Compositions and methods for altering a nucleobase in a transthyretin polynucleotide

Abstract

Compositions for modifying or editing a polynucleotide (e.g., a gene) and methods of using the same to treat or prevent conditions associated with the extracellular deposition in various tissues of amyloid fibrils formed by the aggregation of misfolded transthyretin (TTR) proteins.  Such conditions include, but are not limited to, polyneuropathy due to hereditary transthyretin amyloidosis (hATTR-PN) and hereditary cardiomyopathy due to transthyretin amyloidosis (hATTR-CM), both associated with autosomal dominant mutations of the TTR gene, and an age-related cardiomyopathy associated with wild-type TTR proteins (ATTRwt), also known as senile cardiac amyloidosis are disclosed. Compositions and methods for editing TTR polynucleotides using base editor systems are disclosed.

Description

COMPOSITIONS AND METHODS FOR ALTERING A NUCLEOBASE IN A TRANSTHYRETIN POLYNUCLEOTIDE CROSS REFERENCE TO RELATED APPLICATIONSThe present application claims priority to U.S. Provisional Application No. 63 / 624,030, filed January 23, 2024, the entire contents of which are hereby incorporated by reference in its entirety. SEQUENCE LISTINGThis 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 January 13, 2025, is named 180802-056202PCT_SL.xml, and is 1,550,753 bytes in size. BACKGROUNDAmyloidosis is a condition characterized by the buildup of abnormal deposits of amyloid protein in the body's organs and tissues. These protein deposits can occur in the peripheral nervous system, which is made up of nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound. Protein deposits in these nerves can result in a loss of sensation in the extremities (peripheral neuropathy). The autonomic nervous system, which controls involuntary body functions, such as blood pressure, heart rate, and digestion, can also be affected by amyloidosis. In some cases, the brain and spinal cord (central nervous system) are affected. Mutations in the transthyretin (TTR) gene are associated with transthyretin amyloidosis. Furthermore, patients expressing wild-type TTR may also develop amyloidosis. Liver transplant remains the gold standard for treating transthyretin amyloidosis. However, there are a limited number of organ donors, and patients may wait years for an available organ. Accordingly, there is a need for compositions and methods for treating amyloidosis. SUMMARYProvided herein are compositions for modifying or editing a polynucleotide (e.g., DNA, RNA, genomic DNA, gene) and methods of using the same to treat or prevent conditions associated with the extracellular deposition in various tissues of amyloid fibrils formed by the aggregation of misfolded transthyretin (TTR) proteins. Such conditions include, but are not limited to, polyneuropathy due to hereditary transthyretin amyloidosis (hATTR-PN) and hereditary cardiomyopathy due to transthyretin amyloidosis (hATTR-CM), both of which are associated with autosomal dominant mutations of the TTR gene, and an age-related cardiomyopathy associated with wild-type TTR proteins (ATTRwt), also known as senile cardiac amyloidosis. Compositions and methods for editing TTR polynucleotides using base editor systems are disclosed herein.In one aspect, the disclosure features a lipid nanoparticle (LNP) containing components A), B), and C). Component A) is a guide RNA, or a polynucleotide encoding the guide RNA, where the guide RNA contains a spacer containing a nucleotide sequence selected from GCCAUCCUGCCAAGAAUGAG (SEQ ID NO: 472) and those listed in any of Tables 1B, 1C, 1D, 1E, 2A, 2B, 2D, or 2E. Component B) is an mRNA molecule, or a polynucleotide encoding the mRNA molecule, where the mRNA molecule encodes a base editor polypeptide containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and an adenosine deaminase domain. The adenosine deaminase domain contains an amino acid sequence having at least 90% identity to the following TadA*7.10 amino acid sequence, or a truncation thereof lacking only the first M: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1). The adenosine deaminase also contains a combination of amino acid alterations relative to the TadA*7.10 amino acid sequence selected from one or more of: a) I76Y, V82T, Y123H, Y147R, and Q154R; b)V82T, Y123H, D147R, and Q154R; c) V82T, Y123H, D147T, and Q154S; d) V82T and Q154R; e) V82T, Y147T, and Q154S; and f) I76Y, V82T, Y123H, Y147T, and Q154S. Component C) is an ionizable lipid according to any one of the following formulas, or a pharmaceutically acceptable salt thereof:i) a compound of Formula (Ih):  (Ih)where:each L1 and L1’ is independently -C(O)- or -OC(O)-;each L2 and L2’ is independently an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain;L3 is a covalent bond, -O-, -C(O)O-, -OC(O)-, or -OC(O)O-;R1 is optionally substituted C1-20 aliphatic, , or ;LCyA is a covalent bond or an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain;CyA is an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2adamantyl, sterolyl, and phenyl;LRa is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain;each Ra and R1’ is independently optionally substituted C1-20 aliphatic;Y1 is -C(O)- or -C(O)O-;Y2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-6 hydrocarbon chain;Y3 is optionally substituted C1-20 aliphatic;X1 is a covalent bond, -O-, or -NR-;X2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with -O- or -NR-;X3 is hydrogen or an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach R is independently hydrogen or optionally substituted C1-6 aliphatic;ii) a compound of Formula (Ia): Iawhere:R1 is C9-C20 alkyl or C9-C20 alkenyl with 1-3 units of unsaturation;X1 and X2 are each independently absent or selected from –O–, –NR2– and , where each R2 is independently hydrogen or C1-C6 alkyl;each a is independently an integer between 1 and 6;X3 and X4 are each independently absent or selected from one or more of: 4- to 8-membered heterocyclyl optionally substituted with 1 or 2 C1-C6 alkyl groups, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C1-C6 alkyl groups, 5- to 6-membered aryl optionally substituted with 1 or 2 C1-C6 alkyl groups, 4- to 7-membered cycloalkyl optionally substituted with 1 or 2 C1-C6 alkyl groups, –O– and –NR3–, where each R3 is a independently a hydrogen atom or C1-C6 alkyl and where X1-X2-X3-X4 does not contain any oxygen-oxygen, oxygen-nitrogen or nitrogen-nitrogen bonds;X5 is –(CH2)b–, where b is an integer between 0 and 6;X6 is hydrogen, C1-C6 alkyl, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C1-C6 alkyl groups, or –NR4R5, where R4 and R5 are each independently hydrogen or C1-C6 alkyl; or alternatively R4 and R5 join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C1-C6 alkyl groups, where the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen;each X7 is independently hydrogen, hydroxyl or –NR6R7, where R6 and R7 