGGATAAGGCTGGA TTATTCTGAGTCCAAGCTAGGCCCTTTTGCTAATCATGTTCATACCTCTTATCTTCCTCCCACA GCTCCTGGGCAACGTGCTGGTCTGTGTGCTGGCCCATCACTTTGGCAAAGAATTCACCCCACCA GTGCAGGCTGCCTATCAGAAAGTGGTGGCTGGTGTGGCTAATGCCCTGGCCCACAAGTATCACT AAGCTCGCTTTCTTGCTGTCCAATTTCTATTAAAGGTTCCTTTGTTCCCTAAGTCCAACTACTA AACTGGGGGATATTATGAAGGGCCTTGAGCATCTGGATTCTGCCTAATAAAAAACATTTATTTT CATTGCAA (SEQ ID NO: 897). A “binding polypeptide” refers to a polypeptide, or an antigen binding portion or fragment thereof, that has specificity for and specifically binds to a CD117 polypeptide. In an embodiment, a binding polypeptide is an anti-CD117 antibody or immunoglobulin or an antigen binding portion or fragment thereof. By “cluster of differentiation 117 (CD117; C-kit; SCFR) polypeptide” is meant a polypeptide having at least about 85% amino acid sequence identity to an amino acid sequence provided at GenBank Accession No. NP_000213, which is provided below, or a fragment thereof that binds an anti-CD117 antibody. CD117 (KIT) is a type III receptor tyrosine kinase operating in cell signal transduction in several cell types. Normally KIT is activated (phosphorylated) by binding of its ligand, the stem cell factor (SCF). This leads to a phosphorylation cascade ultimately activating various transcription factors in different cell types. Such activation regulates apoptosis, cell differentiation, proliferation, chemotaxis, and cell ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 adhesion. In some embodiments, an CD117 polypeptide or fragment thereof has SCF signaling activity. >NP_000213.1 mast / stem cell growth factor receptor Kit isoform 1 precursor [Homo sapiens] MRGARGAWDFLCVLLLLLRVQTGSSQPSVSPGEPSPPSIHPGKSDLIVRVGDEIRLLCTDPGFV KWTFEILDETNENKQNEWITEKAEATNTGKYTCTNKHGLSNSIYVFVRDPAKLFLVDRSLYGKE DNDTLVRCPLTDPEVTNYSLKGCQGKPLPKDLRFIPDPKAGIMIKSVKRAYHRLCLHCSVDQEG KSVLSEKFILKVRPAFKAVPVVSVSKASYLLREGEEFTVTCTIKDVSSSVYSTWKRENSQTKLQ EKYNSWHHGDFNYERQATLTISSARVNDSGVFMCYANNTFGSANVTTTLEVVDKGFINIFPMIN TTVFVNDGENVDLIVEYEAFPKPEHQQWIYMNRTFTDKWEDYPKSENESNIRYVSELHLTRLKG TEGGTYTFLVSNSDVNAAIAFNVYVNTKPEILTYDRLVNGMLQCVAAGFPEPTIDWYFCPGTEQ RCSASVLPVDVQTLNSSGPPFGKLVVQSSIDSSAFKHNGTVECKAYNDVGKTSAYFNFAFKGNN KEQIHPHTLFTPLLIGFVIVAGMMCIIVMILTYKYLQKPMYEVQWKVVEEINGNNYVYIDPTQL PYDHKWEFPRNRLSFGKTLGAGAFGKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSE LKVLSYLGNHMNIVNLLGACTIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEAALYK NLLHSKESSCSDSTNEYMDMKPGVSYVVPTKADKRRSVRIGSYIERDVTPAIMEDDELALDLED LLSFSYQVAKGMAFLASKNCIHRDLAARNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLP VKWMAPESIFNCVYTFESDVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAP AEMYDIMKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRINSV GSTASSSQPLLVHDDV (SEQ ID NO: 898) >CD117 variant with Y259C and N260D alterations (shown in bold-underline) MRGARGAWDFLCVLLLLLRVQTGSSQPSVSPGEPSPPSIHPGKSDLIVRVGDEIRLLCTDPGFV KWTFEILDETNENKQNEWITEKAEATNTGKYTCTNKHGLSNSIYVFVRDPAKLFLVDRSLYGKE DNDTLVRCPLTDPEVTNYSLKGCQGKPLPKDLRFIPDPKAGIMIKSVKRAYHRLCLHCSVDQEG KSVLSEKFILKVRPAFKAVPVVSVSKASYLLREGEEFTVTCTIKDVSSSVYSTWKRENSQTKLQ EKCDSWHHGDFNYERQATLTISSARVNDSGVFMCYANNTFGSANVTTTLEVVDKGFINIFPMIN TTVFVNDGENVDLIVEYEAFPKPEHQQWIYMNRTFTDKWEDYPKSENESNIRYVSELHLTRLKG TEGGTYTFLVSNSDVNAAIAFNVYVNTKPEILTYDRLVNGMLQCVAAGFPEPTIDWYFCPGTEQ RCSASVLPVDVQTLNSSGPPFGKLVVQSSIDSSAFKHNGTVECKAYNDVGKTSAYFNFAFKGNN KEQIHPHTLFTPLLIGFVIVAGMMCIIVMILTYKYLQKPMYEVQWKVVEEINGNNYVYIDPTQL PYDHKWEFPRNRLSFGKTLGAGAFGKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSE LKVLSYLGNHMNIVNLLGACTIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEAALYK NLLHSKESSCSDSTNEYMDMKPGVSYVVPTKADKRRSVRIGSYIERDVTPAIMEDDELALDLED LLSFSYQVAKGMAFLASKNCIHRDLAARNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLP VKWMAPESIFNCVYTFESDVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAP ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 AEMYDIMKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRINSV GSTASSSQPLLVHDDV (SEQ ID NO: 899) >CD117 variant with an N260D alteration (shown in bold-underline) MRGARGAWDFLCVLLLLLRVQTGSSQPSVSPGEPSPPSIHPGKSDLIVRVGDEIRLLCTDPGFV KWTFEILDETNENKQNEWITEKAEATNTGKYTCTNKHGLSNSIYVFVRDPAKLFLVDRSLYGKE DNDTLVRCPLTDPEVTNYSLKGCQGKPLPKDLRFIPDPKAGIMIKSVKRAYHRLCLHCSVDQEG KSVLSEKFILKVRPAFKAVPVVSVSKASYLLREGEEFTVTCTIKDVSSSVYSTWKRENSQTKLQ EKYDSWHHGDFNYERQATLTISSARVNDSGVFMCYANNTFGSANVTTTLEVVDKGFINIFPMIN TTVFVNDGENVDLIVEYEAFPKPEHQQWIYMNRTFTDKWEDYPKSENESNIRYVSELHLTRLKG TEGGTYTFLVSNSDVNAAIAFNVYVNTKPEILTYDRLVNGMLQCVAAGFPEPTIDWYFCPGTEQ RCSASVLPVDVQTLNSSGPPFGKLVVQSSIDSSAFKHNGTVECKAYNDVGKTSAYFNFAFKGNN KEQIHPHTLFTPLLIGFVIVAGMMCIIVMILTYKYLQKPMYEVQWKVVEEINGNNYVYIDPTQL PYDHKWEFPRNRLSFGKTLGAGAFGKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSE LKVLSYLGNHMNIVNLLGACTIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEAALYK NLLHSKESSCSDSTNEYMDMKPGVSYVVPTKADKRRSVRIGSYIERDVTPAIMEDDELALDLED LLSFSYQVAKGMAFLASKNCIHRDLAARNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLP VKWMAPESIFNCVYTFESDVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAP AEMYDIMKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRINSV GSTASSSQPLLVHDDV (SEQ ID NO: 900) By “cluster of differentiation 117 (CD117; C-kit; SCFR) polynucleotide” is meant a nucleic acid molecule that encodes a CD117 polypeptide as well as the introns, exons, 3′ untranslated regions, 5′ untranslated regions, and regulatory sequences associated with its expression, or fragments thereof. In embodiments, a CD117 polynucleotide is the genomic sequence, cDNA, mRNA, or gene associated with and / or required for CD117 expression. An exemplary CD117 polynucleotide sequence from Homo sapiens is provided below (NCBI Ref. Seq. Accession No. NM_000222.2), and an exemplary CD117 gene sequence is provided at ENSEMBL Accession No. ENSG00000157404. >NM_000222.2 Homo sapiens KIT proto-oncogene, receptor tyrosine kinase (KIT), transcript variant 1, mRNA, where positions targeted for prime editing according to the methods of the disclosure are shown in bold TCTGGGGGCTCGGCTTTGCCGCGCTCGCTGCACTTGGGCGAGAGCTGGAACGTGGACCAGAGCT CGGATCCCATCGCAGCTACCGCGATGAGAGGCGCTCGCGGCGCCTGGGATTTTCTCTGCGTTCT GCTCCTACTGCTTCGCGTCCAGACAGGCTCTTCTCAACCATCTGTGAGTCCAGGGGAACCGTCT CCACCATCCATCCATCCAGGAAAATCAGACTTAATAGTCCGCGTGGGCGACGAGATTAGGCTGT ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 TATGCACTGATCCGGGCTTTGTCAAATGGACTTTTGAGATCCTGGATGAAACGAATGAGAATAA GCAGAATGAATGGATCACGGAAAAGGCAGAAGCCACCAACACCGGCAAATACACGTGCACCAAC AAACACGGCTTAAGCAATTCCATTTATGTGTTTGTTAGAGATCCTGCCAAGCTTTTCCTTGTTG ACCGCTCCTTGTATGGGAAAGAAGACAACGACACGCTGGTCCGCTGTCCTCTCACAGACCCAGA AGTGACCAATTATTCCCTCAAGGGGTGCCAGGGGAAGCCTCTTCCCAAGGACTTGAGGTTTATT CCTGACCCCAAGGCGGGCATCATGATCAAAAGTGTGAAACGCGCCTACCATCGGCTCTGTCTGC ATTGTTCTGTGGACCAGGAGGGCAAGTCAGTGCTGTCGGAAAAATTCATCCTGAAAGTGAGGCC AGCCTTCAAAGCTGTGCCTGTTGTGTCTGTGTCCAAAGCAAGCTATCTTCTTAGGGAAGGGGAA GAATTCACAGTGACGTGCACAATAAAAGATGTGTCTAGTTCTGTGTACTCAACGTGGAAAAGAG AAAACAGTCAGACTAAACTACAGGAGAAATATAATAGCTGGCATCACGGTGACTTCAATTATGA ACGTCAGGCAACGTTGACTATCAGTTCAGCGAGAGTTAATGATTCTGGAGTGTTCATGTGTTAT GCCAATAATACTTTTGGATCAGCAAATGTCACAACAACCTTGGAAGTAGTAGATAAAGGATTCA TTAATATCTTCCCCATGATAAACACTACAGTATTTGTAAACGATGGAGAAAATGTAGATTTGAT TGTTGAATATGAAGCATTCCCCAAACCTGAACACCAGCAGTGGATCTATATGAACAGAACCTTC ACTGATAAATGGGAAGATTATCCCAAGTCTGAGAATGAAAGTAATATCAGATACGTAAGTGAAC TTCATCTAACGAGATTAAAAGGCACCGAAGGAGGCACTTACACATTCCTAGTGTCCAATTCTGA CGTCAATGCTGCCATAGCATTTAATGTTTATGTGAATACAAAACCAGAAATCCTGACTTACGAC AGGCTCGTGAATGGCATGCTCCAATGTGTGGCAGCAGGATTCCCAGAGCCCACAATAGATTGGT ATTTTTGTCCAGGAACTGAGCAGAGATGCTCTGCTTCTGTACTGCCAGTGGATGTGCAGACACT AAACTCATCTGGGCCACCGTTTGGAAAGCTAGTGGTTCAGAGTTCTATAGATTCTAGTGCATTC AAGCACAATGGCACGGTTGAATGTAAGGCTTACAACGATGTGGGCAAGACTTCTGCCTATTTTA ACTTTGCATTTAAAGGTAACAACAAAGAGCAAATCCATCCCCACACCCTGTTCACTCCTTTGCT GATTGGTTTCGTAATCGTAGCTGGCATGATGTGCATTATTGTGATGATTCTGACCTACAAATAT TTACAGAAACCCATGTATGAAGTACAGTGGAAGGTTGTTGAGGAGATAAATGGAAACAATTATG TTTACATAGACCCAACACAACTTCCTTATGATCACAAATGGGAGTTTCCCAGAAACAGGCTGAG TTTTGGGAAAACCCTGGGTGCTGGAGCTTTCGGGAAGGTTGTTGAGGCAACTGCTTATGGCTTA ATTAAGTCAGATGCGGCCATGACTGTCGCTGTAAAGATGCTCAAGCCGAGTGCCCATTTGACAG AACGGGAAGCCCTCATGTCTGAACTCAAAGTCCTGAGTTACCTTGGTAATCACATGAATATTGT GAATCTACTTGGAGCCTGCACCATTGGAGGGCCCACCCTGGTCATTACAGAATATTGTTGCTAT GGTGATCTTTTGAATTTTTTGAGAAGAAAACGTGATTCATTTATTTGTTCAAAGCAGGAAGATC ATGCAGAAGCTGCACTTTATAAGAATCTTCTGCATTCAAAGGAGTCTTCCTGCAGCGATAGTAC TAATGAGTACATGGACATGAAACCTGGAGTTTCTTATGTTGTCCCAACCAAGGCCGACAAAAGG AGATCTGTGAGAATAGGCTCATACATAGAAAGAGATGTGACTCCCGCCATCATGGAGGATGACG AGTTGGCCCTAGACTTAGAAGACTTGCTGAGCTTTTCTTACCAGGTGGCAAAGGGCATGGCTTT CCTCGCCTCCAAGAATTGTATTCACAGAGACTTGGCAGCCAGAAATATCCTCCTTACTCATGGT ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 CGGATCACAAAGATTTGTGATTTTGGTCTAGCCAGAGACATCAAGAATGATTCTAATTATGTGG TTAAAGGAAACGCTCGACTACCTGTGAAGTGGATGGCACCTGAAAGCATTTTCAACTGTGTATA CACGTTTGAAAGTGACGTCTGGTCCTATGGGATTTTTCTTTGGGAGCTGTTCTCTTTAGGAAGC AGCCCCTATCCTGGAATGCCGGTCGATTCTAAGTTCTACAAGATGATCAAGGAAGGCTTCCGGA TGCTCAGCCCTGAACACGCACCTGCTGAAATGTATGACATAATGAAGACTTGCTGGGATGCAGA TCCCCTAAAAAGACCAACATTCAAGCAAATTGTTCAGCTAATTGAGAAGCAGATTTCAGAGAGC ACCAATCATATTTACTCCAACTTAGCAAACTGCAGCCCCAACCGACAGAAGCCCGTGGTAGACC ATTCTGTGCGGATCAATTCTGTCGGCAGCACCGCTTCCTCCTCCCAGCCTCTGCTTGTGCACGA CGATGTCTGAGCAGAATCAGTGTTTGGGTCACCCCTCCAGGAATGATCTCTTCTTTTGGCTTCC ATGATGGTTATTTTCTTTTCTTTCAACTTGCATCCAACTCCAGGATAGTGGGCACCCCACTGCA ATCCTGTCTTTCTGAGCACACTTTAGTGGCCGATGATTTTTGTCATCAGCCACCATCCTATTGC AAAGGTTCCAACTGTATATATTCCCAATAGCAACGTAGCTTCTACCATGAACAGAAAACATTCT GATTTGGAAAAAGAGAGGGAGGTATGGACTGGGGGCCAGAGTCCTTTCCAAGGCTTCTCCAATT CTGCCCAAAAATATGGTTGATAGTTTACCTGAATAAATGGTAGTAATCACAGTTGGCCTTCAGA ACCATCCATAGTAGTATGATGATACAAGATTAGAAGCTGAAAACCTAAGTCCTTTATGTGGAAA ACAGAACATCATTAGAACAAAGGACAGAGTATGAACACCTGGGCTTAAGAAATCTAGTATTTCA TGCTGGGAATGAGACATAGGCCATGAAAAAAATGATCCCCAAGTGTGAACAAAAGATGCTCTTC TGTGGACCACTGCATGAGCTTTTATACTACCGACCTGGTTTTTAAATAGAGTTTGCTATTAGAG CATTGAATTGGAGAGAAGGCCTCCCTAGCCAGCACTTGTATATACGCATCTATAAATTGTCCGT GTTCATACATTTGAGGGGAAAACACCATAAGGTTTCGTTTCTGTATACAACCCTGGCATTATGT CCACTGTGTATAGAAGTAGATTAAGAGCCATATAAGTTTGAAGGAAACAGTTAATACCATTTTT TAAGGAAACAATATAACCACAAAGCACAGTTTGAACAAAATCTCCTCTTTTAGCTGATGAACTT ATTCTGTAGATTCTGTGGAACAAGCCTATCAGCTTCAGAATGGCATTGTACTCAATGGATTTGA TGCTGTTTGACAAAGTTACTGATTCACTGCATGGCTCCCACAGGAGTGGGAAAACACTGCCATC TTAGTTTGGATTCTTATGTAGCAGGAAATAAAGTATAGGTTTAGCCTCCTTCGCAGGCATGTCC TGGACACCGGGCCAGTATCTATATATGTGTATGTACGTTTGTATGTGTGTAGACAAATATTTGG AGGGGTATTTTTGCCCTGAGTCCAAGAGGGTCCTTTAGTACCTGAAAAGTAACTTGGCTTTCAT TATTAGTACTGCTCTTGTTTCTTTTCACATAGCTGTCTAGAGTAGCTTACCAGAAGCTTCCATA GTGGTGCAGAGGAAGTGGAAGGCATCAGTCCCTATGTATTTGCAGTTCACCTGCACTTAAGGCA CTCTGTTATTTAGACTCATCTTACTGTACCTGTTCCTTAGACCTTCCATAATGCTACTGTCTCA CTGAAACATTTAAATTTTACCCTTTAGACTGTAGCCTGGATATTATTCTTGTAGTTTACCTCTT TAAAAACAAAACAAAACAAAACAAAAAACTCCCCTTCCTCACTGCCCAATATAAAAGGCAAATG TGTACATGGCAGAGTTTGTGTGTTGTCTTGAAAGATTCAGGTATGTTGCCTTTATGGTTTCCCC CTTCTACATTTCTTAGACTACATTTAGAGAACTGTGGCCGTTATCTGGAAGTAACCATTTGCAC TGGAGTTCTATGCTCTCGCACCTTTCCAAAGTTAACAGATTTTGGGGTTGTGTTGTCACCCAAG ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 AGATTGTTGTTTGCCATACTTTGTCTGAAAAATTCCTTTGTGTTTCTATTGACTTCAATGATAG TAAGAAAAGTGGTTGTTAGTTATAGATGTCTAGGTACTTCAGGGGCACTTCATTGAGAGTTTTG TCTTGGATATTCTTGAAAGTTTATATTTTTATAATTTTTTCTTACATCAGATGTTTCTTTGCAG TGGCTTAATGTTTGAAATTATTTTGTGGCTTTTTTTGTAAATATTGAAATGTAGCAATAATGTC TTTTGAATATTCCCAAGCCCATGAGTCCTTGAAAATATTTTTTATATATACAGTAACTTTATGT GTAAATACATAAGCGGCGTAAGTTTAAAGGATGTTGGTGTTCCACGTGTTTTATTCCTGTATGT TGTCCAATTGTTGACAGTTCTGAAGAATTCTAATAAAATGTACATATATAAATCAAAAAAAAAA AAAAAA (SEQ ID NO: 901) The term “Cas9” or “Cas9 domain” refers to an RNA guided nuclease comprising a Cas9 protein, or a fragment thereof (e.g., a protein comprising an active, inactive, or partially active DNA cleavage domain of Cas9, and / or the gRNA binding domain of Cas9). A Cas9 nuclease is also referred to sometimes as a casnl nuclease or a CRISPR (clustered regularly interspaced short palindromic repeat) associated nuclease. By “percent chimerism” or “chimerism” is meant the proportion of cells of a given type(s) of interest in a subject that were administered to the subject or altered in the subject or that are descended or derived from the cells administered to or edited in the subject. In some cases, percent chimerism is calculated as the percent of hCD45+ cells in a subject that were administered to the subject or derived or descended from the cells administered to the subject. In embodiments, the cell type of interest is bulk bone marrow, CD34+ cells, CD235a+ cells, CD19+ cells, or CD45+ cells. In embodiments, chimerism is measured in a subject 1 day, 1 wk, 2 wks, 3 wks, 4 wks, 5 wks, 6 wks, 7 wks, 8 wks, 9 wks, 10 wks, 11 wks, 12 wks, 6 months, a year, or longer following administration of cells to the subject. In embodiments, chimerism is measured in a subject 1 day, 1 wk, 2 wks, 3 wks, 4 wks, 5 wks, 6 wks, 7 wks, 8 wks, 9 wks, 10 wks, 11 wks, 12 wks, 6 months, a year, or longer following administration of an anti-CD117 antibody to the subject. In embodiments, the percent chimerism measured at the time point is about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some cases, the percent chimerism is greater than that measured for a subject administered cells expressing a wild type CD117 polypeptide and not prime edited according to the methods provided herein to express an altered CD117 polypeptide with reduced binding to an anti-CD117 antibody. As used herein, the term “complementarity determining region” (CDR) refers to a hypervariable region found both in the light chain and the heavy chain variable regions ((VL and VH domains, respectively). CDRs are noncontiguous antigen-binding sites found within the variable regions of both heavy and light chain polypeptides. These particular regions have been ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 described by Kabat et al., J. Biol. Chem.252:6609-6616, 1977 and Kabat, et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242, 1991; by Chothia et al., (J. Mol. Biol.196:901-917, 1987), and by MacCallum et al., (J. Mol. Biol.262:732-745, 1996) where the definitions include overlapping or subsets of amino acid residues when compared against each other. In certain embodiments, the term “CDR” is a CDR as defined by Kabat based on sequence comparisons. The more highly conserved portions of variable regions are called the framework regions (FRs). As is appreciated in the art, the amino acid positions that delineate a hypervariable region of an antibody can vary, depending on the context and the various definitions known in the art. Some positions within a variable domain may be viewed as hybrid hypervariable positions in that these positions can be deemed to be within a hypervariable region under one set of criteria while being deemed to be outside a hypervariable region under a different set of criteria. One or more of these positions can also be found in extended hypervariable regions. The variable regions of native heavy and light chains each comprise four framework regions (FR1, FR2, FR3, FR4) that primarily adopt a beta-sheet configuration, connected by three CDRs (CDR1, CDR2, CDR3), which form loops that connect, and in some cases form part of, the beta-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions in the order FR1- CDR1-FR2-CDR2-FR3-CDR3-FR4. and the CDRs in each antibody chain contribute to the formation of the target binding site of antibodies (see Kabat et al, Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md.1987; incorporated herein by reference). As used herein, numbering of immunoglobulin amino acid residues is done according to the immunoglobulin amino acid residue numbering system of Kabat et al, unless otherwise indicated. In various embodiments, complementarity determining regions are identified using any of the methodologies available to one of skill in the art such as those methods described in “Antibody structure-Function Relationships.” Therapeutic Antibody Engineering, edited by William R. Strohl and Lilia M. Strohl, Woodhead Publishing Series in Biomedicine, 2012, 37-56, 459-595, the entirety of which is incorporated herein in its entirety for all purposes, where such methods include, as non-limiting examples, those of Kabat, Chothia, Lefranc, Honegger, Martin, MacCallum, and Zhao. CDRs can be identified using sequence or structure based methods. Various software programs are available to one of skill in the art to identify CDRs for an antibody amino acid sequence. In various embodiments, a CDR as provided herein may be modified to include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional amino acids and / or to exclude 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids at the N-terminal and / or C-terminal end (e.g., in an embodiment VH CDR1 of ABTx196 is modified to be RASQSVSS (SEQ ID NO: ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 902), rather than QSVSSSY (SEQ ID NO: 903) by extendingQSVSSSY (SEQ ID NO: 903) by 3 amino acids at the N-terminus and excluding two amino acids at the C-terminus). The present disclosure contemplates that the CDRs identified for a particular antibody can vary in location or length depending upon the method by which they are determined. The term “conservative amino acid substitution” or “conservative mutation” refers to the replacement of one amino acid by another amino acid with a common property. A functional way to define common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Schulz, G. E. and Schirmer, R. H., Principles of Protein Structure, Springer-Verlag, New York (1979)). According to such analyses, groups of amino acids can be defined where amino acids within a group exchange preferentially with each other, and therefore resemble each other most in their impact on the overall protein structure (Schulz, G. E. and Schirmer, R. H., supra). Non- limiting examples of conservative mutations include amino acid substitutions of amino acids, for example, lysine for arginine and vice versa such that a positive charge can be maintained; glutamic acid for aspartic acid and vice versa such that a negative charge can be maintained; serine for threonine such that a free –OH can be maintained; and glutamine for asparagine such that a free –NH2 can be maintained. Amino acids generally can be grouped into classes according to the following common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, He; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe. In some embodiments, conservative substitutions can involve the exchange of a member of one of these classes for another member of the same class. In some embodiments, non- conservative amino acid substitutions can involve exchanging a member of one of these classes for another class. The term “coding sequence” or “protein coding sequence” as used interchangeably herein refers to a segment of a polynucleotide that codes for a protein. Coding sequences can also be referred to as open reading frames. The region or sequence is bounded nearer the 5′ end by a start codon and nearer the 3′ end with a stop codon. Stop codons useful with the prime editors described herein include the following: TAG, TAA, and TGA. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 As used herein, the terms “condition” and “conditioning” refer to processes by which a patient is prepared for receipt of a transplant containing hematopoietic stem cells. Such procedures promote the engraftment of a hematopoietic stem cell transplant (for instance, as inferred from a sustained increase in the quantity of viable hematopoietic stem cells within a blood sample isolated from a patient following a conditioning procedure and subsequent hematopoietic stem cell transplantation). According to the methods described herein, a patient may be conditioned for hematopoietic stem cell transplant therapy by administration to the patient of an antibody or antigen-binding fragment thereof capable of binding an antigen expressed by hematopoietic stem cells, such as CD117. Such antibodies are expected to act via complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity. As described herein, the transplanted cells have been edited so that the antibody no longer binds a CD117 antigen. Administration of an antibody, antigen-binding fragment thereof, drug-antibody conjugate, or chimeric antigen receptor expressing T-cell (CAR-T) capable of binding a CD117 antigen to a patient in need of hematopoietic stem cell transplant therapy can promote the engraftment of a hematopoietic stem cell graft, for example, by selectively depleting endogenous hematopoietic stem cells, thereby creating a vacancy filled by an exogenous hematopoietic stem cell transplant. By “complex” is meant a combination of two or more molecules whose interaction relies on inter-molecular forces. Non-limiting examples of inter-molecular forces include covalent and non-covalent interactions. Non-limiting examples of non-covalent interactions include hydrogen bonding, ionic bonding, halogen bonding, hydrophobic bonding, van der Waals interactions (e.g., dipole-dipole interactions, dipole-induced dipole interactions, and London dispersion forces), and π-effects. In an embodiment, a complex comprises polypeptides, polynucleotides, or a combination of one or more polypeptides and one or more polynucleotides. In one embodiment, a complex comprises one or more polypeptides that associate to form a prime editor (e.g., prime editor comprising a nucleic acid programmable DNA binding protein, such as Cas9, and a polymerase, such as a reverse transcriptase) and a polynucleotide (e.g., a guide RNA). In an embodiment, the complex is held together by hydrogen bonds. It should be appreciated that one or more components of a prime editor (e.g., a polymerase, or a nucleic acid programmable DNA binding protein) may associate covalently or non-covalently. As one example, a prime editor may include a reverse transcriptase covalently linked to a nucleic acid programmable DNA binding protein (e.g., by a peptide bond). Alternatively, a prime editor may include a reverse transcriptase and a nucleic acid programmable DNA binding protein that associate noncovalently (e.g., where one or more components of the prime editor are supplied in ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 trans and associate directly or via another molecule such as a protein or nucleic acid). In an embodiment, one or more components of the complex are held together by hydrogen bonds. The term, “detect” refers to identifying the presence, absence or amount of the analyte to be detected. In one embodiment, a sequence alteration in a polynucleotide or polypeptide is detected. In another embodiment, the presence of indels is detected. By “detectable label” is meant a composition that when linked to a molecule of interest renders the latter detectable, via spectroscopic, photochemical, biochemical, immunochemical, or chemical means. For example, useful labels include radioactive isotopes, magnetic beads, metallic beads, colloidal particles, fluorescent dyes, electron-dense reagents, enzymes (for example, as commonly used in an enzyme linked immunosorbent assay (ELISA)), biotin, digoxigenin, or haptens. By “disease” is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. Exemplary diseases include diseases amenable to treatment with hematopoietic stem cell transplantation, such as β-thalassemia, sickle cell disease (SCD), or adenosine deaminase deficiency. An “editing template” of a PEgRNA is a single -stranded portion of the PEgRNA that is 5′ of the PBS and comprises a region of complementarity to the PAM strand (i.e., the non-target strand or the edit strand), and comprises one or more intended nucleotide edits compared to the endogenous sequence of the double stranded target DNA. In some embodiments, the editing template and the PBS are immediately adjacent to each other. Accordingly, in some embodiments, a PEgRNA in prime editing comprises a single-stranded portion that comprises the PBS and the editing template immediately adjacent to each other. In some embodiments, the single stranded portion of the PEgRNA comprising both the PBS and the editing template is complementary or substantially complementary to an endogenous sequence on the PAM strand (i.e., the non-target strand or the edit strand) of the double stranded target DNA except for one or more non-complementary nucleotides at the intended nucleotide edit positions. As used herein, regardless of relative 5′-3′ positioning in other context, the relative positions as between the PBS and the editing template, and the relative positions as among elements of a PEgRNA, are determined by the 5′ to 3′ order of the PEgRNA as a single molecule regardless of the position of sequences in the double stranded target DNA that may have complementarity or identity to elements of the PEgRNA. In some embodiments, the editing template is complementary or substantially complementary to a sequence on the PAM strand that is immediately downstream of the nick site, except for one or more non-complementary nucleotides at the intended nucleotide edit positions. The endogenous, e.g., genomic, sequence that is complementary or ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 substantially complementary to the editing template, except for the one or more non- complementary nucleotides at the position corresponding to the intended nucleotide edit, may be referred to as an “editing target sequence”. In some embodiments, the editing template has identity or substantial identity to a sequence on the target strand that is complementary to, or having the same position in the genome as, the editing target sequence, except for one or more insertions, deletions, or substitutions at the intended nucleotide edit positions. In some embodiments, the editing template encodes a single stranded DNA, wherein the single stranded DNA has identity or substantial identity to the editing target sequence except for one or more insertions, deletions, or substitutions at the positions of the one or more intended nucleotide edits. The endogenous, e.g., genomic, sequence that is partially complementary to the editing template may be referred to as an “editing target sequence”. By “effective amount” is meant the amount of an agent (e.g., a prime editor, cell) as described herein, that is required to ameliorate the symptoms of a disease relative to an untreated patient or an individual without disease, i.e., a healthy individual, or is the amount of the agent sufficient to elicit a desired biological response. The effective amount of active compound(s) used to practice embodiments of the present disclosure for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an “effective” amount. In one embodiment, an effective amount is the amount of a prime editor of the disclosure sufficient to introduce an alteration in a gene of interest in a cell (e.g., a cell in vitro or in vivo). In one embodiment, an effective amount is the amount of a prime editor required to achieve a therapeutic effect. Such therapeutic effect need not be sufficient to alter a pathogenic gene in all cells of a subject, tissue or organ, but only to alter the pathogenic gene in about 1%, 5%, 10%, 25%, 50%, 75% or more of the cells present in a subject, tissue or organ. In one embodiment, an effective amount is sufficient to ameliorate one or more symptoms of a disease. By “fragment” is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids. In some embodiments, the fragment is a functional fragment. As used herein, the term “framework region” or “FR region” includes amino acid residues that are adjacent to the CDRs. FR region residues may be present in, for example, human antibodies, rodent-derived antibodies (e.g., murine antibodies), humanized antibodies, ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 primatized antibodies, chimeric antibodies, antibody fragments (e.g., Fab fragments), single- chain antibody fragments (e.g., scFv fragments), antibody domains, and bispecific antibodies, among others. By “guide polynucleotide” is meant a polynucleotide or polynucleotide complex which is specific for a target sequence and can form a complex with a polynucleotide programmable nucleotide binding domain protein (e.g., Cas9 or Cpf1). In an embodiment, the guide polynucleotide is a guide RNA (gRNA). gRNAs can exist as a complex of two or more RNAs, or as a single RNA molecule. As used herein, the term “hematopoietic stem cells” (“HSCs”) refers to immature blood cells having the capacity to self-renew and to differentiate into mature blood cells containing diverse lineages including but not limited to granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells). Such cells may include CD34+ cells. CD34+ cells are immature cells that express the CD34 cell surface marker. In humans, CD34+ cells are believed to include a subpopulation of cells with the stem cell properties defined above, whereas in mice, HSCs are CD34-. In addition, HSCs also refer to long term repopulating HSCs (LT-HSC) and short term repopulating HSCs (ST-HSC). LT-HSCs and ST-HSCs are differentiated, based on functional potential and on cell surface marker expression. For example, human HSCs are CD34+, CD38-, CD45RA-, CD90+, CD49F+, and lin-(negative for mature lineage markers including CD2, CD3, CD4, CD7, CD8, CD10, CD11 B, CD19, CD20, CD56, CD235A). In mice, bone marrow LT-HSCs are CD34-, SCA-1 +, C-kit+, CD135-, Slamfl / CD150+, CD48-, and lin- (negative for mature lineage markers including Ter119, CD11b, Gr1 , CD3, CD4, CD8, B220, IL7ra), whereas ST-HSCs are CD34+, SCA-1+, C-kit+, CD135-, Slamfl / CD150+, and lin-(negative for mature lineage markers including Ter119, CD11 b, Gr1 , CD3, CD4, CD8, B220, IL7ra). In addition, ST-HSCs are less quiescent and more proliferative than LT-HSCs under homeostatic conditions. However, LT- HSC have greater self-renewal potential (i.e., they survive throughout adulthood, and can be serially transplanted through successive recipients), whereas ST-HSCs have limited self-renewal (i.e., they survive for only a limited period of time, and do not possess serial transplantation potential). Any of these HSCs can be used in the methods described herein. ST-HSCs are particularly useful because they are highly proliferative and thus, can more quickly give rise to differentiated progeny. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 As used herein, the term “hematopoietic stem cell functional potential” refers to the functional properties of hematopoietic stem cells which include 1 ) multi-potency (which refers to the ability to differentiate into multiple different blood lineages including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells), 2) self-renewal (which refers to the ability of hematopoietic stem cells to give rise to daughter cells that have equivalent potential as the mother cell, and further that this ability can repeatedly occur throughout the lifetime of an individual without exhaustion), and 3) the ability of hematopoietic stem cells or progeny thereof to be reintroduced into a transplant recipient whereupon they home to the hematopoietic stem cell niche and re-establish productive and sustained hematopoiesis.” “Hybridization” means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. For example, adenine and thymine are complementary nucleobases that pair through the formation of hydrogen bonds. By “increases” is meant a positive alteration of at least 10%, 25%, 50%, 75%, or 100%, or about 1.5 fold, about 2 fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7- fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 30-fold, about 35-fold, about 40-fold, about 45-fold, about 50-fold, or about 100-fold. The terms “isolated,” “purified,” or “biologically pure” refer to material that is free to varying degrees from components which normally accompany it as found in its native state. “Isolate” denotes a degree of separation from original source or surroundings. “Purify” denotes a degree of separation that is higher than isolation. A “purified” or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of this disclosure is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high performance liquid chromatography. The term “purified” can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. For a protein that can be subjected to modifications, for example, phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 By “isolated polynucleotide” is meant a nucleic acid molecule that is free of the genes which, in the naturally occurring genome of the organism from which the nucleic acid molecule of the disclosure is derived, flank the gene. The term therefore includes, for example, a recombinant DNA that is incorporated into a vector; into an autonomously replicating plasmid or virus; or into the genomic DNA of a prokaryote or eukaryote; or that exists as a separate molecule (for example, a cDNA or a genomic or cDNA fragment produced by PCR or restriction endonuclease digestion) independent of other sequences. In addition, the term includes an RNA molecule that is transcribed from a DNA molecule, as well as a recombinant DNA that is part of a hybrid gene encoding additional polypeptide sequence. By an “isolated polypeptide” is meant a polypeptide of the disclosure that has been separated from components that naturally accompany it. Typically, the polypeptide is isolated when it is at least 60%, by weight, free from the proteins and naturally occurring organic molecules with which it is naturally associated. In embodiments, the preparation is at least 75%, at least 90%, or at least 99%, by weight, a polypeptide of the disclosure. An isolated polypeptide of the disclosure may be obtained, for example, by extraction from a natural source, by expression of a recombinant nucleic acid encoding such a polypeptide; or by chemically synthesizing the protein. Purity can be measured by any appropriate method, for example, column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis. The term “linker”, as used herein, refers to a molecule that links two moieties. In one embodiment, the term “linker” refers to a covalent linker (e.g., covalent bond) or a non-covalent linker. Thus, the present disclosure includes compositions and methods for altering a thymidine (T) to a cytidine (C) in the codon of the sixth amino acid of a sickle cell disease variant of the β- globin protein (Sickle HbS; E6V), thereby substituting an alanine for a valine (V6A) at this amino acid position. Substitution of alanine for valine at position 6 of HbS generates a β-globin protein variant that does not have a sickle cell phenotype (e.g., does not have the potential to polymerize as in the case of the pathogenic variant HbS). Accordingly, the compositions and methods of the disclosure are useful for the treatment of sickle cell disease (SCD). By “marker” is meant any protein or polynucleotide having an alteration in expression, level, structure, or activity that is associated with a disease or disorder. In some cases, the disease or disorder is sickle cell disease. Non-limiting examples of markers include a Makassar variant of beta globin, beta globin, fetal hemoglobin, CD117, and variants of CD117 provided herein. The term “mutation,” as used herein, refers to a substitution of a residue within a sequence, e.g., a nucleic acid or amino acid sequence, with another residue, or a deletion or ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 insertion of one or more residues within a sequence. Mutations are typically described herein by identifying the original residue followed by the position of the residue within the sequence and by the identity of the newly substituted residue. Various methods for making the amino acid substitutions (mutations) provided herein are well known in the art, and are provided by, for example, Green and Sambrook, Molecular Cloning: A Laboratory Manual (4thed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)). As used herein, the term “nickase” refers to a nuclease capable of cleaving only one strand of a double -stranded DNA target. The term “nick guide RNA (nickRNA; nsgRNA; ngRNA; nRNA)”, or “nicking guide RNA (nickRNA; nsgRNA; ngRNA; nRNA)”, refers to a guide polynucleotide comprising a spacer and a scaffold sequence and that is capable of guiding a nucleic acid programmable DNA binding (napDNAbp) protein domain of a prime editor to nick a target site in a target polynucleotide, where the nick guide RNA does not comprise an intended nucleotide edit for incorporation into a double stranded target polynucleotide. In some instances, the target polynucleotide is double stranded DNA. As used herein, a “nick site” refers to a specific position in between two nucleotides or two base pairs of the double stranded target DNA. In some embodiments, the position of a nick site is determined relative to the position of a specific PAM sequence. In some embodiments, the nick site is the particular position where a nick will occur when the double stranded target DNA is contacted with a nickase, for example, a Cas nickase, that recognizes a specific PAM sequence. In some embodiments, the nick site is upstream of a specific PAM sequence on the PAM strand of the double stranded target DNA. In some embodiments, the nick site is downstream of a specific PAM sequence on the PAM strand of the double stranded target DNA. In some embodiments, the nick site is upstream of a PAM sequence recognized by a Cas9 nickase, wherein the Cas9 nickase comprises a nuclease active RuvC domain and a nuclease inactive NHN domain. In some embodiments, the nick site is 3 nucleotides upstream of the PAM sequence, and the PAM sequence is recognized by a Streptococcus pyogenes Cas9 nickase, a P. lavamentivorans Cas9 nickase, a C. diphtheriae Cas9 nickase, a N. cinerea Cas9, a S. aureus Cas9, or a A. lari Cas9 nickase that comprises a nuclease active RuvC domain and a nuclease inactive NHN domain. In some embodiments, the nick site is 2 nucleotides upstream of the PAM sequence, and the PAM sequence is recognized by a S. thermophilus Cas9 nickase that comprises a nuclease active RuvC domain and a nuclease inactive NHN domain. In some embodiments, the double stranded target DNA comprises a nick site on the PAM strand (or non- target strand). ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 The terms “nucleic acid” and “nucleic acid molecule,” as used herein, refer to a compound comprising a nucleobase and an acidic moiety, e.g., a nucleoside, a nucleotide, or a polymer of nucleotides. Typically, polymeric nucleic acids, e.g., nucleic acid molecules comprising three or more nucleotides are linear molecules, in which adjacent nucleotides are linked to each other via a phosphodiester linkage. In some embodiments, “nucleic acid” refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides). In some embodiments, “nucleic acid” refers to an oligonucleotide chain comprising three or more individual nucleotide residues. As used herein, the terms “oligonucleotide” and “polynucleotide” can be used interchangeably to refer to a polymer of nucleotides (e.g., a string of at least three nucleotides). In some embodiments, “nucleic acid” encompasses RNA as well as single and / or double- stranded DNA. Nucleic acids may be naturally occurring, for example, in the context of a genome, a transcript, an mRNA, tRNA, rRNA, siRNA, snRNA, a plasmid, cosmid, chromosome, chromatid, or other naturally occurring nucleic acid molecule. On the other hand, a nucleic acid molecule may be a non-naturally occurring molecule, e.g., a recombinant DNA or RNA, an artificial chromosome, an engineered genome, or fragment thereof, or a synthetic DNA, RNA, DNA / RNA hybrid, or including non-naturally occurring nucleotides or nucleosides. Furthermore, the terms “nucleic acid,” “DNA,” “RNA,” and / or similar terms include nucleic acid analogs, e.g., analogs having other than a phosphodiester backbone. Nucleic acids can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, nucleic acids comprise nucleoside analogs such as analogs having chemically modified bases or sugars, and backbone modifications. A nucleic acid sequence is presented in the 5′ to 3′ direction unless otherwise indicated. In some embodiments, a nucleic acid is or comprises natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5- methylcytidine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5- propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7- deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothioates and 5′-N-phosphoramidite linkages). ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 The term “nuclear localization sequence,” “nuclear localization signal,” or “NLS” refers to an amino acid sequence that promotes import of a protein into the cell nucleus. Nuclear localization sequences are known in the art and described, for example, in Plank et al., International PCT application, PCT / EP2000 / 011690, filed November 23, 2000, published as WO / 2001 / 038547 on May 31, 2001, the contents of which are incorporated herein by reference for their disclosure of exemplary nuclear localization sequences. In other embodiments, the NLS is an optimized NLS described, for example, by Koblan et al., Nature Biotech.2018 doi:10.1038 / nbt.4172. In some embodiments, an NLS comprises the amino acid sequence KRTADGSEFESPKKKRKV (SEQ ID NO: 904),KRPAATKKAGQAKKKK (SEQ ID NO: 905), KKTELQTTNAENKTKKL (SEQ ID NO: 906),KRGINDRNFWRGENGRKTR (SEQ ID NO: 907), RKSGKIAAIVVKRPRK (SEQ ID NO: 908),PKKKRKV (SEQ ID NO: 909), MDSLLMNRRKFLYQFKNVRWAKGRRETYLC (SEQ ID NO: 16), PKKKRKVEGADKRTADGSEFESPKKKRKV (SEQ ID NO: 910), or RKSGKIAAIVVKRPRKPKKKRKV (SEQ ID NO: 911). The term “nucleobase,” “nitrogenous base,” or “base,” used interchangeably herein, refers to a nitrogen-containing biological compound that forms a nucleoside, which in turn is a component of a nucleotide. The ability of nucleobases to form base pairs and to stack one upon another leads directly to long-chain helical structures such as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Five nucleobases – adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U) – are called primary or canonical. Adenine and guanine are derived from purine, and cytosine, uracil, and thymine are derived from pyrimidine. DNA and RNA can also contain other (non-primary) bases that are modified. Non-limiting exemplary modified nucleobases can include hypoxanthine, xanthine, 7-methylguanine, 5,6-dihydrouracil, 5- methylcytosine (m5C), and 5-hydromethylcytosine. Hypoxanthine and xanthine can be created through mutagen presence, both of them through deamination (replacement of the amine group with a carbonyl group). Hypoxanthine can be modified from adenine. Xanthine can be modified from guanine. Uracil can result from deamination of cytosine. A “nucleoside” consists of a nucleobase and a five carbon sugar (either ribose or deoxyribose). Examples of a nucleoside include adenosine, guanosine, uridine, cytidine, 5-methyluridine (m5U), deoxyadenosine, deoxyguanosine, thymidine, deoxyuridine, and deoxycytidine. Examples of a nucleoside with a modified nucleobase includes inosine (I), xanthosine (X), 7-methylguanosine (m7G), dihydrouridine (D), 5-methylcytidine (m5C), and pseudouridine (Ψ). A “nucleotide” consists of a nucleobase, a five carbon sugar (either ribose or deoxyribose), and at least one phosphate group. Non-limiting examples of modified nucleobases and / or chemical modifications that a ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 modified nucleobase may include are the following: pseudo-uridine, 5-Methyl-cytosine, 2′-O- methyl-3′-phosphonoacetate, 2′-O-methyl thioPACE (MSP), 2′-O-methyl-PACE (MP), 2′-fluoro RNA (2′-F-RNA), constrained ethyl (S-cEt), 2′-O-methyl (‘M’), 2′-O-methyl-3′- phosphorothioate (‘MS’), 2′-O-methyl-3′-thiophosphonoacetate (‘MSP’), 5-methoxyuridine, phosphorothioate, and N1-Methylpseudouridine. The term “nucleic acid programmable DNA binding protein” or “napDNAbp” may be used interchangeably with “polynucleotide programmable nucleotide binding domain” to refer to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide nucleic acid or guide polynucleotide (e.g., gRNA), that guides the napDNAbp to a specific nucleic acid sequence. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable RNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a Cas9 protein. A Cas9 protein can associate with a guide RNA that guides the Cas9 protein to a specific DNA sequence that is complementary to the guide RNA. In some embodiments, the napDNAbp is a Cas9 domain, for example a nuclease active Cas9, a Cas9 nickase (nCas9), or a nuclease inactive Cas9 (dCas9). Non-limiting examples of nucleic acid programmable DNA binding proteins include, Cas9 (e.g., dCas9 and nCas9), Cas12a / Cpfl, Cas12b / C2cl, Cas12c / C2c3, Cas12d / CasY, Cas12e / CasX, Cas12g, Cas12h, Cas12i, and Cas12j / CasΦ (Cas12j / Casphi). Non-limiting examples of Cas enzymes include Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas8a, Cas8b, Cas8c, Cas9 (also known as Csn1 or Csx12), Cas10, Cas10d, Cas12a / Cpfl, Cas12b / C2cl, Cas12c / C2c3, Cas12d / CasY, Cas12e / CasX, Cas12g, Cas12h, Cas12i, Cas12j / CasΦ, Cpf1, Csy1 , Csy2, Csy3, Csy4, Cse1, Cse2, Cse3, Cse4, Cse5e, Csc1, Csc2, Csa5, Csn1, Csn2, Csm1, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx1S, Csx11, Csf1, Csf2, CsO, Csf4, Csd1, Csd2, Cst1, Cst2, Csh1, Csh2, Csa1, Csa2, Csa3, Csa4, Csa5, Type II Cas effector proteins, Type V Cas effector proteins, Type VI Cas effector proteins, CARF, DinG, homologues thereof, or modified or engineered versions thereof. Other nucleic acid programmable DNA binding proteins are also within the scope of this disclosure, although they may not be specifically listed in this disclosure. See, e.g., Makarova et al. “Classification and Nomenclature of CRISPR-Cas Systems: Where from Here?” CRISPR J.2018 Oct;1: 325-336. Doi: 10.1089 / crispr.2018.0033; Yan et al., “Functionally diverse type V CRISPR-Cas systems” Science.2019 Jan 4;363(6422):88-91. Doi: 10.1126 / science.aav7271, the entire contents of each are hereby incorporated by reference. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 Exemplary nucleic acid programmable DNA binding proteins and nucleic acid sequences encoding nucleic acid programmable “Nucleotide edit” or “intended nucleotide edit” refers to an intended alteration of a target polynucleotide. In some instances, the nucleotide edit is a specified deletion of one or more nucleotides at one specific position, insertion of one or more nucleotides at one specific position, substitution of a single nucleotide, or other alterations at one specific position to be incorporated into the sequence of a target polynucleotide. Intended nucleotide edit may refer to the edit on the editing template as compared to the sequence on the target strand of the double stranded target DNA, e.g., a target gene, or may refer to the edit encoded by the editing template on the newly synthesized single stranded DNA that replaces the editing target sequence, as compared to the editing target sequence. As used herein, “obtaining” as in “obtaining an agent” includes synthesizing, purchasing, or otherwise acquiring the agent. “Patient in need thereof” or “subject in need thereof” is referred to herein as a patient diagnosed with, at risk or having, predetermined to have, or suspected of having a disease or disorder. The terms “pathogenic mutation”, “pathogenic variant”, “disease causing mutation”, “disease causing variant”, “deleterious mutation”, or “predisposing mutation” refers to a genetic alteration or mutation that is associated with a disease or disorder or that increases an individual’s susceptibility or predisposition to a certain disease or disorder. In some embodiments, the pathogenic mutation comprises at least one wild-type amino acid substituted by at least one pathogenic amino acid in a protein encoded by a gene. In some embodiments, the pathogenic mutation is in a terminating region (e.g., stop codon). In some embodiments, the pathogenic mutation is in a non-coding region (e.g., intron, promoter, etc.). By “prime editor (PE)” is meant the polypeptide or polypeptide components involved in prime editing. In various embodiments, a prime editor comprises a polypeptide domain having DNA binding activity (e.g., a DNA binding domain) and a polypeptide domain (e.g., a DNA polymerase domain) having DNA polymerase activity. In embodiments, a prime editor contains Cas9 protein domain of S. pyogenes, or a functional fragment or variant thereof, and a reverse transcriptase domain from a retrovirus (e.g., Moloney murine leukemia virus), or a functional fragment or variant thereof. Prime editors and methods for use thereof are described in International Patent Application Publication No. WO 2023 / 283092, the disclosure of which is incorporated herein by reference in its entirety for all purposes. An embodiment of a prime editor is shown in FIG.4. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 The term “prime editing” refers to programmable editing of a target DNA using a prime editor complexed with a prime editing guide RNA (PEgRNA) to incorporate an intended nucleotide alteration into the target DNA through target-primed DNA synthesis. A target DNA polynucleotide, e.g., a target gene of prime editing can comprise a double stranded DNA molecule having two complementary strands: a first strand that may be referred to as a “target strand” or a “non-edit strand”, and a second strand that may be referred to as a “non-target strand,” or an “edit strand.” In some embodiments, in a prime editing guide RNA (PEgRNA), a spacer sequence is complementary or substantially complementary to a specific sequence on the target strand, which may be referred to as a “search target sequence”. In some embodiments, the spacer sequence anneals with the target strand at the search target sequence. The target strand can also be referred to as the “non-Protospacer Adjacent Motif (non-PAM strand).” In some embodiments, the non-target strand can also be referred to as the “PAM strand”. In some embodiments, the PAM strand comprises a protospacer sequence and optionally a protospacer adjacent motif (PAM) sequence. In prime editing using a Cas-protein -based prime editor, a PAM sequence refers to a short DNA sequence immediately adjacent to the protospacer sequence on the PAM strand of the target gene. A PAM sequence can be specifically recognized by a programmable DNA binding protein, e.g., a Cas nickase or a Cas nuclease. In some embodiments, a specific PAM is characteristic of a specific programmable DNA binding protein, e.g., a Cas nickase or a Cas nuclease, e.g., a Cas9 nickase or a Cas9 nuclease. A protospacer sequence refers to a specific sequence in the PAM strand of the double stranded target DNA (e.g., target gene) that is complementary to the search target sequence. In a PEgRNA, a spacer sequence can have a substantially identical sequence as the protospacer sequence on the edit strand of the double stranded target DNA (e.g., target gene) except that the spacer sequence can comprise Uracil (U) and the protospacer sequence can comprise Thymine (T). The term “prime editing guide RNA”, or “PEgRNA”, refers to a guide polynucleotide that comprises one or more intended nucleotide edits for incorporation into a double stranded target polynucleotide. In some instances, the target polynucleotide is double stranded DNA. In some embodiments, the PEgRNA associates with and directs a prime editor to incorporate the one or more intended nucleotide edits into the double stranded target DNA, e.g., a target gene via prime editing. An embodiment of a prime editing guide RNA is shown in FIG.5. The term “prime editing system” or “prime editor system” refers to an intermolecular complex for editing a nucleobase of a target nucleotide sequence. In various embodiments, the prime editor (PE) system comprises (1) a fusion protein comprising a domain having DNA binding activity (e.g., a nucleic acid programmable DNA binding protein) and a polymerase ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 (e.g., a DNA polymerase or a reverse transcriptase); and (2) one or more guide polynucleotides (e.g., prime editing guide RNA and / or a nick guide RNA (“nickRNA”)) in conjunction with the domain having DNA binding activity. An embodiment of a prime editor system bound to a target sequence is provided in FIG.6. A “primer binding site” (also referred to as PBS or primer binding site sequence) is a single-stranded portion of the PEgRNA that comprises a region of complementarity to the PAM strand (i.e., the non-target strand or the edit strand). The PBS is complementary or substantially complementary to a sequence on the PAM strand of the double stranded target DNA that is immediately upstream of the nick site. In some embodiments, in the process of prime editing, the PEgRNA complexes with and directs a prime editor to bind the search target sequence on the target strand of the double stranded target DNA and generates a nick at the nick site on the non- target strand of the double stranded target DNA. In some embodiments, the PBS is complementary to or substantially complementary to, and can anneal to, a free 3′ end on the non- target strand of the double stranded target DNA at the nick site. In some embodiments, the PBS annealed to the free 3′ end on the non-target strand can initiate target-primed DNA synthesis. The terms “protein”, “peptide”, “polypeptide”, and their grammatical equivalents are used interchangeably herein, and refer to a polymer of amino acid residues linked together by peptide (amide) bonds. A protein, peptide, or polypeptide can be naturally occurring, recombinant, or synthetic, or any combination thereof. The term “fusion protein” as used herein refers to a hybrid polypeptide which comprises protein domains from at least two different proteins. As used herein, the term “human antibody” refers to an antibody in which substantially every part of the protein (e.g., CDR, framework, CL, CH domains (e.g., CH1, CH2, CH3), hinge, (VL, VH)) is substantially non-immunogenic in humans, with only minor sequence changes or variations. A human antibody can be produced in a human cell (e.g., by recombinant expression), or by a non-human animal or a prokaryotic or eukaryotic cell (e.g., yeast) that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and / or light chain) genes. Further, when a human antibody is a single-chain antibody, it can include a linker peptide that is not found in native human antibodies. For example, an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are considered to be of human origin. Human antibodies can be made by a variety of methods known in the art including phage display methods using antibody libraries derived from human immunoglobulin sequences. See U.S. Pat. Nos.4,444,887 and 4,716,111; and PCT publications ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 WO 1998 / 46645; WO 1998 / 50433; WO 1998 / 24893; WO 1998 / 16654; WO 1996 / 34096; WO 1996 / 33735; and WO 1991 / 10741; incorporated herein by reference. Human antibodies can also be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. See, e.g., PCT publications WO 98 / 24893; WO 92 / 01047; WO 96 / 34096; WO 96 / 33735; U.S. Pat. Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; and 5,939,598; incorporated by reference herein. As used herein, the term “humanized” antibodies refers to forms of non-human (e.g., murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab’, F(ab’)2 or other target-binding subdomains of antibodies) which contain minimal sequences derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable regions, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin. All or substantially all of the FR regions may also be those of a human immunoglobulin sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin consensus sequence. Methods of antibody humanization are known in the art. See, e.g., Riechmann et al., Nature 332: 323-7, 1988; U.S. Pat. Nos.5,530,101; 5,585,089; 5,693,761; 5,693,762; and U.S. Pat. No.6,180,370 to Queen et al; EP239400; PCT publication WO 91 / 09967; U.S. Pat. No. 5,225,539; EP592106; and EP519596; incorporated herein by reference. The term “recombinant” as used herein in the context of proteins or nucleic acids refers to proteins or nucleic acids that do not occur in nature but are the product of human engineering. For example, in some embodiments, a recombinant protein or nucleic acid molecule comprises an amino acid or nucleotide sequence that comprises at least one, at least two, at least three, at least four, at least five, at least six, or at least seven mutations as compared to any naturally occurring sequence. By “reduces” is meant a negative alteration of at least 10%, 25%, 50%, 75%, or 100%. By “reference” is meant a standard or control condition. In one embodiment, the reference is a wild type or healthy cell. In other embodiments and without limitation, a reference is an untreated cell that is not subjected to a test condition, or is subjected to placebo or normal saline, medium, buffer, and / or a control vector that does not harbor a polynucleotide of interest. In some cases, a “reference” is a n untreated subject, such as a subject not administered a hematopoietic stem cell edited according to the methods of the present disclosure. In some ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 cases, the subject is a healthy subject (e.g., a subject not having sickle cell disease). In some embodiments, the reference is an unedited or wild type cell, polypeptide, or polynucleotide. A “reference sequence” is a defined sequence used as a basis for sequence comparison. A reference sequence may be a subset of or the entirety of a specified sequence; for example, a segment of a full-length cDNA or gene sequence, or the complete cDNA or gene sequence. For polypeptides, the length of the reference polypeptide sequence will generally be at least about 16 amino acids, at least about 20 amino acids, at least about 25 amino acids, about 35 amino acids, about 50 amino acids, or about 100 amino acids. For nucleic acids, the length of the reference nucleic acid sequence will generally be at least about 50 nucleotides, at least about 60 nucleotides, at least about 75 nucleotides, about 100 nucleotides or about 300 nucleotides or any integer thereabout or therebetween. In some embodiments, a reference sequence is a wild-type sequence of a protein of interest. In other embodiments, a reference sequence is a polynucleotide sequence encoding a wild-type protein. The terms “RNA-programmable nuclease,” and “RNA-guided nuclease” refer to a nuclease that forms a complex with (e.g., binds or associates with) one or more RNA(s) that is not a target for cleavage. In some embodiments, an RNA-programmable nuclease, when in a complex with an RNA, may be referred to as a nuclease-RNA complex. Typically, the bound RNA(s) is referred to as a guide RNA (gRNA). By “Stem Cell Factor (SCF) polypeptide” is meant a polypeptide having at least about 85% amino acid sequence identity to an amino acid sequence provided at NCBI Ref. Seq. Accession No. NP_000890, reproduced below, or a fragment thereof that functions in hematopoiesis. In some embodiments, a SCF polypeptide or fragment thereof binds CD117. >NP_000890.1 kit ligand isoform b precursor [Homo sapiens] MKKTQTWILTCIYLQLLLFNPLVKTEGICRNRVTNNVKDVTKLVANLPKDYMITLKYVPGMDVL PSHCWISEMVVQLSDSLTDLLDKFSNISEGLSNYSIIDKLVNIVDDLVECVKENSSKDLKKSFK SPEPRLFTPEEFFRIFNRSIDAFKDFVVASETSDCVVSSTLSPEKDSRVSVTKPFMLPPVAASS LRNDSSSSNRKAKNPPGDSSLHWAAMALPALFSLIIGFAFGALYWKKRQPSLTRAVENIQINEE DNEISMLQEKEREFQEV (SEQ ID NO: 912). By “stem cell factor (SCF) polynucleotide” is meant a nucleic acid molecule that encodes an SCF polypeptide as well as the introns, exons, 3′ untranslated regions, 5′ untranslated regions, and regulatory sequences associated with its expression, or fragments thereof. In embodiments, an SCF polynucleotide is the genomic sequence, cDNA, mRNA, or gene associated with and / or required for SCF expression. An exemplary SCF polynucleotide sequence from Homo sapiens is provided at NCBI Ref. Seq. Accession No. NM_003994.5 (see SEQ ID NO: 1055). ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 By “subject” or “patient” is meant a mammal, including, but not limited to, a human or non-human mammal. In embodiments, the mammal is a bovine, equine, canine, ovine, rabbit, rodent, nonhuman primate, or feline. In an embodiment, “patient” refers to a mammalian subject with a higher than average likelihood of developing a disease or a disorder. Exemplary patients can be humans, non-human primates, cats, dogs, pigs, cattle, cats, horses, camels, llamas, goats, sheep, rodents (e.g., mice, rabbits, rats, or guinea pigs) and other mammalians that can benefit from the therapies disclosed herein. Exemplary human patients can be male and / or female. As used herein, the term “scFv” refers to a single chain Fv antibody in which the variable regions of the heavy chain and the light chain from an antibody have been joined to form one chain. scFv fragments contain a single polypeptide chain that includes the variable region of an antibody light chain (VL) (e.g., CDR-L1 , CDR-L2, and / or CDR-L3) and the variable region of an antibody heavy chain (VH) (e.g., CDR-H1 , CDR-H2, and / or CDR-H3) separated by a linker. The linker that joins the VL and VH regions of a scFv fragment can be a peptide linker composed of proteinogenic amino acids. Alternative linkers can be used to so as to increase the resistance of the scFv fragment to proteolytic degradation (for example, linkers containing D- amino acids), in order to enhance the solubility of the scFv fragment (for example, hydrophilic linkers such as polyethylene glycol-containing linkers or polypeptides containing repeating glycine and serine residues), to improve the biophysical stability of the molecule (for example, a linker containing cysteine residues that form intramolecular or intermolecular disulfide bonds), or to attenuate the immunogenicity of the scFv fragment (for example, linkers containing glycosylation sites). It will also be understood by one of ordinary skill in the art that the variable regions of the scFv molecules described herein can be modified such that they vary in amino acid sequence from the antibody molecule from which they were derived. For example, nucleotide or amino acid substitutions leading to conservative substitutions or changes at amino acid residues can be made (e.g., in CDR and / or framework residues) so as to preserve or enhance the ability of the scFv to bind to the antigen recognized by the corresponding antibody. By “selectively binds” is meant specifically binds a wild-type version of the cell surface protein but exhibits reduced binding or fails to detectably bind to the cell surface protein comprising a mutation. In embodiments, an antibody of the present disclosure selectively binds to a wild type CD117 polypeptide but exhibits reduced binding to a CD117 polypeptide comprising one or more amino acid alterations, such as those provided herein, relative to the wild type CD117 polypeptide. In embodiments, an antibody of the present disclosure binds a wild type CD117 polypeptide 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1-fold, 5-fold, 1.75-fold, 2- fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 100-fold, 1000-fold, 10000- ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 fold, 100000-fold, or 1000000-fold more strongly (e.g., as quantified using KD(M), where a lower KD(M) indicates stronger binding) than to an altered CD117 polypeptide of the present disclosure. The term “single nucleotide polymorphism (SNP)” is a variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population (e.g., > 1%). SNPs can fall within coding regions of genes, non-coding regions of genes, or in the intergenic regions (regions between genes). In some embodiments, SNPs within a coding sequence do not necessarily change the amino acid sequence of the protein that is produced, due to degeneracy of the genetic code. SNPs in the coding region are of two types: synonymous and nonsynonymous SNPs. Synonymous SNPs do not affect the protein sequence, while nonsynonymous SNPs change the amino acid sequence of protein. The nonsynonymous SNPs are of two types: missense and nonsense. SNPs that are not in protein-coding regions can still affect gene splicing, transcription factor binding, messenger RNA degradation, or the sequence of noncoding RNA. Gene expression affected by this type of SNP is referred to as an eSNP (expression SNP) and can be upstream or downstream from the gene. A single nucleotide variant (SNV) is a variation in a single nucleotide without any limitations of frequency and can arise in somatic cells. A somatic single nucleotide variation can also be called a single-nucleotide alteration. By “specifically binds” is meant a nucleic acid molecule, polypeptide, polypeptide / polynucleotide complex, compound, or molecule that recognizes and binds a polypeptide and / or nucleic acid molecule of the disclosure, but which does not substantially recognize and bind other molecules in a sample, for example, a biological sample. By “substantially identical” is meant a polypeptide or nucleic acid molecule exhibiting at least 50% identity to a reference amino acid sequence. In one embodiment, a reference sequence is a wild-type amino acid or nucleic acid sequence. In another embodiment, a reference sequence is any one of the amino acid or nucleic acid sequences described herein. In one embodiment, such a sequence is at least about 60%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, or even 99.99%, identical at the amino acid level or nucleic acid level to the sequence used for comparison. Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis.53705, BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or other ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. Nucleic acid molecules useful in the methods of the disclosure include any nucleic acid molecule that encodes a polypeptide of the disclosure or a functional fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a double- stranded nucleic acid molecule. Nucleic acid molecules useful in the methods of the disclosure include any nucleic acid molecule that encodes a polypeptide of the disclosure or a functional fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a double-stranded nucleic acid molecule. By “hybridize” is meant pair to form a double-stranded molecule between complementary polynucleotide sequences (e.g., a gene described herein), or portions thereof, under various conditions of stringency. (See, e.g., Wahl, G. M. and S. L. Berger (1987) Methods Enzymol.152: 399; Kimmel, A. R. (1987) Methods Enzymol.152:507). The term “target site” refers to a nucleotide sequence or nucleobase of interest within a nucleic acid molecule that is modified. In embodiments, the modification is alteration of a base. As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and / or symptoms associated therewith or obtaining a desired pharmacologic and / or physiologic effect. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated. In some embodiments, the effect is therapeutic, i.e., without limitation, the effect partially or completely reduces, diminishes, abrogates, abates, alleviates, reduces the intensity of, or cures a disease and / or adverse symptom attributable to the disease. In some embodiments, the effect is preventative, i.e., the effect protects or prevents an occurrence or reoccurrence of a disease or condition. To this end, the presently disclosed methods comprise administering a therapeutically effective amount of a composition as described herein. Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. The term “transfecting” or “transfection” is used synonymously and according to some aspects and embodiments herein means the introduction of heterologous nucleic acid (DNA / RNA) into a eukaryotic cell, in particular yeast cells. By “upstream” and “downstream” it is intended to define relevant positions at least two regions or sequences in a nucleic acid molecule orientated in a 5′-to-3′ direction. For example, a first sequence is upstream of a second sequence in a DNA molecule where the first sequence is positioned 5′ to the second sequence. Accordingly, the second sequence is downstream of the first sequence. As used herein, the term “vector” refers to a means of introducing a nucleic acid into a cell, resulting in a transformed cell. Vectors include plasmids, transposons, phages, viruses, liposomes, lipid nanoparticles, and episomes. “Expression vectors” are nucleic acid sequences comprising the nucleotide sequence to be expressed in the recipient cell. Expression vectors contain a polynucleotide sequence as well as additional nucleic acid sequences to promote and / or facilitate the expression of the introduced sequence, such as start, stop, enhancer, promoter, and secretion sequences, into the genome of a mammalian cell. Examples of vectors include nucleic acid vectors, e.g., DNA vectors, such as plasmids, RNA vectors, viruses or other suitable replicons (e.g., viral vectors). A variety of vectors have been developed for the delivery of polynucleotides encoding exogenous proteins into a prokaryotic or eukaryotic cell. Examples of such expression vectors are disclosed in, e.g., WO 1994 / 11026; incorporated herein by reference. Certain vectors that can be used for the expression of antibodies, antibody fragments, prime editors, guide polynucleotides, and / or prime editor systems of some aspects and embodiments herein include plasmids that contain regulatory sequences, such as promoter and enhancer regions, which direct gene transcription. Other useful vectors for expression of antibodies and antibody fragments contain polynucleotide sequences that enhance the rate of translation of these genes or improve the stability or nuclear export of the mRNA that results from gene transcription. These sequence elements include, e.g., 5′ and 3′ untranslated regions, an internal ribosomal entry site (IRES), and polyadenylation signal site in order to direct efficient transcription of the gene carried on the expression vector. The expression vectors of some aspects and embodiments herein may also contain a polynucleotide encoding a marker for selection of cells that contain such a vector. Examples of a suitable marker include genes that encode resistance to antibiotics, such as ampicillin, chloramphenicol, kanamycin, or nourseothricin. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 As used herein, the term “VH” refers to the variable region of an immunoglobulin heavy chain of an antibody, including the heavy chain of an Fv, scFv, or Fab. References to “VL” refer to the variable region of an immunoglobulin light chain, including the light chain of an Fv, scFv, dsFv or Fab. Antibodies (Abs) and immunoglobulins (Igs) are glycoproteins having the same structural characteristics. While antibodies exhibit binding specificity to a specific target, immunoglobulins include both antibodies and other antibody-like molecules which lack target specificity. Native antibodies and immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each heavy chain of a native antibody has at the amino terminus a variable domain (VH) followed by a number of constant domains. Each light chain of a native antibody has a variable domain at the amino terminus (VL) and a constant domain at the carboxy terminus. The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended. This wording indicates that specified elements, features, components, and / or method steps are present, but does not exclude the presence of other elements, features, components, and / or method steps. Any embodiments specified as “comprising” a particular component(s) or element(s) are also contemplated as “consisting of” or “consisting essentially of” the particular component(s) or element(s) in some embodiments. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 composition of the present disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure. The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Reference in the specification to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosures. BRIEF DESCRIPTION OF THE DRAWINGS FIGs.1A and 1B provide stacked bar graphs showing results from prime editing of CD117 polynucleotides in HEK293T cells to yield encoded CD117 polypeptides with altered epitopes. FIG.1A provides stacked bar graphs showing the frequency of the indicated alleles in HEK293T cells contacted with the indicated prime editing systems. FIG.1B provides stacked bar graphs showing the frequency of the indicated alleles in HEK293T cells contacted with the indicated prime editing systems. In FIGs.1A and 1B, the term “PE2” indicates a prime editor system containing an mRNA encoding a prime editor and a single prime editing gRNA, the term “PE3” indicates a prime editor system containing an mRNA encoding a prime editor, a prime editing gRNA (PEgRNA), and a nick guide RNA (nickRNA), and the term “PAM-disrupt” indicates a supplemental edit encoded in the PEgRNA, whereby the reverse transcribed DNA produced by the prime editor contains both a therapeutically relevant mutation(s) as well as a PAM motif-disrupting mutation that does not alter the target gene’s encoded amino acid sequence. The nucleotide positions 33, 41 (alternatively 5), and 43 (alternatively 7) indicated in FIGs.1A and 1B correspond to the nucleotides numbered with the subscripts “33,” “41,” and “43” in the following nucleotide sequence, respectively: 5′- ACTACAG33GAGAAATA41TA43ATAGCTGGCATCA-3′ (SEQ ID NO: 1056)). The letters following each of the position numbers 5, 7, 33, 41, and 43 in FIGs.1A and 1B represent the nucleotide at each position following prime editing. In each of the first four bars from the left of FIG.1A and each of the first 8 bars from the left of FIG.1B, the stacked bars each correspond to, from top-to-bottom: 41G, 33A_41G, and 33A. In the fifth bar from the left of FIG.1A and 9thand 10thbar from the left of FIG.1B, the stacked bars each correspond to, from top-to- bottom: 43G, 41G_43G, and 41G. In the final two bars from the left of FIG.1A and the final four bars from the left of FIG.1B, the stacked bars each correspond to, from top-to-bottom: ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 43G, 41G_43G, 41G, 33A_41G_43G, 33A_41G, and 33A. In FIGs.1A and 1B, the prime editing guide RNAs used in each prime editor system is indicated along the x-axis (e.g., gRNA7206) and the nick RNA’s used are indicated above the corresponding bars (e.g., nickRNA7195 or nickRNA7196). FIGs.2A and 2B provide stacked bar graphs showing results from prime editing of CD117 or beta globin (HBB) polynucleotides in human CD34 (hCD34) cells to yield encoded CD117 polypeptides with altered epitopes or altered HBB polypeptides. FIG.2A provides stacked bar graphs showing the frequency of the indicated alleles in hCD34 cells contacted with the indicated prime editing systems. All of the cells of FIG.2A were administered a prime editor system for altering a CD117 polynucleotide. FIG.2B provides stacked bar graphs showing the frequency of the indicated alleles in HEK293T cells contacted with the indicated prime editing systems. The first four bars from the left in FIG.2B correspond to hCD34 cells edited to alter a CD117 polynucleotide and the last bar from the left in FIG.2B corresponds to hCD34 cells edited to alter an HBB polynucleotide to install a single nucleotide polymorphism associated with sickle cell disease. In FIGs.2A and 2B, the term “PEgRNA” indicates a prime editing guide RNA and the term “nRNA” indicates a nick guide RNA. The nucleotide positions 33, 41, and 43 indicated in FIGs.2A and 2B correspond to the nucleotides numbered with the subscripts “33,” “41,” and “43” in the following nucleotide sequence, respectively: 5′- ACTACAG33GAGAAATA41TA43ATAGCTGGCATCA-3′ (SEQ ID NO: 1056)). The letters following each of the position numbers 5, 7, 21, 22, 33, 41, and 43 in FIGs.2A and 2B represent the nucleotide at each position following prime editing. The terms “21T” and “21T_22A” indicate alleles of the HBB polynucleotide, where nucleotide positions 21 and 22 correspond to the positions indicated by the subscript “21” or “22,” respectively, in the following nucleotide sequence:CATCTGACTCCTGA21G22GAGAAG (SEQ ID NO: 921). FIGs.3A and 3B provide bar graphs showing results from prime editing of CD117 and / or beta globin (HBB) polynucleotides in HEK293T cells to yield encoded CD117 polypeptides with altered epitopes and / or altered HBB polypeptides. FIG.3A provides a stacked bar graph showing the frequency of the indicated alleles in HEK293T cells contacted with a PE2 or a PE3 prime editing system for altering both an HBB polynucleotide and a CD117 polynucleotide in the cells in multiplex. In FIG.3A, the first and third bars from the left are stacked bars, where the bars within each stacked bar, from top-to-bottom, correspond to: 33A_41G (PAM disrupt + 5G), and to 41G (5G). FIG.3B provides a bar graphs showing the frequency of the indicated allele in HEK293T cells contacted with a PE3 prime editing system for altering an HBB polynucleotide in the cells, where the cells were also contacted with filler ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 RNA. In FIGs.3A and 3B, the term “PE2” indicates a prime editor system containing an mRNA encoding a prime editor and a single prime editing gRNA, the term “PE3” indicates a prime editor system containing an mRNA encoding a prime editor, a prime editing gRNA (PEgRNA), and a nick guide RNA (nickRNA), and the term “PAM-disrupt” indicates a supplemental edit encoded in the PEgRNA, whereby the reverse transcribed DNA produced by the prime editor contains both a therapeutically relevant mutation(s) as well as a PAM motif-disrupting mutation that does not alter the target gene’s encoded amino acid sequence. In FIGs.3A and 3B, “PE2 multiplex” indicates a prime editor system containing the guides gRNA_232 and gRNA2709, and “PE3” indicates a prime editor system containing the guides gRNA232, gRNA2709, gRNA_225, and gRNA7196. FIG.4 provides a schematic diagram showing an exemplary prime editor fusion protein comprising a Cas9 nickase, a reverse transcriptase, and a linker. FIG.5 provides a schematic diagram showing a prime editing guide RNA (PEgRNA) architectural overview in an exemplary schematic of PEgRNA designed for a prime editor. FIG.6 provides a schematic diagram showing a prime editor system containing a prime editing guide RNA (PEgRNA) binding to a double stranded target DNA sequence. DETAILED DESCRIPTION The disclosure features compositions and methods for non-genotoxic monoclonal antibody (mAb) conditioning, where the methods involve altering a cluster of differentiation 117 (CD117; c-KIT) polynucleotide sequence in a hematopoietic stem cell (HSC) or progenitor thereof to encode a CD117 polypeptide with reduced binding to the antibody. In various embodiments, the methods further include introducing a therapeutic alteration to a gene of the HSC or progenitor thereof for treatment of a hemoglobinopathy (e.g., sickle cell disease). The embodiments of the disclosure are based, at least in part, upon the development of a non-genotoxic, busulfan-free, conditioning approach that combines a non-genotoxic conditioning strategy with a gene editing strategy for the treatment of sickle cell disease. The embodiments of the disclosure were developed with the goal, among others, of reducing challenges associated with the standard of care conditioning regimen. The non-genotoxic conditioning efforts aimed to leverage prime editing technologies to engineer hemopoietic stem cells (eHSCs) that can be coupled with a monoclonal antibody (mAb) reagent capable of conditioning a patient prior to transplantation. Through prime editing, an engineered stem cell antibody paired evasion, or “ESCAPE”, approach was developed that enables the engineered HSCs to be resistant to mAb still present in the system and / or allows the ability to administer a second dose of the mAb after ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 administration of the HSCs. In embodiments, the engineered hematopoietic stem cells (eHSCs) can selectively escape ablation and be engineered to contain alterations to a pathogenic beta globin gene, towards a potential treatment of sickle cell disease. The methods described herein provide for the selective targeting of endogenous HSCs, while sparing edited HSCs. Accordingly, antibody or antibody-drug conjugate (ADC) treatment used for conditioning prior to hematopoietic stem cell transplantation (HSCT) can continue to be administered following HSCT to expand gene edited cells in vivo or treat malignant disease with repeated dosing. This minimizes the risk of killing edited cells. Edited cells would allow for the administration of antibody or ADC without Fc modifications to reduce their half-life. This has the potential to enable the use of antibodies with longer half-lives and simplify the development of ADCs. Clinical trial design is also simplified – HSCs could be infused prior to or concurrently with conditioning with little or no risk of being depleted. The methods provide a benefit for all patients regardless of immune status. In one embodiment, CD117 is altered (e.g., using prime editing) in a cell for transplantation to prevent binding of anti-CD117 antibody, but not interfere with normal SCF signaling. Using prime editing, a nucleobase change may be generated to create an amino acid substitution in CD117. Stem cell factor (SCF) drives HSC self-renewal and differentiation into progenitor cells. Administering anti-CD117 antibody blocks SCF binding to CD117, thereby depleting HSCs and progenitor cells in the patient (conditioning). Autologous gene edited HSCs are transplanted into the patient. Gene-edited cells compete with residual host HSCs to repopulate bone marrow (BM). Anti-CD117 antibody blocks SCF binding to wildtype (WT) CD117 but cannot bind to HSCs with an edited CD117. Thus, native, wild type HSCs are targeted by anti-CD117 antibody, but gene edited HSCs are not. Thus, both cells express CD117 polypeptides that are activated by SCF binding. However, binding of anti-CD117 antibody to wild type CD117 disrupts SCF binding and results in inhibition of SCF signaling wild type cells. In contrast, gene-edited HSCs are refractory to anti-CD117 antibody because the amino acid substitution introduced in CD117 prevents the binding of anti-CD117 antibody but does not interfere with normal SCF binding and signaling. In embodiments, the methods of the disclosure enable a reduction or elimination of use of alkylating agents for conditioning. In some instances, the reduction is a reduction of about, or at least about, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some instances, the methods of the disclosure are associated with a reduction in, or avoidance of side effects associated with an alkylating agent (e.g., busulphan). In some cases, the side effect is selected from one or more of intestinal ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 mucosal damage, alopecia, pancytopenia, anemia, amenorrhea, impaired spermatogenesis, increased risk of malignancy, and infertility. Exemplary, yet nonlimiting, examples of compositions and methods for treating hemoglobinopathies are described in International Publications No. WO2021041945, WO2020168133, WO2019217942, WO2019079347, and WO2024006774, which are incorporated herein by reference in their entireties for all purposes. CLUSTER OF DIFFERENTIATION 117 (CD117; C-KIT) CD117 is expressed in hematopoietic stem cells (HSCs) and is critical for their self- renewal, survival & differentiation. Upon differentiation, CD117 expression is lost. Mature mast cells retain CD117 expression. High level of expression the long term and short-term HSCs make CD117 an attractive target for immunologic conditioning. Therefore, one approach to eliminate hematopoietic stem cells from a niche is to contact the cells with an anti-CD117 antibody that interferes with proper functioning of the CD117 polypeptide (e.g., blocks binding to SCF). Accordingly, CD117 / c-KIT is a target for hematopoietic stem cell transplantation (HSCT) antibody-based conditioning. Non-limiting examples of antibodies suitable for use in the methods of the disclosure include ABTx135, ABTx052, JSP191, and MGTA-117. In some embodiments, the antibody is selected from one or more of ABTx135, ABTx052, ABTx196, ABTx198, ABTx202, ABTx203, ABTx205, ABTx206, ABTx248, ABTx250, ABTx251, ABTx253, ABTx254, ABTx255, ABTx256, ABTx265, ABTx268, ABTx270, ABTx271, ABTx272, ABTx273, ABTx274, ABTx307, ABTx308, ABTx309, and ABTx313. Critical events in the CD117 life cycle include SCF binding, CD117 homo-dimerization, trans-phosphorylation of tyrosine residues, ubiquitinization, internalization, and proteolytic degradation. Trans-phosphorylation of the tyrosine residues is associated with cell activation and downstream phosphorylation, calcium mobilization, and cell migration. HBB GENE EDITING In some embodiments, the target gene to be edited in a subject is a HBB gene. In some embodiments, the HBB gene comprises a mutation associated with sickle cell disease. In some embodiments, the HBB gene comprises a mutation that encodes a E6V amino acid substitution in the beta globin protein encoded by the HBB gene compared to a wild type beta globin protein. In some embodiments, provided herein is a prime editing composition comprising a prime editor and a PEgRNA, wherein the PEgRNA is capable of directing the prime editor to correct the ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 mutation associated with sickle cell diseases in a HBB gene. In some embodiments, the PEgRNA comprises an editing template that comprises an intended nucleotide edit, and wherein incorporation of the intended nucleotide edit in the HBB gene corrects the mutation in the HBB gene associated with sickle cell disease. In some embodiments, the editing template comprises a wild type sequence of a wild type HBB gene. Accordingly, in some embodiments, provided herein are methods of correcting a mutation associated with sickle cell disease in a HBB gene. In some embodiments, the method comprises contacting the HBB gene with a PEgRNA and a prime editor, wherein the PEgRNA directs the prime editor to incorporate an intended nucleotide edit in the HBB gene, thereby correcting the mutation associated with sickle cell disease in the HBB gene. In some embodiments, the HBB gene is in a cell. Accordingly, in some embodiments, the method comprises introducing into the cell comprising the HBB gene with a PEgRNA and a prime editor, wherein the PEgRNA directs the prime editor to incorporate an intended nucleotide edit in the HBB gene, thereby correcting the mutation associated with sickle cell disease in the HBB gene. In some embodiments, the method comprises introducing into the cell comprising the HBB gene with a PEgRNA and a polynucleotide encoding the prime editor, wherein upon expression of the prime editor, the PEgRNA directs the prime editor to incorporate an intended nucleotide edit in the HBB gene, thereby correcting the mutation associated with sickle cell disease in the HBB gene. In some embodiments, the cell is a blood cell. In some embodiments, the HBB gene is a hematopoietic stem cell (HSC). In some embodiments, the cell is in vivo. In some embodiments, the cell is ex vivo. In some embodiments, the PEgRNA and the prime editor are introduced into the cell simultaneously. In some embodiments, the PEgRNA and the polynucleotide encoding the prime editor are introduced into the cell simultaneously. In some embodiments, the PEgRNA and the prime editor are introduced into the cell sequentially, for example, the PEgRNA may be introduced prior to or after introduction of the prime editor. In some embodiments, the PEgRNA and the polynucleotide encoding the prime editor are introduced into the cell sequentially, for example, the PEgRNA may be introduced prior to or after introduction of the polynucleotide encoding the prime editor. Accordingly, in some embodiments, provided herein is a method of treating sickle cell disease, wherein the method comprises administering to a subject in need thereof a PEgRNA and a prime editor or a polynucleotide encoding the prime editor, wherein the PEgRNA directs the prime editor to incorporate the intended nucleotide edit in a HBB gene in the subject, thereby correcting a mutation in the HBB gene and treating sickle cell disease. In some embodiments, the method of treating sickle cell disease comprises introducing a PEgRNA and a prime editor or a polynucleotide encoding the prime editor to a cell or a population of cells to correct a mutation ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 associated with sickle cell disease in a HBB, and subsequently administering the edited cell or the edited population of cells to a subject in need thereof. In some embodiments, the cell or the population of cells are obtained from the subject in need thereof prior to editing. In some embodiments, the cell or the population of cells are obtained from a donor prior to editing. In some embodiments, the cell or the population of cells are hematopoietic stem cells. In some embodiments, the PEgRNA and the prime editor are administered simultaneously. In some embodiments, the PEgRNA and the polynucleotide encoding the prime editor are administered simultaneously. In some embodiments, the PEgRNA and the prime editor are administered sequentially, for example, the PEgRNA may be administered prior to or after administration of the prime editor. In some embodiments, the PEgRNA and the polynucleotide encoding the prime editor are administered sequentially, for example, the PEgRNA may be administered prior to or after administration of the polynucleotide encoding the prime editor. METHODS OF TREATMENT The methods and compositions disclosed herein may be used to condition a subject’s tissues (e.g., bone marrow) for engraftment or transplant and following such conditioning, a stem cell population is administered to the subject. The transplanted cells (e.g., HSCs) can be autologous cells or allogeneic cells. In certain aspects, the stem cell population comprises an exogenous stem cell population. In some embodiments, the stem cell population comprises the subject’s endogenous stem cells (e.g., endogenous stem cells that have been genetically modified to correct a disease or genetic defect, such as those associated with sickle cell disease). Such methods and compositions may be useful for treating such diseases without causing the toxicities that are observed in response to traditional conditioning therapies, such as irradiation. Hematopoietic stem cell transplant therapy can be administered to a subject in need of treatment so as to populate or re-populate one or more blood cell types. Hematopoietic stem cells generally exhibit multi-potency, and can thus differentiate into multiple different blood lineages including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells). Hematopoietic stem cells are additionally capable of self-renewal and can thus give rise to daughter cells that have equivalent potential as the mother cell, and also feature the capacity to be reintroduced into a transplant recipient whereupon they home to the hematopoietic stem cell niche and re-establish productive and sustained hematopoiesis. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 Hematopoietic stem cells can thus be administered to a patient defective or deficient in one or more cell types of the hematopoietic lineage in order to reconstitute the defective or deficient population of cells in vivo, thereby treating the pathology associated with the defect or depletion in the endogenous blood cell population. The compositions and methods described herein can thus be used to treat a non-malignant hemoglobinopathy (e.g., a hemoglobinopathy selected from the group consisting of sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome). Additionally, or alternatively, the compositions and methods described herein can be used to treat a malignancy or proliferative disorder, such as a hematologic cancer, myeloproliferative disease. In the case of cancer treatment, the compositions and methods described herein may be administered to a patient so as to deplete a population of endogenous hematopoietic stem cells prior to hematopoietic stem cell transplantation therapy, in which case the transplanted cells can home to a niche created by the endogenous cell depletion step and establish productive hematopoiesis. This, in turn, can re-constitute a population of cells depleted during cancer cell eradication, such as during systemic chemotherapy. Exemplary hematological cancers that can be treated using the compositions and methods described herein include, without limitation, acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, and non-Hodgkin’s lymphoma, as well as other cancerous conditions, including neuroblastoma. Antibodies, antigen-binding fragments thereof, and ligands described herein can be administered to a patient (e.g., a human patient suffering from cancer, an autoimmune disease, or in need of hematopoietic stem cell transplant therapy) in a variety of dosage forms. For instance, antibodies, antigen-binding fragments thereof, and ligands described herein can be administered to a patient suffering from cancer, an autoimmune disease, or in need of hematopoietic stem cell transplant therapy in the form of an aqueous solution, such as an aqueous solution containing one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients for use with the compositions and methods described herein include viscosity-modifying agents. The aqueous solution may be sterilized using techniques known in the art. Non-limiting examples of antibodies suitable for use in the methods of the disclosure include ABTx135, ABTx052, JSP191, and MGTA-117. Further non-limiting examples of anti-CD117 antibodies useful in embodiments of the methods of the disclosure include 1C5, 2B8, 104D2, ACK2, JSP191, K45, Y45.B8, ST04-99, 22HCLC, G.813.2, 8D7, ACK4, 2B8 / BM, OTI2B12, OTI1B6, OTI2E3, OTI1E2, OTI2C1D5, OTI3F9, OTI9A11, OTI14B1, 6F2, UMAB216, OTI2B5, OTI1F6, OTI2C1H4, OTI6F8, and derivatives thereof available, for example, from ThermoFisher Scientific. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 In various embodiments, an antibody of the disclosure is administered to a subject before, after, or concurrently with administration of transplanted cells (e.g., HSCs) to the subject. In embodiments, the methods of the disclosure involve administering cells (e.g., HSCs of the disclosure) to a subject previously that was previously administered an anti-CD117 antibody of the disclosure. In some cases, the blood of the subject contains a therapeutically effective amount of the anti-CD117 antibody at the time at which the cells are administered to the subject. The antibody of the disclosure may persist at a therapeutically effective level in a subject (e.g., in the blood of the subject) for about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 1 wk, 2 wks, 3 wks, 4 wks, 5 wks, 10 wks, 15 wks, or 20 wks after administration of the antibody to the subject. An antibody or antigen binding fragment thereof, antibody drug conjugate, or a chimeric antigen receptor T (CAR-T) cell may be administered to a subject before, after, or concurrently with a edited cell of the disclosure. IgG1 antibodies targeting CD117 can cause mast cell degranulation, which can result from Fcγ receptor interactions. Accordingly, in some embodiments an antibody (e.g., ABTx135, ABTx052) can be modified to include one or more amino acid residue alterations in an Fc domain to reduce or eliminate binding to FcγR, binding to FcRn, and / or mast cell activation. In embodiments, an antibody is modified to include amino acid alterations that prevent or reduce hypersensitivity reactions (HSRs). In some embodiments, an antibody (e.g., ABTx052) is modified to include an amino acid alteration at one or more of the following sites: L234, L235, G236, D265, N297, and P329. In some cases, the antibody includes an amino acid alteration and / or combination of amino acid alterations selected from: N297Q (aglycosylated); L234A and L235A (LALA); L234A, L235A, and P329G (LALAPG); L234A, L235A, and D265A (LALADA); L234S, L235T, and G236R (STR or LSLTGR); M252Y, S254T, and T256E (YTE); and LS M428L and N434S (LS) (see, e.g., Rosenberg, et al., PloS One, 14:e0212649, the disclosure of which is incorporated herein by reference in its entirety for all purposes); where the amino acid positions are referenced to the following amino acid sequence: SGAAVKKPGESLKISCKGSGYRFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTI SAGKSISTAYLQWSSLKASDTAMYYCARHGRGYNGYEGAFDIWGQGTMVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 922). ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 The antibodies, antigen-binding fragments, and ligands described herein may be administered by a variety of routes, such as orally, transdermally, subcutaneously, intranasally, intravenously, intramuscularly, intraocularly, or parenterally. The most suitable route for administration in any given case will depend on the particular antibody, antigen-binding fragment, or ligand administered, the patient, pharmaceutical formulation methods, administration methods (e.g., administration time and administration route), the patient’s age, body weight, sex, severity of the diseases being treated, the patient’s diet, and the patient’s excretion rate. One of ordinary skill in the art would recognize that multiple administrations of the pharmaceutical compositions contemplated in particular embodiments may be required to affect the desired therapy. For example, a composition may be administered to the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more times over a span of 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 5, years, 10 years, or more. Administration of the pharmaceutical compositions contemplated herein may be carried out using conventional techniques including, but not limited to, infusion, transfusion, or parenterally. In some embodiments, parenteral administration includes infusing or injecting intravascularly, intravenously, intramuscularly, intraarterially, intrathecally, intratumorally, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidly and intrasternally. PRIME EDITING Prime editing involves the programmable editing of a target DNA using a prime editor complexed with a prime editing guide RNA (PEgRNA) to incorporate an intended nucleotide edit (also referred to herein as a nucleotide change or alteration) into the target DNA through target-primed DNA synthesis. In some embodiments, a PEgRNA complexes with and directs a prime editor to bind to the search target sequence of the target gene. In some embodiments, the bound prime editor generates a nick on the edit strand (PAM strand) of the target gene. In some embodiments, a primer binding site (PBS) of the PEgRNA anneals with a free 3′ end formed at the nick site, and the prime editor initiates DNA synthesis from the nick site, using the free 3′ end as a primer. Subsequently, a single -stranded DNA encoded by the editing template of the PEgRNA is synthesized. In some embodiments, the newly synthesized single-stranded DNA comprises one or more intended nucleotide edits compared to an endogenous target gene sequence. Accordingly, in some embodiments, the editing template of a PEgRNA is complementary to a ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 sequence in the edit strand except for one or more mismatches at the intended nucleotide edit positions in the editing template. In some embodiments, the newly synthesized single stranded DNA has identity or substantial identity to a sequence in the editing target sequence, except for one or more insertions, deletions, or substitutions at the intended nucleotide edit positions. In some embodiments, the newly synthesized single-stranded DNA equilibrates with the editing target on the edit strand of the double stranded target DNA (e.g., the target gene) for pairing with the target strand of the targe gene. In some embodiments, the editing target sequence of the double stranded target DNA (e.g., target gene) is excised by a flap endonuclease (FEN), for example, FEN1. In some embodiments, the FEN is an endogenous FEN, for example, in a cell comprising the double stranded target DNA, e.g., a target gene. In some embodiments, the FEN is provided as part of the prime editor, either linked to other components of the prime editor or provided in trans. In some embodiments, the newly synthesized single stranded DNA, which comprises the intended nucleotide edit, replaces the endogenous single stranded editing target sequence on the edit strand of the double stranded target DNA (e.g., target gene). In some embodiments, the newly synthesized single stranded DNA and the endogenous DNA on the target strand form a heteroduplex DNA structure at the region corresponding to the editing target sequence of the double stranded target DNA (e.g., target gene). In some embodiments, the newly synthesized single-stranded DNA comprising the nucleotide edit is paired in the heteroduplex with the target strand of the target DNA that does not comprise the nucleotide edit, thereby creating a mismatch between the two otherwise complementary strands. In some embodiments, the mismatch is recognized by DNA repair machinery, e.g., an endogenous DNA repair machinery. In some embodiments, through DNA repair, the intended nucleotide edit is incorporated into the double stranded target DNA (e.g., the target gene). PRIME EDITOR In various embodiments, a prime editor includes a polypeptide domain having DNA binding activity (e.g., a DNA binding domain) and a polypeptide domain (e.g., a DNA polymerase domain) having DNA polymerase activity. In some embodiments, a prime editor comprises a polypeptide domain (e.g., a DNA binding domain) having DNA binding activity. In some embodiments, a prime editor comprises a polypeptide that comprises a DNA binding domain. In some embodiments, a prime editor comprises a DNA binding domain. In some embodiments, a prime editor comprises a polypeptide domain having DNA polymerase activity (e.g., a DNA polymerase domain). In some embodiments, a prime editor comprises a polypeptide that comprises a DNA polymerase domain. In some embodiments, a prime editor ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 comprises a DNA polymerase domain. In some embodiments, a prime editor comprises a polypeptide that comprises a DNA binding domain and a polypeptide that comprises a DNA polymerase domain. In some embodiments, a prime editor comprises a DNA binding domain and a DNA polymerase domain. In some embodiments, the prime editor comprises a DNA binding domain and DNA polymerase domain that is linked by a linker, e.g., a peptide linker, e.g., a GS rich peptide linker. In some embodiments, the prime editor comprises a fusion polypeptide that comprises a DNA binding domain and a DNA polymerase domain linked by a linker, e.g., a peptide linker, e.g., a GS rich peptide linker. In some embodiments, the prime editor comprises a polypeptide domain having a nuclease activity. In some embodiments, the polypeptide domain having DNA binding activity comprises a nuclease domain or nuclease activity. In some embodiments, the DNA binding domain comprises a nuclease domain or nuclease activity. In some embodiments, the polypeptide domain having the nuclease activity comprises a nickase, or a fully active nuclease. In some embodiments, the DNA binding domain comprises a nickase, or a fully active nuclease. In some embodiments, the prime editor comprises a polypeptide domain that is an inactive nuclease. In some embodiments, the DNA binding domain comprises a nuclease domain that is an inactive nuclease; e.g., dCas9. In some embodiments, the DNA binding domain comprises a comprises a nucleic acid guided DNA binding domain, for example, a CRISPR-Cas protein, for example, a Cas9 nickase, a Cpfl nickase, or another CRISPR-Cas nuclease. In some embodiments, the DNA binding domain (e.g., a nucleic acid guided DNA binding domain) is a Cas protein domain. In some embodiments, the Cas protein is a Cas9; e.g., Cas9 nuclease; e.g., dCas9, Cas9 nickase. In some embodiments, the Cas protein domain comprises a nickase or a nickase activity. In some embodiments, the DNA binding domain is a Cas9 or a variant thereof (e.g., a nickase variant). In some embodiments, the polypeptide domain having programmable DNA binding activity comprises a nucleic acid guided DNA binding domain, for example, a CRISPR-Cas protein, for example, a Cas9 nickase, a Cpfl nickase, or another CRISPR-Cas nuclease. In some embodiments, the polypeptide domain having DNA polymerase activity comprises a template-dependent DNA polymerase, for example, a DNA-dependent DNA polymerase or an RNA-dependent DNA polymerase. In some embodiments, the DNA binding domain comprises a template-dependent DNA polymerase for example, a DNA-dependent DNA polymerase or an RNA -dependent DNA polymerase. In some embodiments, the DNA polymerase domain comprises a reverse transcriptase domain (RT domain) or a reverse transcriptase (RT). In some embodiments, the DNA polymerase domain is a RT domain or a RT. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 In some embodiments, a prime editor comprises a reverse transcriptase (RT) activity. For example, the first polypeptide of the prime editor may have activity for target primed reverse transcription. In some embodiments, the polypeptide domain having DNA polymerase activity comprises a reverse transcriptase activity (e.g., activity for target primed reverse transcription). In some embodiments, the DNA polymerase is a reverse transcriptase. In some embodiments, the prime editor comprises additional polypeptides involved in prime editing, for example, a polypeptide domain having 5′ endonuclease activity, e.g., a 5′ endogenous DNA flap endonucleases (e.g., FEN1), for helping to drive the prime editing process towards the edited product formation. In some embodiments, the prime editor further comprises an RNA -protein recruitment polypeptide, for example, a MS2 coat protein. In some embodiments, a prime editor comprises a Cas polypeptide (i.e., a DNA binding domain) and a reverse transcriptase polypeptide (i.e., a DNA polymerase domain) that are derived from different species. For example, a prime editor may comprise a S. pyogenes Cas9 polypeptide and a Moloney murine leukemia virus (M-MLV) reverse transcriptase polypeptide. In some embodiments, the prime editor comprises a fusion polypeptide that comprises a comprises a Cas polypeptide (i.e., a DNA binding domain) and a reverse transcriptase polypeptide (i.e., a DNA polymerase domain) that are derived from different species. For example, a prime editor may comprise a S. pyogenes Cas9 polypeptide and a Moloney murine leukemia virus (M-MLV) reverse transcriptase (RT) polypeptide. In some embodiments, polypeptide domains of a prime editor (e.g., a DNA binding domain and a DNA polymerase domain) are fused or linked by a peptide linker to form a fusion protein. In other embodiments, a prime editor comprises one or more polypeptide domains (e.g., a DNA binding domain and a DNA polymerase domain) provided in trans as separate proteins, which are capable of being associated to each other through non-peptide linkages or through aptamers or recruitment sequences. In some embodiments, a prime editor comprises a DNA binding domain and a DNA polymerase domain (e.g., a reverse transcriptase domain or RT) fused or linked with each other by a peptide linker (e.g., linkers disclosed set forth in SEQ ID NOs: 286-411). In some embodiments, the prime editor comprises a DNA binding domain and a DNA polymerase domain (e.g., a reverse transcriptase domain or RT) fused or linked with each other by an RNA-protein recruitment aptamer, e.g., a MS2 aptamer, which can, in some embodiments, be linked to a PEgRNA. In some embodiments, a prime editor further comprises one or more nuclear localization sequence (NLS). In some embodiments, one or more polypeptides of the prime editor are fused ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 to or linked to (e.g., via a peptide linker) one or more NLSs. In some embodiments, the prime editor comprises a DNA binding domain and a DNA polymerase domain that are provided in trans, wherein the DNA binding domain and / or the DNA polymerase domain is fused or linked to one or more NLSs. Prime editor polypeptide components can be encoded by one or more polynucleotides in whole or in part. The present disclosure contemplates polynucleotides encoding the prime editor components, for example, a polynucleotide encoding a DNA binding domain, and a polynucleotide encoding a DNA polymerase domain. The present disclosure also contemplates a single polynucleotide comprising a polynucleotide encoding a DNA binding domain, and a polynucleotide encoding a DNA polymerase domain. In some embodiments, a prime editing composition comprises a polynucleotide encoding a DNA polymerase domain. In some embodiments, the polynucleotide encoding a DNA polymerase domain is a DNA. In some embodiments, the polynucleotide encoding a DNA polymerase domain is an RNA (e.g., a mRNA). In some embodiments, a prime editing composition comprises a polynucleotide encoding a DNA binding domain. In some embodiments, the polynucleotide encoding the DNA binding domain is a DNA. In some embodiments, the polynucleotide encoding the DNA binding domain is an RNA (e.g., a mRNA). In some embodiments, the polynucleotide encoding a DNA binding domain, and the polynucleotide encoding a DNA polymerase domain are linked by a linker polynucleotide (e.g., that encodes a peptide linker) to result in a fusion protein (e.g., a prime editor) that comprises the DNA polymerase domain and DNA binding domain linked by a peptide linker. In some embodiments, the linker polynucleotide is a DNA. In some embodiments, the linker polynucleotide Is an RNA (e.g., mRNA). In some embodiments, the polynucleotide sequence encoding a DNA binding domain, and the polynucleotide encoding a DNA polymerase domain are linked by a linker polynucleotide (e.g., that encodes a peptide linker) further comprises one or more polynucleotide sequences encoding one or more NLS to result in a fusion protein (e.g., a prime editor) that comprises the DNA polymerase domain and DNA binding domain linked by a peptide linker and further fused to or linked to one or more NLS. In some embodiments, a single polynucleotide (e.g., a single mRNA) construct, or vector encodes the prime editor fusion protein. In some embodiments, multiple polynucleotides, constructs, or vectors each encode a polypeptide domain or portion of a domain of a prime editor, or a portion of a prime editor fusion protein. For example, a prime editor fusion protein can comprise an N-terminal portion fused to an intein-N and a C-terminal portion fused to an intein-C, each of which is individually encoded by an AAV vector. In some embodiments, components of a prime editor disclosed herein (e.g., a polypeptide comprising a DNA binding ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 domain and / or a polypeptide comprising a DNA polymerase domain) can be brought together post-translationally via a split-intein. In some embodiments, a prime editor polypeptide may comprise an amino acid sequence (e.g., the amino acid sequence of a domain of a prime editor), wherein the initial methionine (at position 1) is optionally not present. In some embodiments, a prime editor polypeptide sequence may comprise a N-terminal methionine residue. In some embodiments, a prime editor polypeptide sequence may lack a N-terminus methionine. In some embodiments, the N-terminal methionine encoded by the translation initiation codon, e.g., ATG, may be removed from the prime editor polypeptide after translation. In some embodiments, the N-terminal methionine encoded by the translation initiation codon, e.g., ATG, may remain present in the prime editor polypeptide sequence. In some embodiments, the amino acid sequence of a prime editor polypeptide can be N-terminally modified by one or more processing enzymes, e.g., by Methionine aminopeptidases (MAP). In some embodiments, a prime editor comprises a DNA polymerase domain and a DNA binding domain, wherein the amino acid sequences of the DNA polymerase domain and / or the DNA binding domain comprise aN terminus methionine. In some embodiments, a prime editor comprises a DNA polymerase domain that comprises an amino acid sequence that lacks a N- terminus methionine relative to a reference DNA polymerase amino acid sequence. In some embodiments, a prime editor comprises a DNA binding domain that comprises an amino acid sequence that lacks a N-terminus methionine relative to a reference DNA binding domain amino acid sequence. In some embodiments, a prime editor and / or a component thereof (e.g., a DNA binding domain or a polypeptide comprising a DNA binding domain and / or a DNA polymerase domain or a polypeptide comprising a DNA polymerase domain) can be engineered. In some embodiments, the polypeptide components of a prime editor do not naturally occur in the same organism or cellular environment. In some embodiments, the polypeptide components of a prime editor can be of different origins or from different organisms. In some embodiments, a prime editor comprises a DNA binding domain and a DNA polymerase domain that are derived from different species. In some embodiments, a prime editor comprises a RT or an RT domain (e.g., a M-MLV RT) that is rationally engineered. Such an engineered RT or RT domain can comprise, for example, sequences or amino acid changes different from a naturally occurring RT or RT domain. In some embodiments, the engineered RT or RT domain comprises improved RT activity relative to a corresponding naturally occurring RT or RT domain. In some embodiments, ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 the engineered RT or RT domain comprises improved prime editing efficiency relative to a corresponding naturally occurring RT or RT domain, when used in a prime editor. In some embodiments, a prime editor polypeptide comprises a DNA binding domain (e.g., a Cas9) comprising an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 2, 6, 7, or 596-613. In some embodiments, a prime editing composition comprises a) a DNA binding domain or a polynucleotide encoding the DNA binding domain, and b) a Moloney Murine Leukemia reverse transcriptase (M-MLV RT) domain or a polynucleotide encoding the M-MLV RT domain, wherein the M-MLV RT domain is truncated at C-Terminus at a position after amino acid L478 as set forth in SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editing composition comprises a) a DNA binding domain or a polynucleotide encoding the DNA binding domain, and b) a Moloney Murine Leukemia reverse transcriptase (M-MLV RT) domain or a polynucleotide encoding the M-MLV RT domain, wherein the M-MLV RT domain is truncated at C-Terminus at a position truncated at a position between L478 and G504 as set forth in SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor polypeptide comprises a DNA polymerase domain comprising a MMLV-RT or a mutant, fragment or variant thereof. In some embodiments, a prime editor comprises a wild type MMLV-RT. In some embodiments, a prime editor comprises a MMLV-RT variant comprising one or more amino acid substitutions, insertions, and / or deletions, e.g., a MMLV-RT variant comprising one or more amino acid substitutions, insertions, and / or deletions compared to the reference MMLV-RT sequence set forth in SEQ ID NO: 1. In some embodiments, the MMLVRT variant comprises one or more D200N, T306K, W313L, T330P, L603W amino acid substitutions as compared to reference MMLVRT sequence SEQ ID No 1. In some embodiments, the MMLVRT variant comprises D200N, T306K, W313L, T330P, and L603W amino acid substitutions as compared to reference MMLVRT sequence SEQ ID No 1 (the variant also referred to as a MMLVRTSM variant). In some embodiments, the MMLV RT variant comprises one or more of D524N, L435K, Y133R, Y271R amino acid substitution as compared to reference MMLVRT sequence SEQ ID No 1. In some embodiments, the MMLV RT variant has one or more amino acid deletion compared to the reference MMLVRT sequence SEQ ID No 1. Lor example, in some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 504 and 505 as set forth in SEQ ID ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 NO: 1. By truncated at the C terminus, it is meant that amino acids C terminal to the truncation position are deleted from the MMLV RT sequence as compared to reference sequence, i.e. the MMLV RT variant that is truncated at the C terminus between positions corresponding to amino acids 504 and 505 as set forth in SEQ ID NO: 1 contains only amino acids at positions 1-504 as set forth in SEQ ID No: 1 (such truncation may be referred to herein as a 504X, or G504X truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 478 and 479 as set forth in SEQ ID NO: 1 (a L478X truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus at any amino acid position between positions 478 and 505 as set forth in SEQ ID NO: 1. In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 365 and 366 as set forth in SEQ ID NO: 1 (a P365X truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 278 and 279 as set forth in SEQ ID NO: 1 (a R278X truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 328 and 329 as set forth in SEQ ID NO: 1 (a T328X truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 378 and 379 as set forth in SEQ ID NO: 1 (a K478X truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 428 and 429 as set forth in SEQ ID NO: 1 (a M428X truncation). In some embodiments, a prime editor polypeptide comprises a DNA polymerase domain (e.g., a MMLV-RT) comprising an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 1, 4, 5, 36, 45, 54, 63, or 623. In some embodiments, a prime editor polypeptide comprises a MMLV-RT domain comprising an amino acid sequence SEQ ID NOs: 5. In some embodiments, a prime editor polypeptide comprises a C- terminal truncated MMLV-RT domain having the amino acid sequence of SEQ ID NO: 36. In some embodiments, a prime editor polypeptide comprises one or more peptide linkers that connect a DNA binding domain and a DNA polymerase domain. In some embodiments, the prime editor comprises, from N terminus to C terminus, a DNA binding domain, a peptide linker, and a DNA polymerase domain. In some embodiments, the prime editor comprises, from C terminus to N terminus, a DNA binding domain, a peptide linker, and a DNA polymerase domain. In some embodiments, a prime editor comprises a peptide linker comprising an amino ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 286-411. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 286-411. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 286-411. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 289-311. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 289-311. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 289-311. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 302. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 302. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that comprises an amino acid sequence of SEQ ID NO: 302. In some embodiments, a prime editor polypeptide comprises one or more NLSs. In some embodiments, a DNA binding domain of a prime editor comprises one or more NLSs. In some embodiments, a DNA polymerase domain of a prime editor comprises one or more NLSs. In some embodiments, a DNA binding domain of a prime editor comprises two or more NLSs. In ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 some embodiments, a DNA polymerase domain of a prime editor comprises two or more NLSs. In some embodiments, a prime editor comprises a fusion protein comprising one or more or two or more NLSs in between a DNA binding domain and a DNA polymerase domain. The NLS sequence can be any NLS known in the art. In some embodiments, a prime editor comprises a NLS comprising an amino acid sequence that is at least at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 8-24, or 621. In some embodiments, a prime editor comprises a fusion protein comprising a DNA binding domain and a DNA polymerase domain. In some embodiments, the prime editor comprises a fusion protein comprising from N terminus to C terminus a DNA binding domain and a DNA polymerase domain. In some embodiments, the fusion protein comprises a NLS at the N terminus, wherein the NLS comprises the sequence of SEQ ID NO 8, 9, or 10. In some embodiments, the fusion protein comprises a NLS at the N terminus, wherein the NLS comprises a sequence selected from the group consisting of SEQ ID NOs 11-24. In some embodiments, the fusion protein comprises a NLS at the N terminus, wherein the NLS comprises the sequence of SEQ ID NO 11, 12, 13, or 14. In some embodiments, a prime editor comprises (a) a DNA binding domain and (b) a DNA polymerase domain comprising a MMLV-RT or a mutant, fragment or variant thereof, wherein the DNA binding domain and the DNA polymerase domain are connect by a peptide linker to form a fusion protein. In some embodiments, the prime editor fusion protein comprises the DNA binding domain and the DNA polymerase domain from N terminus to C terminus. In some embodiments, the prime editor fusion protein comprises the DNA binding domain and the DNA polymerase domain from C terminus to N terminus. In some embodiments, the DNA binding domain comprises an amino acid sequence that is at least at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 2, 6, 7, or 596-613. In some embodiments, the DNA polymerase domain comprises a MMLVRT5M variant. In some embodiments, the DNA polymerase comprises a MMLV RT variant having one or more of D524N, L435K, Y133R, Y271R amino acid substitution as compared to reference MMLVRT sequence SEQ ID No 1. In some embodiments, the DNA polymerase comprises a MMLV RT variant having one or more of D200N, T306K, W313F, T330P, and L603W amino acid substitution as compared to reference ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 MMLVRT sequence SEQ ID No 1. In some embodiments, the DNA polymerase comprises a MMLV RT G504X truncation variant, a MMLV RT L478 truncation variant, a MMLV RT K478X truncation variant, a MMLV RT M428X truncation variant, a MMLV RT T328X truncation variant, a MMLV RT R278X truncation variant, In some embodiments, the DNA polymerase domain comprises an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 1, 4, 5, 36, 45, 54, 63, or 623. In some embodiments, the peptide linker connecting the DNA binding domain and the DNA polymerase domain comprises an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 286-411. In some embodiments, the peptide linker comprises a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 286-411. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 289-311. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 289-311. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 289-311. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 302. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to SEQ ID NO: 302. In some embodiments, a prime editor comprises a peptide linker comprising an amino acid sequence that comprises an amino acid sequence of SEQ ID NO: 302. In some embodiments, the prime editor further comprises one or more NLS comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 8- 24, or 621 wherein the NLS is fused or linked (e.g., via a linker comprising an amino acid sequence at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 286-411) to the C-terminus or N terminus of the DNA binding domain or the DNA polymerase domain. In some embodiments, a prime editor polypeptide comprises a DNA binding domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 2, 6, 7, or 596-613, further comprising a DNA polymerase domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 1, 4, 5, 36, 45, 54, 63, or 623 and optionally wherein the DNA binding domain and the DNA polymerase domain are fused or linked by a peptide linker having an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 286-411 and optionally further comprises one or more NLS comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences recited set forth in SEQ ID NOs: 8-23, or 621 wherein the NLS is fused or linked (e.g., via a linker comprising an amino acid sequence at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 286-411) to the C-terminal or N terminal of the DNA binding domain or the DNA polymerase domain. In some embodiments, a prime editor may comprise a DNA binding domain having an amino acid sequence that is selected from any of the amino acid sequence selected from 2, 6, 7, or 596-613, a DNA polymerase domain having an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 1, 4, 5, 36, 45, 54, 63, or 623, and optionally a linker having an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 286-411. In some embodiments, a prime editor further comprises one or more nuclear localization sequence (NLS) having an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 8-23, or 621 or described herein. In some embodiments, the NLS is fused to the N-terminus of a DNA polymerase domain described herein. In some embodiments, the NLS is fused to the C-terminus of the DNA polymerase domain. In some embodiments, the NLS is fused to the N-terminus or the C-terminus of a DNA binding domain. In some embodiments, a linker sequence is disposed between the NLS and a domain of the prime editor, e.g., a linker comprising an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 286- 411. In some embodiments, a prime editor polypeptide comprises a DNA binding domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequences as set forth in SEQ ID NOs: 7, further comprising a DNA polymerase domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical an amino acid sequence as set forth in SEQ ID NO: 5, optionally wherein the DNA binding domain and the DNA polymerase domain are fused or linked by a peptide linker having an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequence as set forth in SEQ ID NOs: 289 and optionally further comprises one or more NLS comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 9, 10, or 11 wherein the NLS is fused or linked (e.g., via a linker comprising an amino acid sequence at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequences recited as set forth in SEQ ID NO: 288) to the C-terminal or N terminal of the DNA binding domain or the DNA polymerase domain. In some embodiments, a prime editor polypeptide comprises a DNA binding domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequences as set forth in SEQ ID NOs: 7, further comprising a DNA polymerase domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical an amino acid sequence as set forth in SEQ ID NO: 36, optionally wherein the DNA binding domain and the DNA polymerase domain are fused or linked by a peptide linker having an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequence as set forth in SEQ ID NOs: 289 and optionally further comprises one or more NLS comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 9, 10, or 11 wherein the NLS is fused or linked (e.g., via a linker comprising an amino acid sequence at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequences recited as set forth in SEQ ID NO: 288) to the C-terminal or N terminal of the DNA binding domain or the DNA polymerase domain. In some embodiments, a prime editor may comprise a DNA binding domain having an amino acid sequence as set forth in SEQ ID NO: 7, a DNA polymerase domain having an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 5 ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 or 36 and optionally a linker having an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 302 or 309. In some embodiments, a prime editor further comprises one or more nuclear localization sequence (NLS) having an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 9, 10 or 11 as described herein. In some embodiments, a prime editor may comprise a DNA binding domain having an amino acid sequence as set forth in SEQ ID NO: 7, a DNA polymerase domain having an amino acid sequence as set forth in SEQ ID NOs: 5, optionally a linker having an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 288, 289, or 302 and optionally further comprises one or more nuclear localization sequence (NLS) having an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 9, 10 or 11 as described herein. In some embodiments, a prime editor may comprise a DNA binding domain having an amino acid sequence as set forth in SEQ ID NO: 7, a DNA polymerase domain having an amino acid sequence as set forth in SEQ ID NOs: 36, optionally a linker having an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 288, 289, or 302 and optionally further comprises one or more nuclear localization sequence (NLS) having an amino acid sequence that is selected from any of the amino acid sequence selected from SEQ ID NOs: 9, 10 or 11 as described herein. In some embodiments, a prime editor may comprise an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 25, 34, 35, 43, 44, 52, 53, 61, 62, 63, 70-78, 85, 86, 93, 96, 99, 104, 105, 110, 111, 116, 117, 122, 125, 128, 131, 134, 137, 140, 143, 146, 149, 152, 155, 158, 161, 164, 170, 176, 179, 182, 185, 188, 191, 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 620, 622, 624, 625, 647. In some embodiments, a prime editor may comprise an amino acid sequence that is selected from any of the amino acid sequence selected from any one of the amino acid sequences set forth in SEQ ID NOs: 25, 34, 35, 43, 44, 52, 53, 61, 62, 63, 70-78, 85, 86, 93, 96, 99, 104, 105, 110, 111, 116, 117, 122, 125, 128, 131, 134, 137, 140, 143, 146, 149, 152, 155, 158, 161, 164, 170, 176, 179, 182, 185, 188, 191, 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 620, 622, 624, 625, 647. In some embodiments, the prime editor comprises an amino acid sequence that has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 differences e.g., mutations e.g., amino ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 acid deletions, amino acid insertions, and / or amino acid substitutions compared to any of the amino acid sequences set forth in SEQ ID NOs: 25, 34, 35, 43, 44, 52, 53, 61, 62, 63, 70-78, 85, 86, 93, 96, 99, 104, 105, 110, 111, 116, 117, 122, 125, 128, 131, 134, 137, 140, 143, 146, 149, 152, 155, 158, 161, 164, 170, 176, 179, 182, 185, 188, 191, 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 620, 622, 624, 625, or 647. In some embodiments, the prime editor comprises an amino acid sequence that has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 differences e.g., mutations e.g., amino acid deletions, amino acid insertions, and / or amino acid substitutions compared to any of the amino acid sequences set forth in SEQ ID NOs: 25, 34, 35, 43, 44, 52, 53, 61, 62, 63, 70-78, 85, 86, 93, 96, 99, 104, 105, 110, 111, 116, 117, 122, 125, 128, 131, 134, 137, 140, 143, 146, 149, 152, 155, 158, 161, 164, 170, 176, 179, 182, 185, 188, 191, 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 620, 622, 624, 625, or 647. In some embodiments, the prime editor comprises an amino acid sequence identical to any one of the sequences set forth in SEQ ID NOs: 25, 34, 35, 43, 44, 52, 53, 61, 62, 63, 70-78, 85, 86, 93, 96, 99, 104, 105, 110, 111, 116, 117, 122, 125, 128, 131, 134, 137, 140, 143, 146, 149, 152, 155, 158, 161, 164, 170, 176, 179, 182, 185, 188, 191, 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 620, 622, 624, 625, or 647. In some embodiments, the prime editor comprises an amino acid sequence identical to any one of the sequences set forth in SEQ ID NOs: 25, 34, 35, 77, 78, 85, 86, 620, 622, 624, 625, or 647. In some embodiments, the prime editor comprises an amino acid sequence identical to any one of the sequences set forth in SEQ ID NOs: 25, 624, or 625. In some embodiments, the prime editor comprises an amino acid sequence identical to any one of the sequences set forth in SEQ ID NOs: 34, 35, 647. In some embodiments, the prime editor comprises an amino acid sequence identical to any one of the sequences set forth in SEQ ID NOs: 77, 78, or 620. In some embodiments, the prime editor comprises an amino acid sequence identical to any one of the sequences set forth in SEQ ID NOs: 85, 86, or 622. In some embodiments, the prime editor comprises an amino acid sequence that lacks an N-terminus methionine compared to a corresponding prime editor sequence selected from any one of the sequences set forth in SEQ ID NO: 25, 34, 35, 43, 44, 52, 53, 61, 62, 63, 70-78, 85, 86, 93, 96, 99, 104, 105, 110, 111, 116, 117, 122, 125, 128, 131, 134, 137, 140, 143, 146, 149, 152, 155, 158, 161, 164, 170, 176, 179, 182, 185, 188, 191, 194, 197, 200, 203, 206, 209, 212, 215, 218, 221, 224, 227, 230, 620, 622, 624, or 625. In some embodiments, a prime editor comprises a fusion protein comprising the structure: N-Cas9 nickase -Peptide linker-RT-C. In some embodiments, a prime editor comprises a fusion protein comprising the structure: N-Cas9 nickase-Peptide linker-MMLV RT variant-C. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 In some embodiments, the Cas9 nickase comprises a mutation in the HNH domain and comprises an active RuvC domain. In some embodiments, the Cas9 nickase comprises a H840A mutation in the HHN domain. In some embodiments, the MMLV RT variant is MMLVRTSM. In some embodiments, the MMLV RT variant is truncated between positions corresponding to positions 504 and 505 as compared to MMLVRTSM. In some embodiments, the peptide linker comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID Nos 286-411. In some embodiments, the peptide linker comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID Nos 289-311. In some embodiments, the peptide linker comprises a sequence selected from the group consisting of SEQ ID Nos 289-311. In some embodiments, the peptide linker comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID Nos 302. In some embodiments, the peptide linker comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID 309. In some embodiments, the peptide linker comprises the sequence of SEQ ID No 302. In some embodiments, the peptide linker comprises the sequence of SEQ ID No 309. In some embodiments, the prime editor comprises a fusion protein comprising at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID Nos 78, 105, 117, 125, 131, 137, 143, 149, 155, 161, 167, 173, 179, 185, 191, 197, 203, 209, 215, 221, and 227. In some embodiments, the prime editor comprises a fusion protein comprising a sequence selected from the group consisting of SEQ ID Nos 78, 105, 117, 125, 131, 137, 143, 149, 155, 161, 167, 173, 179, 185, 191, 197, 203, 209, 215, 221, and 227. In some embodiments, the prime editor comprises a fusion protein comprising at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID Nos 86, 111, 122, 128, 134, 140, 146, 152, 158, 164, 170, 176, 182, 188, 194, 200, 206, 212, 218, 224, and 230. In some embodiments, the prime editor comprises a fusion protein comprising a sequence selected from the group consisting of SEQ ID Nos 86, 111, 122, 128, 134, 140, 146, 152, 158, 164, 170, 176, 182, 188, 194, 200, 206, 212, 218, 224, and 230. In some embodiments, the prime editor comprises a fusion protein that comprises a sequence having at least about 80%, 81%, 82%, ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID No 78. In some embodiments, the prime editor comprises a fusion protein comprising the sequence of SEQ ID NO: 78. In some embodiments, the prime editor comprises a fusion protein that comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID No 86. In some embodiments, the prime editor comprises a fusion protein comprising the sequence of SEQ ID NO: 86. In some embodiments, a prime editor comprises a fusion protein comprising the structure: N-terminal NLS-Cas9 nickase-Peptide linker-RT-C-terminal NLS. In some embodiments, a prime editor comprises a fusion protein comprising the structure: Cas9 nickase- peptide linker-MMLV RT variant. In some embodiments, the Cas9 nickase comprises a mutation in the HNH domain and comprises an active RuvC domain. In some embodiments, the Cas9 nickase comprises a H840A mutation in the HHN domain. In some embodiments, the MMLV RT variant is MMLVRTSM. In some embodiments, the MMLV RT variant is truncated between positions corresponding to positions 504 and 505 as compared to MMLVRT5M. In some embodiments, the peptide linker comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID Nos 286-411. In some embodiments, the peptide linker comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID Nos 289-311. In some embodiments, the peptide linker comprises a sequence selected from the group consisting of SEQ ID Nos 289-311. In some embodiments, the peptide linker comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID Nos 302. In some embodiments, the peptide linker comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID 309. In some embodiments, the peptide linker comprises the sequence of SEQ ID No 302. In some embodiments, the peptide linker comprises the sequence of SEQ ID No 309. In some embodiments, the N-terminal NLS or the C-terminal comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from SEQ ID Nos 11-24 and 621. In some embodiments, the N-terminal NLS comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from SEQ ID Nos 8-10 and 621. In some embodiments, the N-terminal NLS comprises a sequence selected from SEQ ID Nos 8-10 and 621. In some embodiments, the C-terminal NLS comprises the sequence of SEQ ID NO: 8. In some embodiments, the C-terminal NLS comprises the sequence of SEQ ID NO: 9. In some embodiments, the C-terminal NLS comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from SEQ ID Nos 11-24. In some embodiments, the C-terminal NLS comprises a sequence selected from SEQ ID Nos 11-24. In some embodiments, the C-terminal NLS comprises the sequence of SEQ ID NO: 11. In some embodiments, the C-terminal NLS comprises the sequence of SEQ ID NO: 24. In some embodiments, the prime editor comprises a fusion protein comprising at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID Nos 77, 93, 104, 620, and 116. In some embodiments, the prime editor comprises a fusion protein comprising a sequence selected from the group consisting of SEQ ID Nos 77, 93, 104, 620, and 116. In some embodiments, the prime editor comprises a fusion protein comprising at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID Nos 85, 96, 622, and 110. In some embodiments, the prime editor comprises a fusion protein comprising a sequence selected from the group consisting of SEQ ID Nos 85, 96, 622, and 110. In some embodiments, the prime editor comprises a fusion protein that comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID No 77. In some embodiments, the prime editor comprises a fusion protein comprising the sequence of SEQ ID NO: 77 or 620. In some embodiments, the prime editor comprises a fusion protein that comprises a sequence having at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID No 85 or 622. In some embodiments, the prime editor comprises a fusion protein comprising the sequence of SEQ ID NO: 85 or 622. Prime Editor Nucleotide Polymerase Domain In some embodiments, a prime editor comprises a polypeptide domain (e.g., a DNA polymerase domain) comprising DNA polymerase activity. In some embodiments, the prime editor comprises a polypeptide that comprises a DNA polymerase domain. In some ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 embodiments, a prime editing composition comprises a polynucleotide that encodes a polymerase domain, e.g., a DNA polymerase domain. In some embodiments, a prime editor comprises a nucleotide polymerase domain, e.g., a DNA polymerase domain. In some embodiments, the DNA polymerase domain can be a wild-type DNA polymerase domain, a full- length DNA polymerase protein domain, or can be a functional mutant, a functional variant, or a functional fragment thereof. In some embodiments, the DNA polymerase domain is a template dependent DNA polymerase domain. For example, the DNA polymerase can rely on a template polynucleotide strand, e.g., the editing template sequence, for new strand DNA synthesis. In some embodiments, the prime editor comprises a DNA polymerase domain that is a DNA- dependent DNA polymerase. For example, a prime editor having a DNA-dependent DNA polymerase can synthesize a new single stranded DNA using a PEgRNA editing template that comprises a DNA sequence as a template. In such cases, the PEgRNA is a chimeric or hybrid PEgRNA, and comprising an extension arm comprising a DNA strand. In some embodiments, the chimeric or hybrid PEgRNA can comprise an RNA portion Iding the spacer and the gRNA core) and a DNA portion (the extension arm comprising the editing template that includes a strand of DNA). In some embodiments, the prime editor comprises a DNA polymerase domain that is a RNA-dependent DNA polymerase. In some embodiments, the DNA polymerase domain can be a wild type polymerase, for example, from eukaryotic, prokaryotic, archaeal, or viral organisms. In some embodiments, the DNA polymerase domain is a modified DNA polymerase, for example, a wild-type DNA polymerase that is modified by genetic engineering, mutagenesis, or directed evolution-based processes. In some embodiments, the DNA polymerase is a bacteriophage polymerase, for example, a T4, T7, or phi29 DNA polymerase. In some embodiments, the DNA polymerase is an archaeal polymerase, for example, pol I type archaeal polymerase or a pol II type archaeal polymerase. In some embodiments, the DNA polymerase comprises a thermostable archaeal DNA polymerase. In some embodiments, the DNA polymerase comprises a eubacterial DNA polymerase, for example, Pol I, Pol II, or Pol III polymerase. In some embodiments, the DNA polymerase is a Pol I family DNA polymerase. In some embodiments, the DNA polymerase comprises is an E.coli Pol I DNA polymerase. In some embodiments, the DNA polymerase is a Pol II family DNA polymerase. In some embodiments, the DNA polymerase is a Pyrococcus furiosus (Pfu) Pol II DNA polymerase. In some embodiments, the DNA Polymerase is a Pol IV family DNA polymerase. In some embodiments, the DNA polymerase is a E. coli Pol IV DNA polymerase. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 In some embodiments, the DNA polymerase is an eukaryotic DNA polymerase. In some embodiments, the DNA polymerase is a Pol-beta DNA polymerase, a Pol-lambda DNA polymerase, a Pol-sigma DNA polymerase, or a Pol-mu DNA polymerase. In some embodiments, the DNA polymerase is a Pol-alpha DNA polymerase. In some embodiments, the DNA polymerase is a POLA1 DNA polymerase. In some embodiments, the DNA polymerase is a POLA2 DNA polymIrase. In some embodiments, the DNA polymerase is a Pol-delta DNA polymerase. In some embodiments, the DNA polymerase is a POLD1 DNA polymerase. In some embodiments, the DNA polymerase is a POLD2 DNA polymerase. In some embodiments, the DNA polymerase is a human POLD1 DNA polymerase. In some embodiments, the DNA polymerase is a human POLD2 DNA polymerase. In some embodiments, the DNA polymerase is a POLD3 DNA polymerase. In some embodiments, the DNA polymerase is a POLD4 DNA polymerase. In some embodiments, the DNA polymerase is a Pol-epsilon DNA polymerase. In some embodiments, the DNA polymerase is a POLE1 DNA polymerase. In some embodiments, the DNA polymerase is a POLE2 DNA polymerase. In some embodiments, the DNA polymerase is a POLE3 DNA polymerase. In some embodiments, the DNA polymerase is a Pol-eta (POLH) DNA polymerase. In some embodiments, the DNA polymerase is a Pol-iota (POLI) DNA polymerase. In some embodiments, the DNA polymerase is a Pol-kappa (POLK) DNA polymerase. In some embodiments, the DNA polymerase is a Revl DNA polymerase. In some embodiments, the DNA polymerase is a human Revl DNA polymerase. In some embodiments, the DNA polymerase is a viral DNA-dependent DNA polymerase. In some embodiments, the DNA polymerase is a B family DNA polymerases. In some embodiments, the DNA polymerase is a herpes simplex virus (HSV) UL30 DNA polymerase. In some embodiments, the DNA polymerase is a cytomegalovirus (CMV) UL54 DNA polymerase. In some embodiments, the DNA polymerase is an archaeal polymerase. In some embodiments, the DNA polymerase is a Family B / pol I type DNA polymerase. For example, in some embodiments, the DNA polymerase is a homolog of Pfu from Pyrococcus furiosus. In some embodiments, the DNA polymerase is a pol II type DNA polymerase. For example, in some embodiments, the DNA polymerase is a homolog of P. furiosus DP1 / DP22-subunit polymerase. In some embodiments, the DNA polymerase lacks 5′ to 3′ nuclease activity. Suitable DNA polymerases (pol I or pol II) can be derived from archaea with optimal growth temperatures that are similar to the desired assay temperatures. In some embodiments, the DNA polymerase is a thermostable archaeal DNA polymerase. In some embodiments, the thermostable DNA polymerase is isolated or derived from Pyrococcus species (furiosus, species GB-D, woesii, abysii, horikoshii), Thermococcus species ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 (kodakaraensis KOD1, litoralis, species 9 degrees North-7, species JDF-3, gorgonarius), Pyrodictium occultum, and Archaeoglobus fulgidus. Polymerases may also be from eubacterial species. In some embodiments, the DNA polymerase is a Pol I family DNA polymerase. In some embodiments, the DNA polymerase is an E.coli Pol I DNA polymerase. In some embodiments, the DNA polymerase is a Pol II family DNA polymerase. In some embodiments, the DNA polymerase is a Pyrococcus furiosus (Pfu) Pol II DNA polymerase. In some embodiments, the DNA Polymerase is a Pol III family DNA polymerase. In some embodiments, the DNA Polymerase is a Pol IV family DNA polymerase. In some embodiments, the DNA polymerase is an E.coli Pol IV DNA polymerase. In some embodiments, the Pol I DNA polymerase is a DNA polymerase functional variant that lacks or has reduced 5′ to 3′ exonuclease activity. Suitable thermostable pol I DNA polymerases can be isolated from a variety of thermophilic eubacteria, including Thermus species and Thermotoga maritima such as Thermus aquaticus (Taq), Thermus thermophilus (Tth) and Thermotoga maritima (Tma UlTma). In some embodiments, a prime editor comprises an RNA-dependent DNA polymerase domain, for example, a reverse transcriptase (RT). In some embodiments, the DNA polymerase domain is an RNA-dependent DNA polymerase domain, for example, a reverse transcriptase (RT). In some embodiments, the DNA polymerase domain is a reverse transcriptase (RT) domain, for example, a reverse transcriptase (RT). In some embodiments, the reverse transcriptase (RT), or a RT domain is a M-MLV RT (e.g., a wild-type M-MLV RT, a reference M-MLV RT, a functional mutant, a functional variant, or a functional fragment thereof). An RT or an RT domain can be a wild-type RT domain, a full-length RT domain, or may be a functional mutant, a functional variant, or a functional fragment thereof. An RT or an RT domain of a prime editor can comprise a wild-type RT a full length RT, a functional mutant, a functional variant, or a functional fragment thereof or can be engineered or evolved to contain specific amino acid substitutions, truncations, or variants. An engineered RT can comprise sequences or amino acid changes different from a naturally occurring RT or a corresponding reference RT. In some embodiments, the engineered RT can have improved reverse transcription activity over a naturally occurring RT or RT domain. In some embodiments, the engineered RT can have improved features over a naturally occurring RT, for example, improved thermostability, reverse transcription efficiency, or target fidelity. In some embodiments, a prime editor comprising the engineered RT has improved prime editing efficiency over a prime editor having a reference naturally occurring RT. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 In some embodiments, the reverse transcriptase domain or RT can be between 200 and 800 amino acids in length, between 300 and 700 amino acids in length, or at least 400 and 600 amino acids in length. In some embodiments, the reverse transcriptase domain or RT can be at least 200 amino acids in length, at least 300 amino acids in length, at least 400 amino acids in length, at least 500 amino acids in length, or at least 600 amino acids in length. In some embodiments, the reverse transcriptase domain or RT is 250 amino acids in length. In some embodiments, the reverse transcriptase domain or RT is 350 amino acids in length. In some embodiments, the reverse transcriptase domain or RT is 450 amino acids in length. In some embodiments, the reverse transcriptase domain or RT is 550 amino acids in length. In some embodiments, the reverse transcriptase domain or RT is 650 amino acids in length. In some embodiments, a prime editor comprises a eukaryotic RT, for example, a yeast, Drosophila, rodent, or primate RT. In some embodiments, the prime editor comprises a Group II intron RT, for example, a. Geobacillus stearothermophilus Group II Intron (GsI-IIC) RT or a Eubacterium rectale group II intron (Eu.re.I2) RT. In some embodiments, the prime editor comprises a retron RT. In some embodiments, a prime editor comprises a virus RT, for example, a retrovirus RT. Non limiting examples of virus RT include Moloney murine leukemia virus (M-MLV or MLVRT); human T-cell leukemia virus type 1 (HTLV-1) RT; bovine leukemia virus (BLV) RT; Rous Sarcoma Virus (RSV) RT; human immunodeficiency virus (HIV) RT, M-MFV RT, Avian Sarcoma-Leukosis Virus (ASLV) RT, Rous Sarcoma Virus (RSV) RT, Avian Myeloblastosis Virus (AMV) RT, Avian Erythroblastosis Virus (AEV) Helper Virus MCAV RT, Avian Myelocytomatosis Virus MC29 Helper Virus MCAV RT, Avian Reticuloendotheliosis Virus (REV-T) Helper Virus REV-A RT, Avian Sarcoma Virus UR2 Helper Virus (UR2AV) RT, Avian Sarcoma Virus Y73 Helper Virus YAV RT, Rous Associated Virus (RAV) RT, and Myeloblastosis Associated Virus (MAV) RT, all of which may be suitably used in the methods and composition described herein. In some embodiments, the prime editor comprises a wild-type M-MLV RT, a reference M-MLV RT, a functional mutant, a functional variant, or a functional fragment thereof. In some embodiments, the RT domain or a RT is a M-MLV RT (e.g., wild-type M-MLV RT, a reference M-MLV RT, a functional mutant, a functional variant, or a functional fragment thereof). In some embodiments, a reference M-MLV RT is a wild-type M-MLV RT. An exemplary sequence of a wild-type M-MLV RT is provided in SEQ ID NO: 623. An exemplary sequence of a reference M-MLV RT is provided in SEQ ID NO: 1. Exemplary MMLV-RT amino acid and nucleotide sequences are disclosed at SEQ ID NOs: 623, 1, 4 ,5, 28, 29, 245, 246, 83, 84, 257, 258, 36, 41, ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 42, 91, 92, 63, 68, 69, 45, 50, 51, 54, 59, and 60. In some embodiments, the MMLVRT variant comprises D200N, T306K, W313F, T330P, and L603W amino acid substitutions as compared to reference MMLVRT sequence SEQ ID No 1. The variant, having the sequence of SEQ ID NO: 5, is referred to herein as “MMLVRT5M” or “MMLVRT5M”. In some embodiments, a prime editor comprises an RT that comprises an engineered RNase domain compared to a corresponding reference RT (e.g., a reference M-MLV RT or a wild-type M-MLV RT). In some embodiments, the RT of the prime editor comprises one or more amino acid substitutions, insertions, or deletions compared to a reference RT. In some embodiments, the RT of the prime editor is truncated compared to a corresponding reference RT (e.g., a reference M-MLV RT or a wild-type M-MLV RT). A polypeptide is “truncated” when, compared to a reference polypeptide sequence, the polypeptide lacks an end portion, for example, a N-terminal portion or a C-terminal portion. A polypeptide is truncated after amino acid position n means that the polypeptide, compared to a reference polypeptide sequence, lacks amino acids that are C-terminal to amino acid n or corresponding amino acids thereof, but retains amino acid n. In other words, “truncated after amino acid at position n” or “truncated at C terminus between positions n and n+1” refers to a truncation of a polypeptide between positions n and n+1, wherein amino acids that are C-terminal to amino acid n are deleted compared to a reference polypeptide sequence. In some embodiments, a polypeptide truncated after amino acid n, when compared to a reference polypeptide sequence, comprises amino acid n and all amino acids N terminal to amino acid n and lacks amino acids C terminal to amino acid n, or corresponding amino acids thereof. In some embodiments, a polypeptide truncated before amino acid n, or a polypeptide truncated at N terminus between positions n-1 and n, when compared to a reference polypeptide sequence, comprises amino acid n and all amino acids C terminal to amino acid n and lacks amino acids N terminal to amino acid n, or corresponding amino acids thereof. In some embodiments, a truncated polypeptide is truncated at the N terminus, at the C terminus, or both the N terminus and the C terminus. A C terminal truncated polypeptide may also be truncated at its N terminus. An N terminal truncated polypeptide may also be truncated at its C terminus. In some embodiments, the RT of the prime editor consists of 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10% of amino acids of a corresponding reference RT. In some embodiments, the prime editor comprises a truncated RT compared to a corresponding reference RT, wherein the truncation is at the N-terminus of the RT. In some embodiments, the prime editor comprises a truncated RT compared to a corresponding reference RT, wherein the truncation is at the C-terminus of RT. In some ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 embodiments, the prime editor comprises a truncated RT compared to a corresponding reference RT, wherein the truncation is within the middle of corresponding reference RT. In some embodiments, the prime editor comprises a truncated RT compared to a corresponding reference RT, wherein the RT domain is truncated at both the N-terminus and the C-terminus. In some embodiments, the prime editor comprises a truncated RT compared to a corresponding reference RT, wherein the RT is truncated at the N-terminus, the C-terminus, and / or the middle of the RT referenced by the corresponding RT. In some embodiments, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550 or more amino acids are truncated at the N-terminus of the RT in a prime editor compared to a corresponding reference RT. In some embodiments, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550 or more amino acids are truncated at the C-terminus of the RT in a prime editor compared a corresponding reference RT. In some embodiments, a reference RT sequence has the sequence of SEQ ID NO: 1. In some embodiments, a reference RT sequence has the sequence of SEQ ID NO: 5. In some embodiments, a prime editor comprises an RT that is a Moloney murine leukemia virus (M-MLV) reverse transcriptase (M-MLV RT). In some embodiments, the M- MLV RT of the prime editor comprises one or more amino acid substitutions, insertions, or deletions compared to a wild-type M-MLV RT, a reference M-MLV RT, or MMLVRTSM. In some embodiments, a prime editor comprises a truncated M-MLV RT compared to a wild-type M-MLV RT or a reference M-MLV RT or MMLVRTSM. In some embodiments, the M-MLV RT of the prime editor consists of 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10% of amino acids of a wild-type M-MLV RT or a reference M-MLV RT or MMLVRTSM. In some embodiments, the M-MLV RT of the prime editor is truncated at the N-terminus compared to a wild-type M-MLV RT or a reference M- MLV RT, or MMLVRT5M. In some embodiments, the M-MLV RT of the prime editor is truncated at the C-terminus compared to a wild-type M-MLV RT or a reference M-MLV RT, or MMLVRTSM. In some embodiments, the M-MLV RT of the prime editor is truncated compared to a wild-type M-MLV RT or a reference M-MLV RT, wherein the truncation is within the middle of the RT referenced by a wild-type M-MLV RT or a reference M-MLV RT, or ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 MMLVRTSM. In some embodiments, the M-MLV RT of the prime editor comprises a truncated M-MLV RT compared to a wild-type M-MLV RT or a reference M-MLV RT„ or MMLVRTSM wherein RT is truncated at both the N-terminus and the C-terminus. In some embodiments, the M-MLV RT of the prime editor comprises a truncated M-MLV RT compared to a wild-type M-MLV RT or a reference M-MLV RT, or MMLVRTSM, wherein the RT is truncated at the N-terminus, the C-terminus, and / or the middle of the RT as reference by a wild- type M-MLVRT or a reference M-MLV RT., or MMLVRTSM. In some embodiments, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, or more amino acids are truncated at the N-terminus of the M-MLV RT in a prime editor compared to a wild-type M-MLV RT or a reference M-MLV RT or MMLVRTSM. In some embodiments, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550 or more amino acids are truncated at the C-terminus of the M-MLV RT in a prime editor compared a wild-type M-MLV RT or a reference M-MLV RT or MMLVRTSM. In some embodiments, a prime editor comprises a reverse transcriptase (RT) that comprises a RNase domain. For example, in some embodiments, the RT of the prime editor is a virus RT domain that comprises a RNase domain. In some embodiments, the RT of the prime editor is a virus RT domain that comprises a RNase H domain. In some embodiments, the RT of the prime editor comprises a RNase H domain having 5′ and / or 3′ ribonuclease activity. In some embodiments, the RT of the prime editor comprises a RNase H domain having 3′ and / or 5′ nuclease activity toward the RNA strand when contacted with a DNA-RNA hybrid double strand. In some embodiments, a prime editor comprises an RT that comprises an engineered RNase domain compared to a corresponding reference RT. In some embodiments, a prime editor comprises a RT that comprises an engineered RNase H domain compared to a corresponding reference RT. In some embodiments, the RT of the prime editor comprises one or more amino acid substitutions, insertions, or deletions in the RNase H domain compared to a corresponding. In some embodiments, the one or more amino acid substitutions, insertions, or deletions in the RNase H domain reduces or abolishes RNase activity of the RNase H domain. In some embodiments, the RT of the prime editor comprises a RNase H domain that has decreased or ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 abolished RNase activity. In some embodiments, the RT of the prime editor comprises an inactivated RNase H domain. In some embodiments, the RT of the prime editor comprises one or more amino acid substitutions in a RNase H domain that decrease or abolish activity of the RNase H domain as compared to a corresponding reference RT. In some embodiments, the RT of the prime editor comprises a truncated RNase H domain compared to a corresponding reference RT. In some embodiments, the truncation in the RNase H domain decreases or abolishes RNase activity of the RNase H domain. In some embodiments, the RT of the prime editor comprises a RNase H domain that consists of 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10% of amino acids of a corresponding wild-type RNase H domain (e.g., a wild-type RNase H domain from a reference M-MLV RT or a wild-type M-MLV RT or MMLVRTSM). In some embodiments, a reference RT sequence has the sequence of SEQ ID NO: 1. In some embodiments, a reference RT sequence has the sequence of SEQ ID NO: 5. In some embodiments, the RT of the prime editor comprises a truncated RNase H domain compared to a corresponding reference RT , wherein the truncation is at the N-terminus of the RNase H domain. In some embodiments, the RT of the prime editor comprises a truncated RNase H domain compared to a corresponding reference RT , wherein the truncation is at the C- terminus of the RNase H domain. In some embodiments, the RT of the prime editor comprises a truncated RNase H domain compared to a corresponding reference RT , wherein the truncation is within the middle of the RNase H domain referenced by the RNase H domain of the corresponding reference RT . In some embodiments, the RT of the prime editor comprises a truncated RNase H domain compared to a corresponding reference RT , wherein the truncated RNase H domain is truncated at both the N-terminus and the C-terminus of the RNase H domain. In some embodiments, the RT of the prime editor comprises a truncated RNase H domain compared to a corresponding reference RT , wherein the truncated RNase H domain is truncated at the N-terminus, the C-terminus, and / or the middle of the RNase H domain referenced by the RNase H domain of the corresponding reference RT . In some embodiments, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550 or more amino acids are truncated at the N- terminus of the RNase H domain of the RT in a prime editor compared to the RNase H domain of a corresponding reference RT . In some embodiments, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550 or more amino acids are truncated at the C-terminus of the RNase H domain of the RT in a prime editor compared to the RNase H domain of a corresponding reference RT . In some embodiments, the RT of the prime editor lacks a RNase H domain. In some embodiments, a reference RT sequence has the sequence of SEQ ID NO: 1. In some embodiments, a reference RT sequence has the sequence of SEQ ID NO: 5. In some embodiments, a prime editor comprises an RT that is a Moloney murine leukemia virus (M-MLV) reverse transcriptase (M-MLV RT) that comprises an RNase H domain. In some embodiments, the M-MLV RT of the prime editor comprises one or more amino acid substitutions, insertions, or deletions in the RNase H domain compared to the RNase H domain of a wild-type M-MLV RT. In some embodiments, the one or more amino acid substitutions, insertions, or deletions in the RNase H domain reduces or abolishes RNase activity of the RNase H domain. In some embodiments, the M-MLV RT of the prime editor comprises a RNase H domain that has decreased or abolished RNase activity compared to a RNase H domain in a wild-type M-MLV RT. In some embodiments, the M-MLV RT of the prime editor comprises an inactivated RNase H domain. In some embodiments, a prime editor comprises a M-MMLV RT comprising one or more of amino acid substitutions P51X, S67, E69X, L139X, T197X, D200X, H204X, F209X, E302X, T306X, F309X, W313X, T330X, L345X, L435X, N454X, D524X, E562X, D583X, H594X, L603X, E607X, or D653X as compared to a reference M-MMLV RT as set forth in SEQ ID NO: 1, where X is any amino acid other than the wild-type amino acid.. In some embodiments, the prime editor comprises a M-MMLV RT comprising one or more of amino acid substitutions P51L, S67K, E69K, L139P, T197A, D200N, H204R, F209N, E302K, E302R, T306K, F309N, W313F, T330P, L345G, L435G, N454K, D524G, E562Q, D583N, H594Q, L603W, E607K, and D653N as compared to a reference M-MMLV RT as set forth in SEQ ID NO: 1. In some embodiments, the prime editor comprises a M-MLV RT comprising one or more amino acid substitutions D200N, T330P, L603W, T306K, and W313F as compared to a reference M- MMLV as set forth in SEQ ID NO: 1. In some embodiments, the prime editor comprises a M- MLV RT comprising amino acid substitutions D200N, T330P, L603W, T306K, and W313F as compared to a reference M-MMLV RT as set forth in SEQ ID NO: 1. In some embodiments, a prime editor comprising a reverse transcriptase harboring the D200N, T330P, L603W, T306K, and W313F as compared to the reference M-MMLV RT set forth in SEQ ID NO: 1, maybe referred to as a “PE2” prime editor, and the corresponding prime ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 editing system a PE2 prime editing system. In some embodiments, a prime editor comprises a M- MMLV RT comprising one or more of amino acid substitutions D200N, T306K, W313F, T330P, L603W, or any combination thereof as compared to the reference M-MMLV RT as set forth in SEQ ID NO: 1, or SEQ ID NO: 623, where X is any amino acid other than the wild-type amino acid. In some embodiments, a prime editor comprises a M-MMLV RT comprising one or more of amino acid substitutions Y134X, Y272X, L435X, D524X, or any combination thereof as compared to the reference M-MMLV RT as set forth in SEQ ID NO: 1, or SEQ ID NO: 623, where X is any amino acid other than the wild-type amino acid. In some embodiments, a prime editor comprises a M-MMLV RT comprising one or more of amino acid substitutions Y134R, Y272R, L435K, D524N, or any combination thereof as compared to the reference M-MMLV RT as set forth in SEQ ID NO: 1, or SEQ ID NO: 623, where X is any amino acid other than the wild-type amino acid. In some embodiments, the MMLVRT variant comprises one or more of D200N, T306K, W313F, T330P, and L603W amino acid substitutions as compared to reference MMLVRT sequence SEQ ID No 1. In some embodiments, the MMLVRT variant comprises D200N, T306K, W313F, T330P, and L603W amino acid substitutions as compared to reference MMLVRT sequence SEQ ID No 1. In some embodiments, the MMLV RT variant comprises one or more of D524N, L435K, Y133R, Y271R amino acid substitution as compared to reference MMLVRT sequence SEQ ID No 1. In some embodiments, the MMLV RT variant has one or more amino acid deletion compared to the reference MMLVRT sequence SEQ ID No 1. Lor example, in some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 504 and 505 as set forth in SEQ ID NO: 1 (such truncation may be referred to herein as a 504X, or G504X truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 478 and 479 as set forth in SEQ ID NO: 1 (a L478X truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus at any amino acid position between positions 478 and 505 as set forth in SEQ ID NO: 1. In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 365 and 366 as set forth in SEQ ID NO: 1 (a P365X truncItion). In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 278 and 279 as set forth in SEQ ID NO: 1 (a R278X truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 328 and 329 as set forth in SEQ ID NO: 1 (a T328X ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 378 and 379 as set forth in SEQ ID NO: 1 (a K478X truncation). In some embodiments, the MMLV RT variant is truncated at the C terminus between positions corresponding to amino acids 428 and 429 as set forth in SEQ ID NO: 1 (a M428X truncation). In some embodiments, the truncated M-MLV RT variants further comprise a D200X, T306X, W313X, and / or T330X amino acid substitution compared to a corresponding reference M-MLV RT as set forth in SEQ ID NO: 1, wherein X is any amino acid other than the original amino acid. In some embodiments, the truncated M-MLV RT variants further comprise a D200N, T306K, W313L, and / or T330P amino acid substitution compared to a corresponding reference M-MLV RT as set forth in SEQ ID NO: 1. In some embodiments, a prime editor polypeptide comprises a DNA polymerase domain (e.g., a MMLV-RT) comprising an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of the amino acid sequences set forth in SEQ ID NOs: 1, 4, 5, 36, 45, 54, 63, or 623. In some embodiments, a prime editor polypeptide comprises a MMLV-RT domain comprising an amino acid sequence SEQ ID NOs: 5. In some embodiments, a prime editor polypeptide comprises a C-terminal truncated MMLV-RT domain having the amino acid sequence of SEQ ID NO: 36. In some embodiments, a M-MLV RT comprises an amino acid sequence that is at least about 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to any one of the sequences set forth in SEQ ID NOs: 1, 4, 5, 36, 45, 54, 63, or 623. In some embodiments, the M-MLV RT comprises an amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the M-MLV RT comprises an amino acid sequence set forth in SEQ ID NO: 623. In some embodiments, the M- MLV RT comprises an amino acid sequence set forth in SEQ ID NO: 623. In some embodiments, the M-MLV RT comprises an amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the M-MLV RT comprises an amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the M-MLV RT comprises an amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the M-MLV RT comprises an amino acid sequence set forth in SEQ ID NO: 45. In some embodiments, the M-MLV RT comprises an amino acid sequence set forth in SEQ ID NO: 54. In some embodiments, the M-MLV RT comprises an amino acid sequence set forth in SEQ ID NO: 63. In some embodiments, a prime editing composition ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 comprises a polynucleotide encoding a DNA polymerase domain that comprises an amino acid sequence that is at least about 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to any one of the sequences set forth in SEQ ID NOs: 1, 4, 5, 36, 45, 54, 63, or 623. In some embodiments, an RT variant may be a functional fragment of a corresponding RT (e.g., a M-MLV RT) that has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or up to 100, or up to 200, or up to 300, or up to 400, or up to 500 or more amino acid changes compared to a corresponding RT, e.g., (e.g., a M-MLV RT). In some embodiments, the RT variant comprises a fragment of a corresponding RT, e.g., a (e.g., a M-MLV RT), such that the fragment is about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 96% identical, about 97% identical, about 98% identical, about 99% identical, about 99.5% identical, or about 99.9% identical to the corresponding fragment of the corresponding RT. In some embodiments, the fragment is 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% identical, 96%, 97%, 98%, 99%, or 99.5% of the amino acid length of a corresponding RT (e.g., a M-MLV RT). In some embodiments, the RT functional fragment is at least 100 amino acids in length. In some embodiments, the fragment is at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, or up to 600 or more amino acids in length. In some embodiments, a prime editor comprises a eukaryotic RT, for example, a yeast, drosophila, rodent, or primate RT. In some embodiments, the prime editor comprises a Group II intron RT, for example, a. Geobacillus stearothermophilus Group II Intron (GsI-IIC) RT or a Eubacterium rectale group II intron (Eu.re.I2) RT. In some embodiments, the prime editor comprises a retron RT. In some embodiments, a M-MLV RT of a prime editor comprises a Y133X amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for Y. In some embodiments, the M- MLV RT of the prime editor comprises a Y133R amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a M-MLV RT of a prime editor comprises a Y271X amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for Y. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 In some embodiments, the M-MLV RT of the prime editor comprises a Y271R amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a M-MLV RT of a prime editor comprises a D524X amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for D. In some embodiments, the M- MLV RT of the prime editor comprises a D524N amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a M-MLV RT of a prime editor comprises a L435X amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for L. In some embodiments, the M- MLV RT of the prime editor comprises a L435K amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a M-MLV RT of a prime editor comprises a Y133X, Y271X, L435X, and / or D524X amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for the original amino acid. In some embodiments, the M-MLV RT of the prime editor comprises a Y133R, Y271R, L435K, and / or D524N amino acid substitution as compared to a reference M- MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a M-MLV RT of a prime editor comprises a Y133X amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for Y. In some embodiments, the M-MLV RT of the prime editor comprises a Y133R amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a M-MLV RT of a prime editor comprises a Y271X amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for Y. In some embodiments, the M-MLV RT of the prime editor comprises a Y271R amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLVRT, wherein the M- MLVRT is truncated at C terminus between positions corresponding to amino acids 478 and 479, 478 and 479, 479 and 480, 480 and 481, 481 and 482, 482 and 483, 483 and 484, 484 and 485, ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 485 and 486, 486 and 487, 487 and 488, 488 and 489, 489 and 490, 490 and 491, 491 and 492, 492 and 493, 493 and 494, 494 and 495, 495 and 496, 496 and 497, 497 and 498, 498 and 499, 499 and 500, 500 and 501, 501 and 502, 502 and 503, 503 and 504, or 504 and 505 as set forth in SEQ ID NO: 1. In some embodiments, a prime editor comprises a truncated M-MLVRT, wherein the M-MLVRT is truncated after any amino acid that is C-terminal to amino acid 504 as set for the in SEQ ID NO: 1. In some embodiments, a prime editor comprises a truncated M- MLVRT, wherein the M-MLVRT is truncated after any amino acid that is C-terminal to amino acid 478 as set for the in SEQ ID NO: 1. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids at positions 505-679 of the M-MLV RT are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1 SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids C terminal to position 504 of the M-MLV RT are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 (G504 truncation). In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids 505-679 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids C-terminal to position 504 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids at positions C terminal to amino acid 365 of the M-MLV RT are deleted as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids C terminal to position 365 of the M-MLV RT are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 (P365 truncation). In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids C terminal to amino acid 365 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids C-terminal to position 365 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein the M-MLV RT domain comprises an amino acid sequence that is truncated at C terminus between positions corresponding to amino acids 504 and 505 as set forth in SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein the M-MLV RT ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 domain comprises an amino acid sequence that is truncated at C terminus between positions corresponding to amino acids 365 and 366 as set forth in SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein the M-MLV RT domain comprises an amino acid sequence that is truncated at C terminus between positions corresponding to amino acids 478 and 479 as set forth in SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein the M-MLV RT domain comprises an amino acid sequence that is truncated at C terminus after an amino acid between L478 and G504 compared to SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein the M-MLV RT domain comprises an amino acid sequence that is truncated at C terminus after amino acid L478 compared to SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein the M-MLV RT domain comprises an amino acid sequence that is truncated at C terminus between positions corresponding to amino acids 428 and 429 as set forth in SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein the M-MLV RT domain comprises an amino acid sequence that is truncated at C terminus between positions corresponding to amino acids 378 and 379 as set forth in SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein the M-MLV RT domain comprises an amino acid sequence that is truncated at C terminus between positions corresponding to amino acids 366 and 367 as set forth in SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein the M-MLV RT domain comprises an amino acid sequence that is truncated at C terminus between positions corresponding to amino acids 328 and 329 as set forth in SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein the M-MLV RT domain comprises an amino acid sequence that is truncated at C terminus between positions corresponding to amino acids 278 and 279 as set forth in SEQ ID NO: 1, 5, or 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids at positions 479-679 of the M-MLV RT are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT of the prime editor comprises a truncated RNase H domain, wherein amino acids C terminal to position 478 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, or SEQ ID NO: 623 (L478 truncation). In some embodiments, the M- MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids 479-679 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 amino acids C-terminal to position 478 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids at positions 429-679 of the M-MLV RT are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids C terminal to position 428 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 (M428 truncation). In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids 429-679 relative to a reference M- MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids C-terminal to position 428 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments a prime editor comprises a truncated M-MLV RT, wherein amino acids at positions 379-679 of the M-MLV RT are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids C terminal to position 378 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 (K378 truncation). In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids 379-679 relative to a reference M- MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids C-terminal to position 378 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids at positions 367-679 of the M-MLV RT are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids C terminal to position 365 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 (P365 truncation). In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids 367-679 relative to a reference M- MLV RT as set forth in SEQ ID NO: 1 SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 acids C-terminal to position 365 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids at positions 328-679 of the M-MLV RT are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids C terminal to position 328 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 (T328 truncation). In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids 328-679 relative to a reference M- MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids C-terminal to position 328 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids at positions 279-679 of the M-MLV RT are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids C terminal to position 278 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 (R278 truncation). In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids 279-679 relative to a reference M- MLV RT as set forth in SEQ ID NO: 1 SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids C-terminal to position 278 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids at positions 1-22 of the M-MLV RT are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a truncated M-MLV RT, wherein amino acids N terminal to position 24 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids 1-22 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the M-MLV RT (e.g., a truncated M-MLV RT) comprises a deletion of amino acids N-terminal to position 24 relative to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 In some embodiments, a prime editor comprises an RT domain having one or more amino acid substitutions and / or one or more amino acid deletions compared a corresponding reference RT or a wild-type RT. In some embodiments, a prime editor comprises a M-MLV RT that has one or more amino acid substitutions and one or more amino acid deletions compared to a wild-type M-MLV RT or a reference RT (e.g., SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623). In some embodiments, the M-MLV RT comprises an amino acid sequence that comprises one or more amino acid substitutions and / or one or more amino acid deletions compared to a reference M-MLV RT set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. Any one of the amino acid truncations, deletions, and substitutions described herein or known in the art can be combined in a prime editor RT, e.g., a M-MLV RT. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133X, Y271X, L435X, and / or D524X amino acid substitution, and wherein amino acids at positions 505-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for the original amino acid. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133R, Y271R, L435K, and / or D524N amino acid substitution, and wherein amino acids at positions 505-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133X, Y271X, L435X, and / or D524X amino acid substitution, and wherein amino acids at positions 479-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for the original amino acid. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133R, Y271R, L435K, and / or D524N amino acid substitution, and wherein amino acids at positions 479-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133X, Y271X, L435X, and / or D524X amino acid substitution, and wherein amino acids at positions 429-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 wherein X is any amino acid except for the original amino acid. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133R, Y271R, L435K, and / or D524N amino acid substitution, and wherein amino acids at positions 429-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133X, Y271X, L435X, and / or D524X amino acid substitution, and wherein amino acids at positions 379-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for the original amino acid. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133R, Y271R, L435K, and / or D524N amino acid substitution, and wherein amino acids at positions 379-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133X, Y271X, L435X, and / or D524X amino acid substitution, and wherein amino acids at positions 367-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for the original amino acid. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133R, Y271R, L435K, and / or D524N amino acid substitution, and wherein amino acids at positions 367-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133X, Y271X, L435X, and / or D524X amino acid substitution, and wherein amino acids at positions 328-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for the original amino acid. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133R, Y271R, L435K, and / or D524N amino acid substitution, and wherein amino acids at positions 328-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133X, Y271X, L435X, and / or D524X amino acid substitution, and wherein amino acids at positions 279-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for the original amino acid. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133R, Y271R, L435K, and / or D524N amino acid substitution, and wherein amino acids at positions 279-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133X, Y271X, L435X, and / or D524X amino acid substitution, and wherein amino acids at positions 1- ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 22 are truncated as compared to a reference M-MLV RT as set forth SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for the original amino acid. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133R, Y271R, L435K, and / or D524N amino acid substitution, and wherein amino acids at positions 1-22 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a L435X amino acid substitution, and wherein amino acids at positions 505-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for L. In some embodiments, a prime editor comprises a M- MLV RT that comprises a L435K amino acid substitution, and wherein amino acids at positions 505-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a L435X amino acid substitution, and wherein amino acids at positions 1-22 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for L. In some embodiments, a prime editor comprises a M- MLV RT that comprises a L435K amino acid substitution, and wherein amino acids at positions 1-22 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT, wherein the M-MLV RT comprises a L435X amino acid substitution, and wherein amino acids at positions 1-22 and amino acids at positions 505-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for L. In some embodiments, a prime editor comprises a M-MLV RT, wherein the M-MLV RT comprises a L435K amino acid substitution, and wherein amino acids at positions 1-22 and amino acids at positions 505-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133X amino acid substitution, and wherein amino acids at positions 367-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for Y. In some embodiments, a prime editor comprises a M- MLV RT that comprises a Y133R amino acid substitution, and wherein amino acids at positions ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 367-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT comprises a Y271X amino acid substitution, and wherein amino acids at positions 367-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for Y. In some embodiments, a prime editor comprises a M- MLV RT that comprises a Y271R amino acid substitution, and wherein amino acids at positions 367-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133X and a Y271X amino acid substitution, and wherein amino acids at positions 367-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for Y. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133R and a Y271R amino acid substitution, and wherein amino acids at positions 367-679 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, a prime editor comprises a M-MLV RT that comprises a Y133R, Y271R, L435K, and / or D524N amino acid substitution, and wherein amino acids at positions 1- 22 are truncated as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid except for the original amino acid. In some embodiments, a M-MLV RT comprises a deletion of amino acids C-terminal to position P365, a Y133X amino acid substitution, and / or a Y271X amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, wherein X is any amino acid other than the original. In some embodiments, a M-MLV RT comprises a deletion of amino acids 366-679, a Y133X amino acid substitution, and / or a Y271X amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 wherein X is any amino acid other than the original. In some embodiments, a M-MLV RT comprises a deletion of amino acids C-terminal to position P365, a Y133R amino acid substitution, and / or a Y271R amino acid substitution as compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 wherein X is any amino acid other than the original. In some embodiments, a M-MLV RT comprises a deletion of amino acids C-terminal to position G504, and / or a L435X amino acid substitution compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 wherein X is any amino acid other than the original. In some embodiments, ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 a M-MLV RT comprises a deletion of amino acids residues 505-679, and / or a L435X amino acid substitution compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 wherein X is any amino acid other than the original. In some embodiments, the M-MLV RT comprises a deletion of amino acids C-terminal to position G504, a deletion of amino acid residues 1-22, and / or a L435X amino acid substitution compared to a reference M- MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 wherein X is any amino acid other than the original. In some embodiments, a M-MLV RT comprises a deletion of amino acids residues 505-679, a deletion of N-terminus amino acid residues 1-22, and / or a L435X amino acid substitution compared to a reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623 wherein X is any amino acid other than the original. In some embodiments, a DNA polymerase domain, e.g., a reverse transcriptase domain, for example a M-MLV RT can comprise one or more mutations (e.g., one or more amino acid substitution, amino acid deletion, and / or amino acid insertion). Mutant reverse transcriptase may, for example, be obtained by mutating the gene or genes encoding the reverse transcriptase of interest by site-directed or random mutagenesis. In some embodiments, the mutation increases the efficiency of the DNA polymerase domain, e.g., a reverse transcriptase domain, e.g., by increasing editing efficiency, by increasing reverse transcriptase activity, and / or by increasing stability (e.g., thermostability). In some embodiments, a prime editor comprising the DNA polymerase domain comprising one or more mutations disclosed herein, can exhibit at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% increase in editing efficiency compared to a prime editor comprising a corresponding non-mutated DNA polymerase. In some embodiments, a DNA polymerase domain that is a M-MLV RT comprises one or more mutations selected from the group consisting of a P51X, a S67X, an E69X, an L139X, a T197X, a D200X, a H204X, a F209X, an E302X, a T306X, a F309X , a W313X, a T330X, an L435X, a P448X, a D449X, an N454X, a D524X, an E562X, a D583X, an H594X, an L603X, an E607X, a G615X, an H634X, a G637X, an H638X, a D653X, or an L671X mutation relative to the reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623, where X is any amino acid other than the wild-type amino acid. In some embodiments, a DNA polymerase domain, for example, a M-MLV RT can comprise one or more amino acid substitution selected from the group consisting of a P51L, a S67K, an E69K, an L139P, a T197A, a D200N, a H204R, a F209N, an E302K, a T306K, a F309N, a W313F, a T330P, an L435G, a P448A, a D449G, an N454K, a D524G, an E562Q, a D583N, an H594Q, an ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 L603W, an E607K, a G615, an H634Y, a G637R, an H638G, a D653N, or an L671P relative to the reference M-MLV RT as set forth in SEQ ID NO: 1, SEQ ID NO: 5, or SEQ ID NO: 623. In some embodiments, the engineered RT may have improved stability, reverse transcription activity over a naturally occurring RT or RT domain. In some embodiments, the engineered RT may have improved features over a naturally occurring RT, for example, improved thermostability, reverse transcription efficiency, or target fidelity. In some embodiments, a prime editor comprising the engineered RT has improved prime editing efficiency over a prime editor having a reference naturally occurring RT. A prime editor comprising any of the engineered RTs described herein can have altered functional features compared to a reference prime editor having the corresponding reference RT (e.g., a reference RT such as set forth in SEQ ID NO: 1). In some embodiments, a prime editor comprising an engineered RT described herein has improved stability compared to a reference prime editor having the corresponding reference RT (e.g., a reference RT such as set forth in SEQ ID NO: 1). In some embodiments, a prime editor comprising an engineered RT described herein has improved thermostability compared to a reference prime editor having the corresponding reference RT (e.g., a reference RT such as set forth in SEQ ID NO: 1). In some embodiments, a prime editor comprising an engineered RT described herein has improved solubility or reduced aggregation compared to a reference prime editor having the corresponding reference RT (e.g., a reference RT such as set forth in SEQ ID NO: 1). In some embodiments, the prime editor comprising the engineered RT has improved prime editing efficiency compared to a reference prime editor having the corresponding reference RT (e.g., a reference RT such as set forth in SEQ ID NO: 1). In some embodiments, the prime editor comprising the engineered RT has increased prime editing efficiency by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, at least 200%, at least 210%, at least 220%, at least 230%, at least 240%, at least 250%, at least 260%, at least 270%, at least 280%, at least 290%, at least 300% or more compared to the reference prime editor having the corresponding reference RT (e.g., or a reference RT as set forth in SEQ ID NO: 1). In some embodiments, the prime editor comprising the engineered RT has increased prime editing efficiency by at least 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 1.6 fold, 1.7 fold, 1.8 fold, 1.9 fold, 2 fold, 2.1 fold, 2.2 fold, 2.3 fold, 2.4 fold, 2.5 fold, 2.6 fold, 2.7 fold, 2.8 fold, 2.9 fold, 3 fold, 3.1 fold, 3.2 fold, 3.3 fold, 3.4 fold, 3.5 fold, 3.6 fold, 3.7 fold, 3.8 fold, 3.9 fold, 4 fold, 4.1 ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 fold, 4.2 fold, 4.3 fold, 4.4 fold, 4.5 fold, 4.6 fold, 4.7 fold, 4.8 fold, 4.9 fold, 5 fold or more compared to the reference prime editor having the corresponding reference RT (e.g., a reference RT such as set forth in SEQ ID NO: 1). Programmable DNA Binding Domain In some embodiments, a prime editor comprises a polypeptide domain having DNA binding activity (e.g., a DNA binding domain). In some embodiments, a prime editor comprises a polypeptide domain having DNA binding activity (e.g., a DNA binding domain). In some embodiments, a prime editor comprises a DNA binding domain. In some embodiments, the DNA binding domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to any one of amino acid sequences set forth in SEQ ID NOs: 2, 6, 7, 596-613. In some embodiments, the DNA-binding domain comprises an amino acid sequence that has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 differences e.g., mutations e.g., deletions or substitutions compared to any one of the amino acid sequences set forth in SEQ ID NOs: 2, 6, 7, 596-613. In some embodiments, the DNA binding domain comprises an amino acid sequence that lacks a N-terminus methionine compared to a corresponding DNA binding domain (e.g., a DNA binding domain set forth in any one of SEQ ID NOs: 2, 6, 7, 596-613. In some embodiments, the amino acid sequence of a DNA binding domain can be N- terminally modified by one or more processing enzymes, e.g., by Methionine aminopeptidases (MAP). In some embodiments, the DNA binding domain comprises a nuclease activity, for example, an RNA-guided DNA endonuclease activity of a Cas polypeptide. In some embodiments, the DNA binding domain comprises a nuclease domain or nuclease activity. In some embodiments, the DNA binding domain comprises a nickase, or a fully active nuclease. As used herein, the term “nickase” refers to a nuclease capable of cleaving only one strand of a double -stranded DNA target. In some embodiments, the DNA binding domain is an inactive nuclease. In some embodiments, the DNA-binding domain of a prime editor is a programmable DNA binding domain. A programmable DNA binding domain refers to a protein domain that is designed to bind a specific nucleic acid sequence, e.g., a target DNA or a target RNA. In some embodiments, the DNA-binding domain is a polynucleotide programmable DNA-binding domain that can associate with a guide polynucleotide (e.g., a PEgRNA) that guides the DNA- ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 binding domain to a specific DNA sequence, e.g., a search target sequence in a double stranded target DNA (e.g., the target gene). In some embodiments, the DNA-binding domain comprises a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Associated (Cas) protein. A Cas protein may comprise any Cas protein described herein or a functional fragment or functional variant thereof. In some embodiments, a DNA-binding domain may also comprise a zinc-finger protein domain. In other cases, a DNA-binding domain comprises a transcription activator-like effector domain (TALE). In some embodiments, the DNA-binding domain comprises a DNA nuclease. For example, the DNA-binding domain of a prime editor may comprise an RNA-guided DNA endonuclease, e.g., a Cas protein. In some embodiments, the DNA-binding domain comprises a zinc finger nuclease (ZFN) or a transcription activator like effector domain nuclease (TALEN), where one or more zinc finger motifs or TALE motifs are associated with one or more nucleases, e.g., a Fok I nuclease domain. In some embodiments, the DNA-binding domain comprise a nuclease activity. In some embodiments, the DNA-binding domain of a prime editor comprises an endonuclease domain having single strand DNA cleavage activity. For example, the endonuclease domain may comprise a FokI nuclease domain. In some embodiments, the DNA-binding domain of a prime editor comprises a nuclease having full nuclease activity. In some embodiments, the DNA- binding domain of a prime editor comprises a nuclease having modified or reduced nuclease activity as compared to a wild-type endonuclease domain. For example, the endonuclease domain may comprise one or more amino acid substitutions as compared to a wild-type endonuclease domain. In some embodiments, the DNA-binding domain of a prime editor has nickase activity. In some embodiments, the DNA-binding domain of a prime editor comprises a Cas protein domain that is a nickase. In some embodiments, compared to a wild-type Cas protein, the Cas nickase comprises one or more amino acid substitutions in a nuclease domain that reduces or abolishes its double strand nuclease activity but retains DNA binding activity. In some embodiments, the Cas nickase comprises an amino acid substitution in a HNH domain. In some embodiments, the Cas nickase comprises an amino acid substitution in a RuvC domain. In some embodiments, the DNA-binding domain comprises a CRISPR associated protein (Cas protein) domain. A Cas protein may be a Class 1 or a Class 2 Cas protein. A Cas protein can be a type I, type II, type III, type IV, type V Cas protein, or a type VI Cas protein. Non- limiting examples of Cas proteins include Cas9, Cas 12a (Cpfl), Cas12e (CasX), Cas 12d (CasY), Cas12bl (C2cl), Cas12b2, Cas12c (C2c3), C2c4, C2c8, C2c5, C2cl0, C2c9, Cas14a, Cas14b, Cas14c, Cas14d, Cas14e, Cas14f, Cas14g, Cas14h, Cas14u, Cns2, Cas F, and homologs, functional fragments, or modified versions thereof. A Cas protein can be a chimeric Cas protein ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 that is fused to other proteins or polypeptides. A Cas protein can be a chimera of various Cas proteins, for example, comprising domains of Cas proteins from different organisms. A Cas protein, e.g., Cas9, can be from any suitable organism. In some aspects, the organism is Streptococcus pyogenes ( S . pyogenes). In some aspects, the organism is Staphylococcus aureus (S. aureus). In some aspects, the organism is Streptococcus thermophilus (S. thermophilus) . In some embodiments, the organism is Staphylococcus lugdunensis. A Cas protein, e.g., Cas9, can be a wild-type or a modified form of a Cas protein. A Cas protein, e.g., Cas9, can be a nuclease active variant, nuclease inactive variant, a nickase, or a functional variant or functional fragment of a wild-type Cas protein. In some embodiments, a Cas protein, e.g., Cas9, can comprise an amino acid change such as a deletion, insertion, substitution, fusion, chimera, or any combination thereof relative to a wild-type version of the Cas protein. In some embodiments, a Cas protein can be a polypeptide with at least about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity or sequence similarity to a wild type exemplary Cas protein. A Cas protein, e.g., Cas9, may comprise one or more domains. Non-limiting examples of Cas domains include, guide nucleic acid recognition and / or binding domain, nuclease domains (e.g., Dnase or RNase domains, RuvC, HNH), DNA binding domain, RNA binding domain, helicase domains, protein-protein interaction domains, and dimerization domains. In various embodiments, a Cas protein comprises a guide nucleic acid recognition and / or binding domain can interact with a guide nucleic acid, and one or more nuclease domains that comprise catalytic activity for nucleic acid cleavage. In some embodiments, a Cas protein, e.g., Cas9, comprises one or more nuclease domains. A Cas protein can comprise an amino acid sequence having at least about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a nuclease domain (e.g., RuvC domain, HNH domain) of a wild-type Cas protein. In some embodiments, a Cas protein comprises a single nuclease domain. For example, a Cpfl may comprise a RuvC domain but lacks HNH domain. In some embodiments, a Cas protein comprises two nuclease domains, e.g., a Cas9 protein can comprise an HNH nuclease domain and a RuvC nuclease domain. In some embodiments, a prime editor comprises a Cas protein, e.g., Cas9, wherein all nuclease domains of the Cas protein are active. In some embodiments, a prime editor comprises a Cas protein having one or more inactive nuclease domains. One or a plurality of the nuclease domains (e.g., RuvC, HNH) of a Cas protein can be deleted or mutated so that they are no longer functional or comprise reduced nuclease activity. In some embodiments, a Cas protein, e.g., ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 Cas9, comprising mutations in a nuclease domain has reduced (e.g., nickase) or abolished nuclease activity while maintaining its ability to target a nucleic acid locus at a search target sequence when complexed with a guide nucleic acid, e.g., a PEgRNA. In some embodiments, a prime editor comprises a Cas nickase that can bind to the double stranded target DNA in a sequence-specific manner and generate a single-strand break at a protospacer within double-stranded DNA in the double stranded target DNA, but not a double- strand break. For example, the Cas nickase can cleave the edit strand or the non-edit strand of the double stranded target DNA but may not cleave both. In some embodiments, a prime editor comprises a Cas nickase comprising two nuclease domains (e.g., Cas9), with one of the two nuclease domains modified to lack catalytic activity or deleted. In some embodiments, the Cas nickase of a prime editor comprises a nuclease inactive RuvC domain and a nuclease active HNH domain. In some embodiments, the Cas nickase of a prime editor comprises a nuclease inactive HNH domain and a nuclease active RuvC domain. In some embodiments, a prime editor comprises a Cas9 nickase having an amino acid substitution in the RuvC domain. In some embodiments, the Cas9 nickase comprises a D10X amino acid substitution compared to a wild- type S. pyogenes Cas9, wherein X is any amino acid other than D. In some embodiments, a prime editor comprises a Cas9 nickase having an amino acid substitution in the HNH domain. In some embodiments, the Cas9 nickase comprises a H840X amino acid substitution compared to a wild-type S. pyogenes Cas9, wherein X is any amino acid other than H. In some embodiments, a prime editor comprises a Cas protein that can bind to the double stranded target DNA in a sequence-specific manner but lacks or has abolished nuclease activity and may not cleave either strand of a double stranded DNA in a double stranded target DNA. Abolished activity or lacking activity can refer to an enzymatic activity less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% activity compared to a wild-type exemplary activity (e.g., wild-type Cas9 nuclease activity). In some embodiments, a Cas protein of a prime editor completely lacks nuclease activity. A nuclease, e.g., Cas9, that lacks nuclease activity may be referred to as nuclease inactive or “nuclease dead” (abbreviated by “d”). A nuclease dead Cas protein (e.g., dCas, dCas9) can bind to a target polynucleotide but may not cleave the target polynucleotide. In some aspects, a dead Cas protein is a dead Cas9 protein. In some embodiments, a prime editor comprises a nuclease dead Cas protein wherein all of the nuclease domains (e.g., both RuvC and HNH nuclease domains in a Cas9 protein; RuvC nuclease domain in a Cpfl protein) are mutated to lack catalytic activity or are deleted. ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 A Cas protein can be modified. A Cas protein, e.g., Cas9, can be modified to increase or decrease nucleic acid binding affinity, nucleic acid binding specificity, and / or enzymatic activity. Cas proteins can also be modified to change any other activity or property of the protein, such as stability. For example, one or more nuclease domains of the Cas protein can be modified, deleted, or inactivated, or a Cas protein can be truncated to remove domains that are not essential for the function of the protein or to optimize (e.g., enhance or reduce) the activity of the Cas protein. A Cas protein can be a fusion protein. For example, a Cas protein can be fused to a cleavage domain, an epigenetic modification domain, a transcriptional regulation domain, or a polymerase domain. A Cas protein can also be fused to a heterologous polypeptide providing increased or decreased stability. The fused domain or heterologous polypeptide can be located at the N-terminus, the C-terminus, or internally within the Cas protein. A Cas protein may be provided in any form. For example, a Cas protein may be provided in the form of a protein, such as a Cas protein alone or complexed with a guide nucleic acid. A Cas protein may be provided in the form of a nucleic acid encoding the Cas protein, such as an RNA (e.g., messenger RNA (mRNA)) or DNA. The nucleic acid encoding the Cas protein may be codon optimized for efficient translation into protein in a particular cell or organism. Nucleic acids encoding Cas proteins may be stably integrated in the genome of the cell. Nucleic acids encoding Cas proteins may be operably linked to a promoter active in the cell. Nucleic acids encoding Cas proteins may be operably linked to a promoter in an expression construct. Expression constructs may include any nucleic acid constructs capable of directing expression of a gene or other nucleic acid sequence of interest (e.g., a Cas gene) and which may transfer such a nucleic acid sequence of interest to a target cell. In some embodiments, a Cas protein may comprise a modified form of a wild type Cas protein. In some embodiments, the modified form of the wild type Cas protein may comprise one or more mutations (e.g., amino acid deletion, insertion, and / or substitution) that reduces the nucleic acid-cleaving activity of the Cas protein. For example, the modified form of the Cas protein may have less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or less than 1% of the nucleic acid-cleaving activity compared to the corresponding protein (e.g., Cas9 from S. pyogenes). In some embodiments, the modified form of Cas protein may have no substantial nucleic acid-cleaving activity. When a Cas protein is a modified form that has no substantial nucleic acid-cleaving activity, it may be referred to as enzymatically inactive and / or “dead” (abbreviated by “d”). A dead Cas protein (e.g., dCas, dCas9) may bind to a target polynucleotide ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 but may not cleave the target polynucleotide. In some embodiments, a dead Cas protein is a dead Cas9 protein. Enzymatically inactive can refer to a polypeptide that can bind to a nucleic acid sequence in a polynucleotide in a sequence-specific manner but may not cleave a target polynucleotide. An enzymatically inactive site-directed polypeptide may comprise an enzymatically inactive domain (e.g., nuclease domain). Enzymatically inactive can refer to no activity. Enzymatically inactive may refer to substantially no activity. Enzymatically inactive can refer to essentially no activity. Enzymatically inactive can refer to an activity less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% activity compared to a corresponding wild-type exemplary activity (e.g., nucleic acid cleaving activity, wild-type Cas9 activity). In some embodiments, one or a plurality of the nuclease domains (e.g., RuvC, HNH) of a Cas protein may be deleted or mutated so that they are no longer functional or comprise reduced nuclease activity. For example, in a Cas protein comprising at least two nuclease domains (e.g., Cas9), if one of the nuclease domains is deleted or mutated, the resulting Cas protein, known as a nickase, may generate a single-strand break at a CRISPR RNA (crRNA) recognition sequence within a double-stranded DNA but not a double-strand break. Such a nickase can cleave the complementary strand or the non-complementary strand but may not cleave both. If all of the nuclease domains of a Cas protein (e.g., both RuvC and HNH nuclease domains in a...