are each independently hydrogen or C1-C6 alkyl; or alternatively R6 and R7 join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C1-C6 alkyl groups, where the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen;at least one of X1, X2, X3, X4, and X5 is present;A1 and A2 are each independently selected from one or more of: C5-C12 haloalkyl, C5-C12 alkenyl, C5-C12 alkynyl, (C5-C12 alkoxy)-(CH2)n2–, (C5-C10 aryl)-(CH2)n3– optionally ring substituted with one or two halo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy groups, and (C3-C8 cycloalkyl)-(CH2)n4– optionally ring substituted with 1 or 2 C1-C6 alkyl groups; or alternatively A1 and A2 join together with the atoms to which they are bound to form a 5- to 6-membered cyclic acetal substituted with 1 or 2 C4-C10 alkyl groups;n1, n2 and n3 are each individually an integer between 1 and 4; andn4 is an integer between zero and 4;iii) A compound of Formula (Ib):Ibwhere:R1 is C9-C20 alkyl or C9-C20 alkenyl with 1-3 units of unsaturation;X1 and X2 are each independently absent or selected from –O–, NR2, and , where R2 is C1-C6 alkyl, and where X1 and X2 are not both –O– or NR2;a is an integer between 1 and 6;X3 and X4 are each independently absent or selected from one or more of: 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C1-C6 alkyl groups, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C1-C6 alkyl groups, and –NR3–, where each R3 is a hydrogen atom or C1-C6 alkyl;X5 is –(CH2)b–, where b is an integer between 0 and 6;X6 is hydrogen, C1-C6 alkyl, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C1-C6 alkyl groups, or –NR4R5, where R4 and R5 are each independently hydrogen or C1-C6 alkyl; or alternatively R4 and R5 join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C1-C6 alkyl groups, where the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen;X7 is hydrogen or –NR6R7, where R6 and R7 are each independently hydrogen or C1-C6 alkyl; or alternatively R6 and R7 join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C1-C6 alkyl groups, where the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen;at least one of X1, X2, X3, X4, and X5 is present; andprovided that when either X1 or X2 is –O–, neither X3 nor X4 is , and when either X1 or X2 is –O–, R4 and R5 are not both ethyl;iv) A compound of Formula (Ic):Icor its N-oxide, or a salt thereof, whereL1 is C1-6 alkylenyl, or C2-6 heteroalkylenyl;each L2 is independently C2-10 alkylenyl, or C3-10 heteroalkylenyl;L is absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl;L3 is absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl;X is absent, OC(O), C(O)O, or OC(O)O;each R is independently hydrogen, , or an optionally substituted group selected from C6-20 aliphatic, C6-20 haloaliphatic, a 3- to 7-membered cycloaliphatic ring, 1-adamantyl, 2adamantyl, sterolyl, and phenyl;R1 is hydrogen, a 3- to 7-membered cycloaliphatic ring, a 3- to 7-memberedheterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, OR2, C(O)OR2, C(O)SR2, OC(O)R2, OC(O)OR2, CN, N(R2)2, C(O)N(R2)2, NR2C(O)R2, OC(O)N(R2)2, N(R2)C(O)OR2, NR2S(O)2R2, NR2C(O)N(R2)2, NR2C(S)N(R2)2, NR2C(NR2)N(R2)2, NR2C(CHR2)N(R2)2, N(OR2)C(O)R2, N(OR2)S(O)2R2, N(OR2)C(O)OR2, -N(OR2)C(O)N(R2)2, N(OR2)C(S)N(R2)2, N(OR2)C(NR2)N(R2)2, -N(OR2)C(CHR2)N(R2)2, -C(NR2)N(R2)2, -C(NR2)R2, -C(O)N(R2)OR2, -C(R2)N(R2)2C(O)OR2, , -CR2(OR2)R3, , or , or ;each R2 is independently hydrogen, CN, NO2, OR4, S(O)2R4, S(O)2N(R4)2, (CH2)nR4, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7-membered cycloaliphatic ring, and a 3- to 7-memberedheterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo occurrences of R2, taken together with the atom(s) to which they are attached, form an optionally substituted 4- to 7-membered heterocyclic ring containing 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;each R3 is independently (CH2)nR4, ortwo occurrences of R3, taken together with the atoms to which they are attached, form an optionally substituted 5- to 6-membered heterocyclic ring containing 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;each R4 is independently hydrogen,OR5, N(R5)2,OC(O)R5,OC(O)OR5,CN,C(O)N(R5)2,NR5C(O)R5, OC(O)N(R5)2, N(R5)C(O)OR5, NR5S(O)2R5, NR5C(O)N(R5)2, NR5C(S)N(R5)2, NR5C(NR5)N(R5)2, or;each R5 is independently hydrogen, optionally substituted C1-6 aliphatic, ortwo occurrences of R5, taken together with the atom(s) to which they are attached, form an optionally substituted 4- to 7-membered heterocyclic ring containing 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;each R6 is independently C4-12 aliphatic; andn is 0 to 4;v) A compound of Formula (Id):Idor its N-oxide, or a pharmaceutically acceptable salt thereof, whereL1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl;each L2 is independently optionally substituted C2-15 alkylenyl, or optionally substituted C3-15 heteroalkylenyl;L3 is absent, optionally substituted C1-10 alkylenyl, or optionally substituted C2-10 heteroalkylenyl;X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-;each R’ is independently an optionally substituted group selected from C4-12 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;R is hydrogen, , or an optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2adamantyl, sterolyl, and phenyl;R1 is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-memberedheterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-memberedmonocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-memberedbicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR2, -C(O)OR2, -C(O)SR2, -OC(O)R2, -OC(O)OR2, -CN, -N(R2)2, -C(O)N(R2)2, -S(O)2N(R2)2, -NR2C(O)R2, -OC(O)N(R2)2, -N(R2)C(O)OR2, -NR2S(O)2R2, -NR2C(O)N(R2)2, -NR2C(S)N(R2)2, -NR2C(NR2)N(R2)2, -NR2C(CHR2)N(R2)2, -N(OR2)C(O)R2, -N(OR2)S(O)2R2, -N(OR2)C(O)OR2, -N(OR2)C(O)N(R2)2, -N(OR2)C(S)N(R2)2, -N(OR2)C(NR2)N(R2)2, -N(OR2)C(CHR2)N(R2)2, -C(NR2)N(R2)2, -C(NR2)R2, -C(O)N(R2)OR2, -C(R2)N(R2)2C(O)OR2, -CR2(R3)2, -OP(O)(OR2)2, or -P(O)(OR2)2; or R1 is , or a ring selected from 3- to 7-membered cycloaliphatic and 3- to 7-memberedheterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the cycloaliphatic or heterocyclyl ring is optionally substituted with 1-4 R2 or R3 groups;each R2 is independently hydrogen, oxo, -CN, -NO2, -OR4, -S(O)2R4, -S(O)2N(R4)2, -(CH2)n-R4, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 3- to 7-membered cycloaliphatic, 5- to 6-memberedmonocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-memberedheterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo occurrences of R2, taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl containing 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;each R3 is independently -(CH2)n-R4; ortwo occurrences of R3, taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl containing 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;each R4 is independently hydrogen,-OR5, -N(R5)2,-OC(O)R5,-OC(O)OR5,-CN,-C(O)N(R5)2, -NR5C(O)R5, -OC(O)N(R5)2, -N(R5)C(O)OR5, -NR5S(O)2R5, -NR5C(O)N(R5)2, -NR5C(S)N(R5)2, -NR5C(NR5)N(R5)2, or;each R5 is independently hydrogen, or optionally substituted C1-6 aliphatic; ortwo occurrences of R5, taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl containing 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;each R6 is independently C4-12 aliphatic; andeach n is independently 0 to 4;vi) A compound of Formula (Ie): (Ie) or a pharmaceutically acceptable salt thereof, where:L1 is a covalent bond, -C(O)-, or -OC(O)-;L2 is a covalent bond, an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain, or ;CyA is an optionally substituted ring selected from phenylene and 3- to 7-membered saturated or partially unsaturated carbocyclene;each m is independently 0, 1, or 2;L3 is a covalent bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, or -OC(O)O-;R1 is , or an optionally substituted saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain where 1-3 methylene units are optionally and independently replaced with –O- or –NR-;CyB is an optionally substituted ring selected from 3- to 12-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2adamantyl, , sterolyl, and phenyl;p is 0, 1, 2, or 3;X1 is a covalent bond, –O–, or –NR–;X2 is a covalent bond or an optionally substituted, bivalent saturated or unsaturated, straight or branched, C1-C12 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with -O-, -NR-, or –CyC-;CyC is an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclene, phenylene, 3- to 7-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;X3 is hydrogen or an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is independently hydrogen or an optionally substituted C1-C6 aliphatic group;Z1 is a covalent bond or -O-;Z2 is an optionally substituted group selected from 4- to 12-membered saturated or partially unsaturated carbocyclyl, phenyl, 1-adamantyl, and 2-adamantyl;Z3 is hydrogen, or an optionally substituted group selected from C1-C10 aliphatic, and 4- to 12-membered saturated or partially unsaturated carbocyclyl; andd is 0, 1, 2, 3, 4, 5, or 6;provided that when L3 is a covalent bond, then R1 must be ;vii) A compound of Formula (If):(If)or a pharmaceutically acceptable salt thereof, where:each L1 and L1’ is independently -C(O)- or -C(O)O-;each L2 and L2’ is independently a covalent bond, an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain, or ;each CyA is independently an optionally substituted ring selected from phenylene or a 3- to 7-membered saturated or partially unsaturated carbocyclene;each m is independently 0, 1, or 2;each L3 and L3’ is independently a covalent bond, -C(O)O-, -OC(O)-, -O-, or -OC(O)O-;each R1 and R1’ is independently an optionally substituted group selected from a saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with -O- or -NR-, a 3- to 12-membered saturated or partially unsaturated carbocyclic ring, 1-adamantyl, 2adamantyl, sterolyl, phenyl, and ;each L4 is independently a bivalent saturated or unsaturated, straight or branched C1-C6 hydrocarbon chain;each A1 and A2 is independently an optionally substituted C1-C20 aliphatic or -L5-R5;or A1 and A2, together with their intervening atoms, may form an optionally substituted ring: ;wherex is selected from 1 or 2; and# represents the point of attachment to L4;each L5 is independently a bivalent saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with -O- or -NR-;each R5 is independently an optionally substituted group selected from a 5- to 10-membered aryl ring and a 3- to 8-membered carbocyclic ring ;X1 is a covalent bond, –O–, or –NR–;X2 is a covalent bond or an optionally substituted, bivalent saturated or unsaturated, straight or branched, C1-C12 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with -O- or –NR-;X3 is hydrogen or -CyB;CyB is an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach R is independently hydrogen or an optionally substituted C1-C6 aliphatic group;provided that when X3 is hydrogen, at least one of R1 or R1’ is ;viii) a compound of Formula (Ig):(Ig)or a pharmaceutically acceptable salt thereof, where:each of L1 and L1’ is independently a covalent bond, -C(O)-, or -OC(O)-;each of L2 and L2’ is independently a covalent bond, an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain, or ;each CyA is independently an optionally substituted ring selected from phenylene or 3- to 7-membered saturated or partially unsaturated carbocyclene;each m is independently 0, 1, or 2;each of L3 and L3’ is independently a covalent bond, -O-, -C(O)O-, -OC(O)-, or -OC(O)O-;each of R1 and R1’ is independently an optionally substituted group selected from saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain where 1-3 methylene units are optionally and independently replaced with –O- or –NR-, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, 1-adamantyl, 2adamantyl, sterolyl, phenyl, or ;each L4 is independently a bivalent saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain;each A1 and A2 is independently an optionally substituted C1-C20 aliphatic or –L5-R5,or A1 and A2, together with their intervening atoms, may form an optionally substituted ring:,wherex is selected from 1 or 2; and# represents the point of attachment to L4;each L5 is independently a bivalent saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with -O- or -NR-;each R5 is independently an optionally substituted group selected from a 6- to 10-membered aryl ring or a 3- to 8-membered carbocyclic ring;Y1 is a covalent bond, –C(O)-, or –C(O)O-;Y2 is a bivalent saturated or unsaturated, straight or branched C1-C6 hydrocarbon chain, where 1-2 methylene units are optionally and independently replaced with cyclopropylene, -O-, or –NR-;Y3 is an optionally substituted group selected from saturated or unsaturated, straight or branched C1-C14 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with –O- or –NR-, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, 1-adamantyl, 2adamantyl, or phenyl;X1 is a covalent bond, –O–, or –NR-;X2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with –O-, -NR-, or –CyB-;each CyB is independently an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclene, phenylene, 3- to 7-membered heterocyclene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;X3 is hydrogen or an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach R is independently hydrogen or an optionally substituted C1-C6 aliphatic group;ix) a compound of formula A’:A’or its N-oxide, or a pharmaceutically acceptable salt thereof, whereL1 is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl;each L2 is independently optionally substituted C2-15 alkylenyl, or optionally substituted C3-15 heteroalkylenyl;L is C1-10 alkylenyl, or C2-10 heteroalkylenyl;X2 is -OC(O)-, -C(O)O-, or -OC(O)O-;X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-;R” is hydrogen, , , or an optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;each