Claims

ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 CLAIMS What is claimed:

1. A method for hematopoietic stem cell transplantation in a subject, the method comprising: (a) contacting an isolated hematopoietic stem cell or progenitor thereof with a prime editor guide polynucleotide and a prime editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, or a polynucleotide encoding the prime editor, wherein the prime editor guide polynucleotide targets a nucleic acid molecule encoding a CD117 polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, thereby generating an edited cell; (b) administering the edited cell to the subject; and (c) administering to the subject an antibody or antigen binding fragment thereof, wherein the antibody is selected from the group consisting of ABTx135, ABTx052, ABTx196, ABTx198, ABTx202, ABTx203, ABTx205, ABTx206, ABTx248, ABTx250, ABTx251, ABTx253, ABTx254, ABTx255, ABTx256, ABTx265, ABTx268, ABTx270, ABTx271, ABTx272, ABTx273, ABTx274, ABTx307, ABTx308, ABTx309, and ABTx313.

2. A method for hematopoietic stem cell transplantation in a subject, the method comprising: (a) contacting an isolated hematopoietic stem cell or progenitor thereof with a prime editor guide polynucleotide and a prime editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, or a polynucleotide encoding the prime editor, wherein the prime editor guide polynucleotide targets a nucleic acid molecule encoding a CD117 polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, thereby i) introducing an intended nucleotide edit in a codon encoding a tyrosine at amino acid position 259, wherein the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 259results in the codon expressing a cytosine, or in identical edits at corresponding positions in another CD117 polypeptide, and / or ii) introducing an intended nucleotide edit in a codon encoding an asparagine at amino acid position 260, wherein the intended nucleotide edit in the codon encoding theATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 asparagine at amino acid position 260 results in the codon expressing an aspartate, or in identical edits at corresponding positions in another CD117 polypeptide, and generating an edited cell; (b) administering the edited cell to the subject; and (c) administering to the subject an antibody or antigen binding fragment thereof, antibody drug conjugate, or a chimeric antigen receptor T (CAR-T) cell, each of which selectively binds a wild type CD117 polypeptide.

3. The method of claim 1 or claim 2, wherein the DNA polymerase domain is a reverse transcriptase.

4. The method of claim 3, wherein the reverse transcriptase is a Moloney murine leukemia virus reverse transcriptase.

5. The method of claim 1 or claim 2, wherein the napDNAbp domain is a Cas9.

6. The method of claim 5, wherein the Cas9 is a Cas9 nickase.

7. The method of claim 5 or claim 6, wherein the Cas9 is a Streptococcus pyogenes Cas9, a P. lavamentivorans Cas9, a C. diphtheriae Cas9, an N. cinerea Cas9, a S. aureus Cas9, a staphylococcus lugdunensis Cas9, or an A. lari Cas9.

8. The method of claim 1 or claim 2, wherein the prime editor comprises an amino acid sequence having at least about 85% identity to the following sequence: MKRTADGSEFESPKKKRKVDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKN LIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEED KKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDL NPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLF GNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILL SDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGG ASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFY PFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIER MTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLT LTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 GFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKV MGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLY YLQNGRDMYVDQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKK MKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTK YDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLES EFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETG EIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGF DSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKL PKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQH KHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKY FDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGDSGGSEAAAKEAAAKEAAAKEAA AKSGGSTLNIEDEYRLHETSKEPDVSLGSTWLSDFPQAWAETGGMGLAVRQAPLIIPLKATSTP VSIKQYPMSQEARLGIKPHIQRLLDQGILVPCQSPWNTPLLPVKKPGTNDYRPVQDLREVNKRV EDIHPTVPNPYNLLSGLPPSHQWYTVLDLKDAFFCLRLHPTSQPLFAFEWRDPEMGISGQLTWT RLPQGFKNSPTLFNEALHRDLADFRIQHPDLILLQYVDDLLLAATSELDCQQGTRALLQTLGNL GYRASAKKAQICQKQVKYLGYLLKEGQRWLTEARKETVMGQPTPKTPRQLREFLGKAGFCRLFI PGFAEMAAPLYPLTKPGTLFNWGPDQQKAYQEIKQALLTAPALGLPDLTKPFELFVDEKQGYAK GVLTQKLGPWRRPVAYLSKKLDPVAAGWPPCLRMVAAIAVLTKDAGKLTMGQPLVILAPHAVEA LVKQPPDRWLSNARMTHYQALLLDTDRVQFGPVVALNPATLLPLPEEGLQHNCLDILAEAHGGG SKRTADGSEFEPKKKRKV (SEQ ID NO: 1065).

9. The method of claim 1 or claim 2, wherein the prime editor guide polynucleotide comprises a spacer comprising the following nucleotide sequence:AAACCAGCAGACUAAACUAC (SEQ ID NO: 1049).

10. The method of claim 1 or claim 2, wherein the prime editor guide polynucleotide comprises a scaffold comprising the following nucleotide sequence: GUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCA CCGAGUCGGUGC (SEQ ID NO: 558).

11. The method of claim 1 or claim 2, wherein the prime editor guide polynucleotide comprises a sequence selected from the group consisting of: AUUACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1050); UAUUACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1051);ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 UAUCACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1052); and UAUCACAUUUCUCCUGUAGUUUAGUCUG (SEQ ID NO: 1053).

12. The method of claim 1 or claim 2, wherein the prime editor guide polynucleotide comprises a nucleotide sequence selected from the group consisting of: gRNA 7206 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUmU*mU*mU*U (SEQ ID NO: 1057); gRNA7207 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUGmU*mU*mU*U (SEQ ID NO: 935); gRNA 7209 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1058); gRNA7210 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 936); gRNA 7248 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1059); gRNA7249 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 937); and gRNA7260 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCCUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 938);ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′- O-methyl nucleotide alteration.

13. The method of claim 1 or claim 2 further comprising administering to the cell a nicking guide RNA.

14. The method of claim 13, wherein the nicking guide RNA comprises a spacer comprising a nucleotide sequence selected from the group consisting of: UAGUCUGCUGGUUUCAGAAA (SEQ ID NO: 1062); and UCUCCUGUAGUUUAGUCUGC (SEQ ID NO: 1063).

15. The method of claim 13, wherein the nicking guide RNA comprises a nucleotide sequence selected from the group consisting of: ngRNA 7195 mU*mA*mG*UCUGCUGGUUUCAGAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1060); and ngRNA 7196 mU*mC*mU*CCUGUAGUUUAGUCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1061); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O- methyl nucleotide alteration.

16. The method of claim 1 or claim 2 further comprising altering a protospacer adjacent motif capable of being bound by the napDNAbp.

17. The method of claim 1 or claim 2, wherein the subject has a hemoglobinopathy selected from the group consisting of sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome.

18. The method of claim 1 or claim 2, further comprising contacting the hematopoietic stem cell or progenitor thereof with a prime editor guide polynucleotide that targets a nucleic acid molecule encoding a beta globin (HBB) polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the HBBATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 polypeptide, thereby introducing an amino acid alteration from a valine to a glutamate at position 6 of the HBB polypeptide.

19. The method of claim 1 or claim 2, wherein the hematopoietic stem cell or progenitor thereof is autologous or allogeneic to the subject.

20. The method of claim 1 or claim 2, wherein the subject is a mammal.

21. A method for treating a hemoglobinopathy in a subject, the method comprising: (a) contacting an isolated hematopoietic stem cell or progenitor thereof with two or more prime editor guide polynucleotides and a prime editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, or a polynucleotide encoding the prime editor, wherein one prime editor guide polynucleotide targets a nucleic acid molecule encoding a CD117 polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, and another prime editor guide polynucleotide that targets a nucleic acid molecule encoding a beta globin (HBB) polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the HBB polypeptide, thereby generating an edited cell; (b) administering the edited cell to the subject; and (c) administering to the subject an antibody or antigen binding fragment thereof, wherein the antibody is selected from the group consisting of ABTx135, ABTx052, ABTx196, ABTx198, ABTx202, ABTx203, ABTx205, ABTx206, ABTx248, ABTx250, ABTx251, ABTx253, ABTx254, ABTx255, ABTx256, ABTx265, ABTx268, ABTx270, ABTx271, ABTx272, ABTx273, ABTx274, ABTx307, ABTx308, ABTx309, and ABTx313.

22. A method for treating a hemoglobinopathy in a subject, the method comprising: (a) contacting an isolated hematopoietic stem cell or progenitor thereof with two or more prime editor guide polynucleotides and a prime editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, or a polynucleotide encoding the prime editor, wherein 1) one prime editor guide polynucleotide targets a nucleic acid molecule encoding a CD117 polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, therebyATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 i) introducing an intended nucleotide edit in a codon encoding a tyrosine at amino acid position 259, wherein the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 259 results in the codon expressing a cytosine, or results in an identical edit at corresponding positions in another CD117 polypeptide, and / or ii) introducing intended nucleotide edit in a codon encoding an asparagine at amino acid position 260, wherein intended nucleotide edit in the codon encoding the tyrosine at amino acid position 260 results in the codon expressing an aspartate, or results in identical edits at corresponding positions in another CD117 polypeptide; and 2) another prime editor guide polynucleotide targets a nucleic acid molecule encoding a beta globin (HBB) polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the HBB polypeptide, thereby introducing an amino acid alteration from a valine to a glutamate at position 6 of the HBB polypeptide, thereby generating an edited cell; (b) administering the edited cell to the subject; and (c) administering to the subject an antibody or antigen binding fragment thereof, antibody drug conjugate, or a chimeric antigen receptor T (CAR-T) cell, each of which selectively binds a wild type CD117 polypeptide.

23. The method of claim 21 or claim 22, wherein the DNA polymerase domain is a reverse transcriptase.

24. The method of claim 23, wherein the reverse transcriptase is a Moloney murine leukemia virus reverse transcriptase.

25. The method of claim 21 or claim 21, wherein the napDNAbp domain is a Cas9.

26. The method of claim 25, wherein the Cas9 is a Cas9 nickase.

27. The method of claim 25 or claim 26, wherein the Cas9 is a Streptococcus pyogenes Cas9, a P. lavamentivorans Cas9, a C. diphtheriae Cas9, an N. cinerea Cas9, a S. aureus Cas9, a staphylococcus lugdunensis Cas9, or an A. lari Cas9.

28. The method of claim 21 or claim 22, wherein the prime editor comprises an amino acid sequence having at least about 85% identity to the following sequence:ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 MKRTADGSEFESPKKKRKVDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKN LIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEED KKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDL NPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLF GNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILL SDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGG ASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFY PFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIER MTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLT LTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSD GFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKV MGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLY YLQNGRDMYVDQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKK MKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTK YDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLES EFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETG EIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGF DSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKL PKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQH KHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKY FDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGDSGGSEAAAKEAAAKEAAAKEAA AKSGGSTLNIEDEYRLHETSKEPDVSLGSTWLSDFPQAWAETGGMGLAVRQAPLIIPLKATSTP VSIKQYPMSQEARLGIKPHIQRLLDQGILVPCQSPWNTPLLPVKKPGTNDYRPVQDLREVNKRV EDIHPTVPNPYNLLSGLPPSHQWYTVLDLKDAFFCLRLHPTSQPLFAFEWRDPEMGISGQLTWT RLPQGFKNSPTLFNEALHRDLADFRIQHPDLILLQYVDDLLLAATSELDCQQGTRALLQTLGNL GYRASAKKAQICQKQVKYLGYLLKEGQRWLTEARKETVMGQPTPKTPRQLREFLGKAGFCRLFI PGFAEMAAPLYPLTKPGTLFNWGPDQQKAYQEIKQALLTAPALGLPDLTKPFELFVDEKQGYAK GVLTQKLGPWRRPVAYLSKKLDPVAAGWPPCLRMVAAIAVLTKDAGKLTMGQPLVILAPHAVEA LVKQPPDRWLSNARMTHYQALLLDTDRVQFGPVVALNPATLLPLPEEGLQHNCLDILAEAHGGG SKRTADGSEFEPKKKRKV (SEQ ID NO: 1065).

29. The method of claim 21 or claim 22, wherein the prime editor guide polynucleotide comprises a spacer comprising the following nucleotide sequence:AAACCAGCAGACUAAACUAC (SEQ ID NO: 1049).ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 30. The method of claim 21 or claim 22, wherein the prime editor guide polynucleotide comprises a scaffold comprising the following nucleotide sequence: GUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCA CCGAGUCGGUGC (SEQ ID NO: 558).

31. The method of claim 21 or claim 22, wherein the prime editor guide polynucleotide comprises a sequence selected from the group consisting of: AUUACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1050); UAUUACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1051); UAUCACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1052); and UAUCACAUUUCUCCUGUAGUUUAGUCUG (SEQ ID NO: 1053).

32. The method of claim 21 or claim 22, wherein the prime editor guide polynucleotide comprises a nucleotide sequence selected from the group consisting of: gRNA 7206 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUmU*mU*mU*U (SEQ ID NO: 1057); gRNA7207 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUGmU*mU*mU*U (SEQ ID NO: 935); gRNA 7209 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1058); gRNA7210 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 936); gRNA 7248ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1059); gRNA7249 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 937); and gRNA7260 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCCUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 938); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′- O-methyl nucleotide alteration.

33. The method of claim 21 or claim 22 further comprising administering to the cell a nicking guide RNA.

34. The method of claim 33, wherein the nicking guide RNA comprises a spacer comprising a nucleotide sequence selected from the group consisting of: UAGUCUGCUGGUUUCAGAAA (SEQ ID NO: 1062); and UCUCCUGUAGUUUAGUCUGC (SEQ ID NO: 1063).

35. The method of claim 33, wherein the nicking guide RNA comprises a nucleotide sequence selected from the group consisting of: ngRNA 7195 mU*mA*mG*UCUGCUGGUUUCAGAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1060); and ngRNA 7196 mU*mC*mU*CCUGUAGUUUAGUCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1061); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O- methyl nucleotide alteration.ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 36. The method of claim 21 or claim 22 further comprising altering a protospacer adjacent motif capable of being bound by the napDNAbp.

37. The method of claim 20 or claim 21, wherein the hemoglobinopathy is selected from the group consisting of sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome.

38. The method of claim 21 or claim 22, further comprising contacting the hematopoietic stem cell or progenitor thereof with a prime editor guide polynucleotide that targets a nucleic acid molecule encoding a beta globin (HBB) polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the HBB polypeptide, thereby introducing an amino acid alteration from a valine to a glutamate at position 6 of the HBB polypeptide.

39. The method of claim 21 or claim 22, wherein the hematopoietic stem cell or progenitor thereof is autologous or allogeneic to the subject.

40. The method of claim 21 or claim 22, wherein the subject is a mammal.

41. A method of altering a nucleobase of a CD117 polynucleotide, the method comprising: contacting the CD117 polynucleotide with a prime editor polypeptide comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, and a prime editor guide polynucleotide that targets a nucleic acid molecule encoding a CD117 polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, thereby i) introducing an intended nucleotide edit in a codon encoding a tyrosine at amino acid position 259, wherein the intended nucleotide edit in in the codon encoding the tyrosine at amino acid position 259 results in the codon expressing a cytosine, or results in identical edits at corresponding positions in another CD117 polypeptide, and / or ii) introducing an intended nucleotide edit in a codon encoding an asparagine at amino acid position 260, wherein the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 260 results in the codon expressing an aspartate, or corresponding positions in another CD117 polypeptide; andATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 and wherein the prime editor guide polynucleotide comprises a spacer comprising the sequence AAACCAGCAGACUAAACUAC (SEQ ID NO: 1065) and a sequence selected from the group consisting of AUUACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1050); UAUUACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1051); UAUCACAUUUCUCUUGUAGUUUAGUCUG (SEQ ID NO: 1052); and UAUCACAUUUCUCCUGUAGUUUAGUCUG (SEQ ID NO: 1053).

42. The method of claim 41, wherein the DNA polymerase domain is a reverse transcriptase.

43. The method of claim 42, wherein the reverse transcriptase is a Moloney murine leukemia virus reverse transcriptase.

44. The method of claim 41, wherein the napDNAbp domain is a Cas9.

45. The method of claim 44, wherein the Cas9 is a Cas9 nickase.

46. The method of claim 44 or claim 45, wherein the Cas9 is a Streptococcus pyogenes Cas9, a P. lavamentivorans Cas9, a C. diphtheriae Cas9, an N. cinerea Cas9, a S. aureus Cas9, a staphylococcus lugdunensis Cas9, or an A. lari Cas9.

47. The method of claim 41, wherein the prime editor comprises an amino acid sequence having at least about 85% identity to the following sequence: MKRTADGSEFESPKKKRKVDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKN LIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEED KKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDL NPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLF GNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILL SDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGG ASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFY PFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIER MTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLT LTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSD GFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 MGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLY YLQNGRDMYVDQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKK MKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTK YDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLES EFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETG EIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGF DSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKL PKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQH KHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKY FDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGDSGGSEAAAKEAAAKEAAAKEAA AKSGGSTLNIEDEYRLHETSKEPDVSLGSTWLSDFPQAWAETGGMGLAVRQAPLIIPLKATSTP VSIKQYPMSQEARLGIKPHIQRLLDQGILVPCQSPWNTPLLPVKKPGTNDYRPVQDLREVNKRV EDIHPTVPNPYNLLSGLPPSHQWYTVLDLKDAFFCLRLHPTSQPLFAFEWRDPEMGISGQLTWT RLPQGFKNSPTLFNEALHRDLADFRIQHPDLILLQYVDDLLLAATSELDCQQGTRALLQTLGNL GYRASAKKAQICQKQVKYLGYLLKEGQRWLTEARKETVMGQPTPKTPRQLREFLGKAGFCRLFI PGFAEMAAPLYPLTKPGTLFNWGPDQQKAYQEIKQALLTAPALGLPDLTKPFELFVDEKQGYAK GVLTQKLGPWRRPVAYLSKKLDPVAAGWPPCLRMVAAIAVLTKDAGKLTMGQPLVILAPHAVEA LVKQPPDRWLSNARMTHYQALLLDTDRVQFGPVVALNPATLLPLPEEGLQHNCLDILAEAHGGG SKRTADGSEFEPKKKRKV (SEQ ID NO: 1065).

48. The method of claim 41, wherein the prime editor guide polynucleotide comprises a sequence selected from the group consisting of: gRNA 7206 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUmU*mU*mU*U (SEQ ID NO: 1057); gRNA7207 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUGmU*mU*mU*U (SEQ ID NO: 935); gRNA 7209 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1058);ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 gRNA7210 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 936); gRNA 7248 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1059); gRNA7249 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 937); and gRNA7260 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCCUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 938); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′- O-methyl nucleotide alteration.

49. The method of claim 41 further comprising contacting the CD117 polynucleotide with a nicking guide RNA.

50. The method of claim 49, wherein the nicking guide RNA comprises a spacer comprising a nucleotide sequence selected from the group consisting of: UAGUCUGCUGGUUUCAGAAA (SEQ ID NO: 1062); and UCUCCUGUAGUUUAGUCUGC (SEQ ID NO: 1063).

51. The method of claim 49, wherein the nicking guide RNA comprises a nucleotide sequence selected from the group consisting of: ngRNA 7195 mU*mA*mG*UCUGCUGGUUUCAGAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1060); and ngRNA 7196ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 mU*mC*mU*CCUGUAGUUUAGUCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1061); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O- methyl nucleotide alteration.

52. The method of claim 41 further comprising altering a protospacer adjacent motif capable of being bound by the napDNAbp.

53. A method for preparing an altered hematopoietic stem cell, the method comprising: (a) contacting an isolated hematopoietic stem cell or progenitor thereof with two or more prime editor guide polynucleotides and a prime editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase domain, or a polynucleotide encoding the prime editor, wherein 1) one prime editor guide polynucleotide targets a nucleic acid molecule encoding a CD117 polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, thereby i) introducing an intended nucleotide edit in a codon encoding a tyrosine at amino acid position 259, wherein the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 259 results in the codon expressing a cytosine, or results in identical edits at corresponding positions in another CD117 polypeptide, and / or ii) introducing an intended nucleotide edit in a codon encoding an asparagine at amino acid position 260, wherein the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 260 results in the codon expressing an aspartate, or results in identical edits at corresponding positions in another CD117 polypeptide, and wherein the prime editor guide polynucleotide comprises a sequence selected from the group consisting of: gRNA 7206 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUmU*mU*mU*U (SEQ ID NO: 1057); gRNA7207 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUGmU*mU*mU*U (SEQ ID NO: 935); gRNA 7209ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1058); gRNA7210 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 936); gRNA 7248 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1059); gRNA7249 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 937); and gRNA7260 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCCUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 938); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′- O-methyl nucleotide alteration; and 2) another prime editor guide polynucleotide targets a nucleic acid molecule encoding a beta globin (HBB) polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the HBB polypeptide, thereby introducing an amino acid alteration from a valine to a glutamate at position 6 of the HBB polypeptide, thereby generating the altered hematopoietic stem cell.

54. The method of claim 53, further comprising contacting the isolated hematopoietic stem cell or progenitor thereof with a nicking guide RNA comprising a nucleotide sequence selected from the group consisting of: ngRNA 7195 mU*mA*mG*UCUGCUGGUUUCAGAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1060); andATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 ngRNA 7196 mU*mC*mU*CCUGUAGUUUAGUCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1061); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O- methyl nucleotide alteration.

55. A cell produced by the method of any one of claims 1-54.

56. A pharmaceutical composition comprising an effective amount of the cell of claim 55.

57. A prime editor system comprising a prime editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and a DNA polymerase, or a polynucleotide encoding the prime editor, and a prime editor guide polynucleotide that targets a nucleic acid molecule encoding a CD117 polypeptide and comprises an editing template comprising an intended nucleotide edit to the nucleic acid molecule encoding the CD117 polypeptide, thereby i) introducing an intended nucleotide edit in a codon encoding a tyrosine at amino acid position 259, wherein the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 259 results in the codon expressing a cytosine, or results in identical edits at corresponding positions in another CD117 polypeptide, and / or ii) introducing an intended nucleotide edit in a codon encoding an asparagine at amino acid position 260, wherein the intended nucleotide edit in the codon encoding the tyrosine at amino acid position 260 results in the codon expressing an aspartate, or results in identical edits at corresponding positions in another CD117 polypeptide, and wherein the prime editor guide polynucleotide comprises a sequence selected from the group consisting of: gRNA 7206 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUmU*mU*mU*U (SEQ ID NO: 1057); gRNA7207 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUGmU*mU*mU*U (SEQ ID NO: 935);ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 gRNA 7209 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1058); gRNA7210 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 936); gRNA 7248 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1059); gRNA7249 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 937); and gRNA7260 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCCUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 938); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′- O-methyl nucleotide alteration.

58. The prime editor system of claim 57, further comprising nicking guide RNA comprising a nucleotide sequence selected from the group consisting of: ngRNA 7195 mU*mA*mG*UCUGCUGGUUUCAGAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1060); and ngRNA 7196 mU*mC*mU*CCUGUAGUUUAGUCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1061); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O- methyl nucleotide alteration.ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 59. A polynucleotide encoding the prime editor system of any one of claims 57-58.

60. A prime editor guide polynucleotide comprising a nucleotide sequence selected from the group consisting of: gRNA 7206 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUmU*mU*mU*U (SEQ ID NO: 1057); gRNA7207 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCAUUACAUUUCUCUUGUAGUUUAGUCU GCUGmU*mU*mU*U (SEQ ID NO: 935); gRNA 7209 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 1058); gRNA7210 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUUACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 936); gRNA 7248 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: ); gRNA7249 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCUUGUAGUUUAGUC UGCUGmU*mU*mU*U (SEQ ID NO: 937); and gRNA7260 mA*mA*mA*CCAGCAGACUAAACUACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUAUCACAUUUCUCCUGUAGUUUAGUC UGCUmU*mU*mU*U (SEQ ID NO: 938); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O-methyl nucleotide alteration.ATTORNEY DOCKET NO.180802-047301 / PCT ELECTRONIC DEPOSIT DATE: April 30, 2025 61. A nicking RNA for use in prime editing comprising a nucleotide sequence selected from the group consisting of: ngRNA 7195 mU*mA*mG*UCUGCUGGUUUCAGAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1060); and ngRNA 7196 mU*mC*mU*CCUGUAGUUUAGUCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAG UCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmU*mU*mU*U (SEQ ID NO: 1061); wherein, “*” indicates a phosphorothioate internucleotide linkage, and “m” indicates a 2′-O- methyl nucleotide alteration.

62. A kit comprising the cell, base editor system, polynucleotide, or pharmaceutical composition of any one of claims 1-61 and a container.

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