of R and Ra is independently hydrogen, or an optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyleach of L3 and L3a is independently absent, optionally substituted C1-10 alkylenyl, or optionally substituted C2-10 heteroalkylenyl;R1 is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-memberedheterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-memberedmonocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-memberedbicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR2, -C(O)OR2, -C(O)SR2, -OC(O)R2, -OC(O)OR2, -CN, -N(R2)2, -C(O)N(R2)2, -S(O)2N(R2)2, -NR2C(O)R2, -OC(O)N(R2)2, -N(R2)C(O)OR2, -NR2S(O)2R2, -NR2C(O)N(R2)2, -NR2C(S)N(R2)2, -NR2C(NR2)N(R2)2, -NR2C(CHR2)N(R2)2, -N(OR2)C(O)R2, -N(OR2)S(O)2R2, -N(OR2)C(O)OR2, -N(OR2)C(O)N(R2)2, -N(OR2)C(S)N(R2)2, -N(OR2)C(NR2)N(R2)2, -N(OR2)C(CHR2)N(R2)2, -C(NR2)N(R2)2, -C(NR2)R2, -C(O)N(R2)OR2, -C(R2)N(R2)2C(O)OR2, -CR2(R3)2, -OP(O)(OR2)2, or -P(O)(OR2)2; orR1 is , or a ring selected from 3- to 7-membered cycloaliphatic and 3- to 7-memberedheterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the cycloaliphatic or heterocyclyl ring is optionally substituted with 1-4 R2 or R3 groups;each R2 is independently hydrogen, oxo, -CN, -NO2, -OR4, -S(O)2R4, -S(O)2N(R4)2, -(CH2)n-R4, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 3- to 7-membered cycloaliphatic, 5- to 6-memberedmonocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-memberedheterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo occurrences of R2, taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl containing 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;each R3 is independently -(CH2)n-R4; ortwo occurrences of R3, taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl containing 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;each R4 is independently hydrogen,-OR5, -N(R5)2,-OC(O)R5,-OC(O)OR5,-CN,-C(O)N(R5)2, -NR5C(O)R5, -OC(O)N(R5)2, -N(R5)C(O)OR5, -NR5S(O)2R5, -NR5C(O)N(R5)2, -NR5C(S)N(R5)2, -NR5C(NR5)N(R5)2, or;each R5 is independently hydrogen, or optionally substituted C1-6 aliphatic; ortwo occurrences of R5, taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl containing 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur;each R6 is independently C4-12 aliphatic; andeach n is independently 0 to 4; orx) a compound of Formula I: (I)or a pharmaceutically acceptable salt thereof, where:L1 is a covalent bond, -C(O)-, or -OC(O)-;L2 is a covalent bond, an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain, or ;CyA is an optionally substituted ring selected from phenylene and 3- to 7-membered saturated or partially unsaturated carbocyclene;each m is independently 0, 1, or 2;L3 is a covalent bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, or -OC(O)O-;R1 is , an optionally substituted saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain where 1-3 methylene units are optionally and independently replaced with –O- or –NR-, or ;CyB is an optionally substituted ring selected from 3- to 12-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2adamantyl, , sterolyl, and phenyl;p is 0, 1, 2, or 3;each L4 is independently a bivalent saturated or unsaturated, straight or branched C1-C6 hydrocarbon chain;each A1 and A2 is independently an optionally substituted C1-C20 aliphatic or -L5-R5;or A1 and A2, together with their intervening atoms, may form an optionally substituted ring: ;wherex is selected from 1 or 2; and# represents the point of attachment to L4;each L5 is independently a bivalent saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with -O- or -NR-;each R5 is independently an optionally substituted group selected from a 5- to 10-membered aryl ring or a 3- to 8-membered carbocyclic ring ;X1 is a covalent bond, –O–, or –NR–;X2 is a covalent bond or an optionally substituted, bivalent saturated or unsaturated, straight or branched, C1-C12 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with -O-, -NR-, or –CyC-;CyC is an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclene, phenylene, 3- to 7-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;X3 is hydrogen or an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach R is independently hydrogen or an optionally substituted C1-C6 aliphatic group;provided that when L3 is a covalent bond, then R1 must be .In another aspect, the disclosure features a lipid nanoparticle (LNP) containing components A), B), and C). Component A) is a guide RNA, or a polynucleotide encoding the guide RNA, where the guide RNA is capable of directing a base editor polypeptide to alter a nucleotide in a transthyretin (TTR) polynucleotide. Component B) is an mRNA molecule, or a polynucleotide encoding the mRNA molecule, where the mRNA molecule encodes a base editor polypeptide containing a nucleic acid programmable DNA binding protein (napDNAbp) domain and an adenosine deaminase domain. The adenosine deaminase domain contains i) an amino acid sequence having at least 90% identity to the following TadA*7.10 amino acid sequence, or a truncation thereof lacking only the first M: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1). The adenosine deaminase domain also contains a combination of amino acid alterations relative to the TadA*7.10 amino acid sequence selected from one or more of: a) I76Y, V82T, Y123H, Y147R, and Q154R; b) V82T, Y123H, D147R, and Q154R; c) V82T, Y123H, D147T, and Q154S; d) V82T and Q154R; e) V82T, Y147T, and Q154S; f) I76Y, V82T, Y123H, Y147T, and Q154S; g) Y123H, Y147R, Q154R; h) I76Y, Y147R, and Q154R; i) Y147R, Q154R, and T166R; j) Y147T and Q154R; k) Y147T and Q154S;l) I76Y, Y123H, Y147R, and Q145R; m) I76Y and V82S; n) V82S and Y147R; o) V82S, Y123H, and Y147R; p) V82S and Q154R; q) V82S, Y123H, and Q154R; r) V82S, Y123H, Y147R, and Q154R; s) I76Y, V82S, Y123H, Y147R, and Q154R. Component C) is an ionizable lipid according to Formula (I), or a pharmaceutically acceptable salt thereof:  (Ih)where:each L1 and L1’ is independently -C(O)- or -OC(O)-;each L2 and L2’ is independently an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain;L3 is a covalent bond, -O-, -C(O)O-, -OC(O)-, or -OC(O)O-;R1 is optionally substituted C1-20 aliphatic, , or ;LCyA is a covalent bond or an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain;CyA is an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2adamantyl, sterolyl, and phenyl;LRa is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain;each Ra and R1’ is independently optionally substituted C1-20 aliphatic;Y1 is -C(O)- or -C(O)O-;Y2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-6 hydrocarbon chain;Y3 is optionally substituted C1-20 aliphatic;X1 is a covalent bond, -O-, or -NR-;X2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain, where 1-3 methylene units are optionally and independently replaced with -O- or -NR-;X3 is hydrogen or an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach R is independently hydrogen or optionally substituted C1-6 aliphatic.In another aspect, the disclosure features a lipid nanoparticle (LNP) containing components A), B), and C). Component A) is a guide RNA having the following nucleotide sequence: mGsmCsmCsAUCCUGCCAAGAAUGAGmGUUUUAGmAmGmCmUmAGmAmAmAmUmAmGmCmAmAGUUmAAmAAmUAmAmGmGmCmUmAGUmCmCGUUAmUmCAAmCmUmUGmAmAmAmAmAmGmUmGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 477), where A is adenosine; C is cytidine; G is guanosine; U is uridine; mA is 2’-O-methyladenosine; mC is 2’-O-methylcytidine; mG is 2’-O-methylguanosine; mU is 2’-O-methyluridine, and s is a phosphorothioate (PS) backbone linkage. Component B) is a base editor polypeptide, or a polynucleotide encoding the base editor polypeptide, where the base editor polypeptide contains a nucleic acid programmable DNA binding protein (napDNAbp) domain and an adenosine deaminase domain. The adenosine deaminase domain contains an amino acid sequence with at least 90% identity to the following amino TadA*7.10 amino acid sequence, or a truncation thereof lacking only the first M: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1). The adenosine deaminase domain also contains the following combination of amino acid alterations relative to the TadA*7.10 amino acid sequence: I76Y, V82T, Y123H, Y147R, and Q154R. Component C) is an ionizable lipid having the following structure, or a pharmaceutically acceptable salt thereof: (IZ4). In another aspect, the disclosure features a base editor system containing components A), and B). Component A) is a guide RNA, or a polynucleotide encoding the guide RNA, where the guide RNA is capable of directing a base editor polypeptide to alter a nucleotide in a transthyretin (TTR) polynucleotide. Component B) is a base editor polypeptide, or one or more polynucleotide encoding the base editor polypeptide, where the base editor polypeptide contains a nucleic acid programmable DNA binding protein (napDNAbp) domain and an adenosine deaminase domain. The adenosine deaminase domain contains an amino acid sequence with at least 90% identity to the following amino TadA*7.10 amino acid sequence, or a truncation thereof lacking only the first M: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1). The adenosine deaminase domain also contains a combination of amino acid alterations relative to the TadA*7.10 amino acid sequence selected from one or more of: a) V82T, Y123H, D147R, and Q154R; b) V82T, Y123H, D147T, and Q154S; c) V82T and Q154R; d) V82T, Y147T, and Q154S; e) I76Y, V82T, Y123H, Y147R, and Q154R; and f) I76Y, V82T, Y123H, Y147T, and Q154S.In another aspect, the disclosure features a polynucleotide or set of polynucleotides encoding the base editor system of any aspect of the disclosure, or embodiments thereof.In another aspect, the disclosure features a cell containing the base editor system or the polynucleotide or set of polynucleotides of any aspect of the disclosure, or embodiments thereof.In another aspect, the disclosure features a pharmaceutical composition containing the lipid nanoparticle, the base editor system, the polynucleotide or set of polynucleotides, or the cell of any aspect of the disclosure, or embodiments thereof, and a pharmaceutically acceptable carrier or excipient.In another aspect, the disclosure features a kit containing the lipid nanoparticle, the base editor system, the polynucleotide or set of polynucleotides, the cell, or the pharmaceutical composition of any aspect of the disclosure, or embodiments thereof, and a container.In another aspect, the disclosure features a method for modifying a target nucleobase in a transthyretin (TTR) polynucleotide in a cell. The method involves contacting the cell with the lipid nanoparticle or the base editor system of any aspect of the disclosure, or embodiments thereof, thereby modifying the target nucleobase in the TTR polynucleotide.In another aspect, the disclosure features a method of treating a disease in a subject in need thereof. The disease is associated with a pathogenic mutation in a transthyretin (TTR) polynucleotide in the subject. The method involves administering to the subject the lipid nanoparticle or the base editor system of any aspect of the disclosure, or embodiments thereof, thereby altering a target nucleobase in the TTR polynucleotide.In any aspect of the disclosure, or embodiments thereof, the lipid nanoparticle contains an ionizable lipid having the following structure, or a pharmaceutically acceptable salt thereof: (IZ4).In any aspect of the disclosure, or embodiments thereof, the lipid nanoparticle contains an ionizable lipid having the following structure, or a pharmaceutically acceptable salt thereof:(IZ3). In any aspect of the disclosure, or embodiments thereof, the LNP has a molar ratio of ionizable nitrogen atoms in an ionizable lipid to the total negative charge in the payload (N:P ratio) of between about 30:1 to about 1:1. In any aspect of the disclosure, or embodiments thereof, the LNP has an N:P ratio of about 6:1.In any aspect of the disclosure, or embodiments thereof, the guide RNA contains a scaffold with the following nucleotide sequence: gUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugGcaccgagucggugcuususus (SEQ ID NO: 478), where A is adenosine; C is cytidine; G is guanosine; U is uridine; a is 2’-O-methyladenosine; c is 2’-O-methylcytidine; g is 2’-O-methylguanosine; u is 2’-O-methyluridine, and s is a phosphorothioate (PS) backbone linkage. In any aspect of the disclosure, or embodiments thereof, the guide RNA contains a spacer containing the following nucleotide sequence: GCCAUCCUGCCAAGAAUGAG (SEQ ID NO: 472). In any aspect of the disclosure, or embodiments thereof, the guide RNA contains the following nucleotide sequence: mGsmCsmCsAUCCUGCCAAGAAUGAGmGUUUUAGmAmGmCmUmAGmAmAmAmUmAmGmCmAmAGUUmAAmAAmUAmAmGmGmCmUmAGUmCmCGUUAmUmCAAmCmUmUGmAmAmAmAmAmGmUmGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmUsmUsmUsmU (SEQ ID NO: 477), where A is adenosine; C is cytidine; G is guanosine; U is uridine; mA is 2’-O-methyladenosine; mC is 2’-O-methylcytidine; mG is 2’-O-methylguanosine; mU is 2’-O-methyluridine, and s is a phosphorothioate (PS) backbone linkage. In any aspect of the disclosure, or embodiments thereof, the guide RNA contains a spacer selected from those listed in any of Tables 1B, 1C, 1D, 1E, 2A, 2B, 2D, or 2E. In any aspect of the disclosure, or embodiments thereof, the guide RNA contains 2-5 contiguous 2’-O-methylated nucleobases at the 3’ end and at the 5’ end. In any aspect of the disclosure, or embodiments thereof, the guide RNA contains 2-5 contiguous nucleobases at the 3’ end and at the 5’ end that contain phosphorothioate internucleotide linkages.In any aspect of the disclosure, or embodiments thereof, the napDNAbp domain contains a Cas9 polypeptide. In any aspect of the disclosure, or embodiments thereof, the napDNAbp is a nickase.In any aspect of the disclosure, or embodiments thereof, the base editor polypeptide contains an amino acid sequence with at least about 90% identity to the following amino acid sequence:ABE9.51MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLYDATLYTTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHHPGMNHRVEITEGILADECAALLCRFFRMPRRVFNAQKKAQSSTDSGGSSGGSSGSETPGTSESATPESSGGSSGGSDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGDEGADKRTADGSEFESPKKKRKV (SEQ ID NO: 463).In any aspect of the disclosure, or embodiments thereof, the cell is in a subject.In any aspect of the disclosure, or embodiments thereof, an ionizable lipid of the lipid nanoparticle has a half-life in the liver of the subject that is less than 14 days.In any aspect of the disclosure, or embodiments thereof, the target nucleobase is altered with an editing efficiency of at least about 50% or 60% in in the cell and / or in the liver of the subject. In any aspect of the disclosure, or embodiments thereof, altering the target nucleobase results in a reduction in TTR polypeptide levels in the cell and / or in the subject. In any aspect of the disclosure, or embodiments thereof, TTR polypeptide levels are reduced by at least about 80% or 90%. In any aspect of the disclosure, or embodiments thereof, the method is associated with only a transient increase or no increase in alkaline phosphatase (ALP), alanine transaminase (ALT), and / or aspartate aminotransferase (AST) levels in the subject. In any aspect of the disclosure, or embodiments thereof, the method is associated with no increase in ALP levels in the subject.In any aspect of the disclosure, or embodiments thereof, the disease is selected from one or more of amyloidosis, cardiomyopathy, familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), familial transthyretin amyloidosis (FTA), senile systemic amyloidosis (SSA), and transthyretin amyloidosis.In any aspect of the disclosure, or embodiments thereof, the LNP has a mean diameter of from about 20 nm to about 1000 nm, from about 30 nm to about 150 nm, from about 40 nm to about 150 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 50 nm to 90 nm, from about 55 nm to 85 nm, from about 55 nm to 75 nm, from about 50 nm to about 80 nm, from about 60 nm to about 80 nm, from about 70 nm to about 110 nm, from about 70 nm to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, or from about 70 nm to about 80 nm. In any aspect of the disclosure, or embodiments thereof, the LNP has a mean diameter of about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, or greater. In any aspect of the disclosure, or embodiments thereof, the LNP has a mean diameter of about 70 nm + / - 10 nm, 70 nm + / - 5 nm, 65 nm + / - 10 nm, 65 nm + / - 5 nm, 60 nm + / - 10 nm, or 60 nm + / - 5 nm.In any aspect of the disclosure, or embodiments thereof, the ionizable lipid is present in the lipid nanoparticle (LNP) at from about 30 mole percent to about 70 mole percent, based on total moles of components of the lipid nanoparticle. In any aspect of the disclosure, or embodiments thereof, the ionizable lipid is present in the lipid nanoparticle (LNP) at from about 33 mole percent to about 60 mole percent, based on total moles of components of the lipid nanoparticle. In any aspect of the disclosure, or embodiments thereof, the ionizable lipid is present in the lipid nanoparticle (LNP) at from about 34 mole percent to about 55 mole percent, based on total moles of components of the lipid nanoparticle. In any aspect of the disclosure, or embodiments thereof, the ionizable lipid is present in the lipid nanoparticle (LNP) at from about 33 mole percent to about 51 mole percent, based on total moles of components of the lipid nanoparticle. In any aspect of the disclosure, or embodiments thereof, the ionizable lipid is present in the lipid nanoparticle (LNP) at about 34.7 mole percent, based on total moles of components of the lipid nanoparticle. In any aspect of the disclosure, or embodiments thereof, the ionizable lipid is present in the lipid nanoparticle (LNP) at about 50 mole percent, based on total moles of components of the lipid nanoparticle. In any aspect of the disclosure, or embodiments thereof, the ionizable lipid is present in the lipid nanoparticle (LNP) at about 40 mole percent to about 60 mole percent or about 45 mole percent to about 55 mole percent, based on total moles of components of the lipid nanoparticle.In any aspect of the disclosure, or embodiments thereof, the LNP contains from about 0 mole percent to about 5 mole percent conjugate-linker lipid. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 1.5 mole percent conjugate-linker lipid. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 2.0 mole percent conjugate-linker lipid. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 2.5 mole percent conjugate-linker lipid. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 3 mole percent conjugate-linker lipid. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 3.5 mole percent conjugate-linker lipid.In any aspect of the disclosure, or embodiments thereof, the LNP contains from about 5 mole percent to 25 mole percent of phospholipid. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 5 mole percent to 15 mole percent of phospholipid. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 9 mole percent to 11 mole percent of phospholipid. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 10 mole percent of phospholipid.In any aspect of the disclosure, or embodiments thereof, the LNP contains from about 25 mole percent to about 45 mole percent sterol. In any aspect of the disclosure, or embodiments thereof, the LNP contains from about 30 mole percent to about 45 mole percent sterol. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 40 mole percent sterol. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 35.75 mole percent sterol. In any aspect of the disclosure, or embodiments thereof, the LNP contains about 32.5 mole percent cholesterol.In any aspect of the disclosure, or embodiments thereof, the LNP about 30 mole percent to about 70 mole percent ionizable lipid, about 5 mole percent to about 25 mole percent phospholipid, about 25 mole percent to about 45 mole percent sterol, and about 0 mole percent to about 5 mole percent conjugate-linker lipid.In any aspect of the disclosure, or embodiments thereof, the LNP contains about 47.5 mole percent ionizable lipid, about 10 mole percent phospholipid, about 40 mole percent sterol, and about 2.5 mole percent conjugate-linker lipid.In any aspect of the disclosure, or embodiments thereof, the LNP contains about 51.25 mole percent ionizable lipid, about 10 mole percent phospholipid, about 35.75 mole percent sterol, and about 3 mole percent conjugate-linker lipid.In any aspect of the disclosure, or embodiments thereof, the LNP contains about 55 mole percent ionizable lipid, about 10 mole percent phospholipid, about 32.5 mole percent sterol, and about 2.5 mole percent conjugate-linker lipid.In any aspect of the disclosure, or embodiments thereof, the LNP about 45 mole percent to about 60 mole percent ionizable lipid of any provided compound, about 9 mole percent to about 11 mole percent 1-2-distearoyl-sn-glycero-3-phosphocholine (DSPC), about 1 mole percent to about 5 mole percent PEG2000-DMG , and about 30 mole percent to about 45 mole percent cholesterol, based on the total moles of these four ingredients.In any aspect of the disclosure, or embodiments thereof, the LNP is the formulation LNP1, LNP2, LNP3, or LNP4 in Table10A.In any aspect of the disclosure, or embodiments thereof, the LNP contains about 47.5 mole percent ionizable lipid IZ1, about 10 mole percent 1-2-distearoyl-sn-glycero-3-phosphocholine (DSPC), about 2.5 mole percent PEG2000-DMG , and about 40 mole percent cholesterol, based on the total moles of these four ingredients, an N / P ratio of 6, and a payload containing mRNA encoding an adenosine base editor (ABE) containing a TadA*8.20 adenosine deaminase domain with the amino acid alteration V82T or the combination of the amino acid alterations V82T, Y147T, and Q154S, and a guide RNA containing a spacer containing the nucleotide sequence GCCAUCCUGCCAAGAAUGAG (SEQ ID NO: 472). In some embodiments, the guide RNA is GA521 of Table 1B.In any aspect of the disclosure, or embodiments thereof, the LNP contains about 55 mole percent ionizable lipid IZ2, about 10 mole percent 1-2-distearoyl-sn-glycero-3-phosphocholine (DSPC), about 2.5 mole percent PEG2000-DMG , and about 32.5 mole percent cholesterol, based on the total moles of these four ingredients, an N / P ratio of 6, and a payload containing mRNA encoding an adenosine base editor (ABE) containing a TadA*8.20 adenosine deaminase domain with the amino acid alteration V82T or the combination of the amino acid alterations V82T, Y147T, and Q154S, and a guide RNA containing a spacer containing the nucleotide sequence GCCAUCCUGCCAAGAAUGAG (SEQ ID NO: 472). In some embodiments, the guide RNA is GA521 of Table 1B.In any aspect of the disclosure, or embodiments thereof, the LNP contains about 51.25 mole percent ionizable lipid IZ3, about 10 mole percent 1-2-distearoyl-sn-glycero-3-phosphocholine (DSPC), about 3 mole percent PEG2000-DMG , and about 35.75 mole percent cholesterol, based on the total moles of these four ingredients, an N / P ratio of 6, and a payload containing mRNA encoding an adenosine base editor (ABE) containing a TadA*8.20 adenosine deaminase domain with the amino acid alteration V82T or the combination of the amino acid alterations V82T, Y147T, and Q154S, and a guide RNA containing a spacer containing the nucleotide sequence GCCAUCCUGCCAAGAAUGAG (SEQ ID NO: 472). In some embodiments, the guide RNA is GA521 of Table 1B.In any aspect of the disclosure, or embodiments thereof, the LNP contains about 47.5 mole percent ionizable lipid IZ4, about 10 mole percent 1-2-distearoyl-sn-glycero-3-phosphocholine (DSPC), about 2.5 mole percent PEG2000-DMG , and about 40 mole percent cholesterol, based on the total moles of these four ingredients, an N / P ratio of 6, and a payload containing mRNA encoding an adenosine base editor (ABE) containing a TadA*8.20 adenosine deaminase domain with the amino acid alteration V82T or the combination of the amino acid alterations V82T, Y147T, and Q154S, and a guide RNA containing a spacer containing the nucleotide sequence GCCAUCCUGCCAAGAAUGAG (SEQ ID NO: 472). In some embodiments, the guide RNA is GA521 of Table 1B.In any aspect of the disclosure, or embodiments thereof, the N / P ratio of the lipid nanoparticle is from about 1 to about 30. In any aspect of the disclosure, or embodiments thereof, the N / P ratio of the lipid nanoparticle is from about 2 to about 15, from about 2 to about 10, from about 2 to about 8, from about 2 to about 6, from about 3 to about 15, from about 3 to about 10, from about 3 to about 8, from about 3 to about 6, from about 4 to about 15, from about 4 to about 10, from about 4 to about 8, or from about 4 to about 6. In any aspect of the disclosure, or embodiments thereof, the N / P ratio of the lipid nanoparticle is about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 9, or about 10. In any aspect of the disclosure, or embodiments thereof, the N / P ratio of the lipid nanoparticle is N / P ratio is from about 5 to about 7. In any aspect of the disclosure, or embodiments thereof, the N / P ratio of the lipid nanoparticle is about 6.In any aspect provided herein, or embodiments thereof, the method is not a process for modifying the germline genetic identity of human beings. DefinitionsUnless 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 “TadA*8.8 polypeptide” is meant an adenosine deaminase domain having deaminase activity, comprising the alterations Y123H, Y147R, and Q154R relative to the following reference sequence, and having at least about 85% amino acid sequence identity to the following reference sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1; TadA*7.10). In some embodiments, TadA*8.8 comprises further alterations (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more alterations) relative to the reference sequence.By “TadA*8.8 polynucleotide” is meant a polynucleotide encoding a TadA*8.8 polypeptide. By “TadA*8.13 polypeptide” is meant an adenosine deaminase domain having deaminase activity, comprising the alterations I76Y, Y123H, Y147R, and Q154R relative to the following reference sequence and having at least about 85% amino acid sequence identity to the following reference sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1; TadA*7.10). In some embodiments, TadA*8.13 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more total alterations relative to the reference sequence.By “TadA*8.13 polynucleotide” is meant a polynucleotide encoding a TadA*8.13 polypeptide.By “TadA*8.17 polypeptide” is meant an adenosine deaminase domain having deaminase activity, comprising the alterations V82S and Q154R relative to the following reference sequence, and having at least about 85% amino acid sequence identity to the following reference sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1; TadA*7.10). In some embodiments, TadA*8.17 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more total alterations relative to the reference sequence.By “TadA*8.17 polynucleotide” is meant a polynucleotide encoding a TadA*8.17 polypeptide.By “TadA*8.20 polypeptide” is meant an adenosine deaminase domain having deaminase activity, comprising the alterations I76Y, V82S, Y123H, Y147R, and Q154R relative to the following reference sequence, and having at least about 85% amino acid sequence identity to the following reference sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1; TadA*7.10). In some embodiments, TadA*8.20 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more total alterations relative to the reference sequence.By “TadA*8.20 polynucleotide” is meant a polynucleotide encoding a TadA*8.20 polypeptide.In various embodiments, any adenosine deaminase domain provided herein (e.g., TadA*8.8, TadA*8.17, or TadA*8.20, and variants thereof) comprises the following alterations relative to the TadA*7.10 reference sequence: V82T; or V82T, Y147T, and Q154S.By “ABE9.51 polypeptide” is meant an adenosine deaminase base editor comprising a TadA*8.20 adenosine deaminase polypeptide variant having the amino acid alteration V82T, and a nucleic acid programmable DNA binding protein (napDNAbp) domain. In some embodiments, ABE9.51 comprises an amino acid sequence with at least about 85% sequence identity to the following polypeptide sequence, or a functional fragment thereof capable of deaminating an adenosine nucleotide:MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLYDATLYTTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHHPGMNHRVEITEGILADECAALLCRFFRMPRRVFNAQKKAQSSTDSGGSSGGSSGSETPGTSESATPESSGGSSGGSDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGDEGADKRTADGSEFESPKKKRKV (SEQ ID NO: 463). In some embodiments, an ABE9.51 napDNAbp comprises an spCas9 nickase.In embodiments, ABE9.51 contains one or more uracil glycosylase inhibitor (UGI) domains. In some embodiments, ABE9.51 contains two UGI domains.By “ABE9.51 polynucleotide” is meant a polynucleotide encoding an ABE9.51 polypeptide.By “adenine” or “9H-Purin-6-amine” is meant a purine nucleobase with the molecular formula C5H5N5, having the structure , and corresponding to CAS No. 73-24-5.By “adenosine” or “ 4-Amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2(1H)-one” is meant an adenine molecule attached to a ribose sugar via a glycosidic bond, having the structure , and corresponding to CAS No. 65-46-3. Its molecular formula is C10H13N5O4.By “adenosine deaminase” or “adenine deaminase” is meant a polypeptide or fragment thereof capable of catalyzing the hydrolytic deamination of adenine or adenosine. In some embodiments, the deaminase or deaminase domain is an adenosine deaminase catalyzing the hydrolytic deamination of adenosine to inosine or deoxy adenosine to deoxyinosine. In some embodiments, the adenosine deaminase catalyzes the hydrolytic deamination of adenine or adenosine in deoxyribonucleic acid (DNA). The adenosine deaminases (e.g., engineered adenosine deaminases, evolved adenosine deaminases) provided herein may be from any organism (e.g., eukaryotic, prokaryotic), including but not limited to algae, bacteria, fungi, plants, invertebrates (e.g., insects), and vertebrates (e.g., amphibians, mammals). In some embodiments, the adenosine deaminase is an adenosine deaminase variant with one or more alterations and is capable of deaminating both adenine and cytosine in a target polynucleotide (e.g., DNA, RNA) and may be referred to as a “dual deaminase”. Non-limiting examples of dual deaminases include those described in PCT / US22 / 22050. In some embodiments, the target polynucleotide is single or double stranded. In some embodiments, the adenosine deaminase variant is capable of deaminating both adenine and cytosine in DNA. In some embodiments, the adenosine deaminase variant is capable of deaminating both adenine and cytosine in single-stranded DNA. In some embodiments, the adenosine deaminase variant is capable of deaminating both adenine and cytosine in RNA. In embodiments, the adenosine deaminase variant is selected from those described in PCT / US2020 / 018192, PCT / US2020 / 049975, PCT / US2017 / 045381, and PCT / US2020 / 028568, the full contents of which are each incorporated herein by reference in their entireties for all purposes.By “adenosine deaminase activity” is meant catalyzing the deamination of adenine or adenosine to guanine in a polynucleotide.By “Adenosine Base Editor (ABE)” is meant a base editor comprising an adenosine deaminase.By “Adenosine Base Editor (ABE) polynucleotide” is meant a polynucleotide encoding an ABE.By “Adenosine Base Editor 8 (ABE8) polypeptide” or “ABE8” is meant a base editor as defined herein comprising an adenosine deaminase or adenosine deaminase variant comprising one or more of the alterations listed in Table 5B, one of the combinations of alterations listed in Table 5B, or an alteration at one or more of the amino acid positions listed in Table 5B, such alterations are relative to the following reference sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1), or a corresponding position in another adenosine deaminase. In embodiments, ABE8 comprises alterations at amino acids 82 and / or 166 of SEQ ID NO: 1. In some embodiments, ABE8 comprises further alterations, as described herein, relative to the reference sequence.By “Adenosine Base Editor 8 (ABE8) polynucleotide” is meant a polynucleotide encoding an ABE8 polypeptide.“Administering” is referred to herein as providing one or more 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-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, lipid nanoparticle, polypeptide, polypeptide complex, or fragments thereof. In some embodiments, the agent is a lipid nanoparticle of the disclosure. In some embodiments, the lipid nanoparticle contains a base editor system of the disclosure. In some cases, the agent is a base editor system of the disclosure, or a component thereof. The base editor system contains a base editor, or a polynucleotide (e.g., an mRNA molecule) encoding the base editor, and a guide RNA, or a polynucleotide encoding the guide RNA.The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 carbon atoms. In some embodiments, aliphatic groups contain 1-4 carbon atoms. In some embodiments, aliphatic groups contain 1-3 carbon atoms, and in some embodiments, aliphatic groups contain 1-2 carbon atoms. In some embodiments, “carbocyclic” (or “cycloaliphatic” or “carbocycle” or “cycloalkyl”) refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted C6-C12 bicyclic hydrocarbon, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.As used herein, the term “alkenyl” refers to an alkyl group, as defined herein, having one or more double bonds. In some embodiments, the term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-20, C2-18, C2-16, C2-14, C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.As used herein, the term "alkyl" is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, alkyl has 1-100 carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-C20 for straight chain, C2-C20 for branched chain), and alternatively, about 1-10. In some embodiments, a cycloalkyl ring has from about 3-10 carbon atoms in their ring structure where such rings are monocyclic or bicyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, an alkyl group may be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C1-C4 for straight chain lower alkyls).The term “alkylenyl” or “alkylene” refers to a bivalent alkyl group (i.e., a bivalent saturated hydrocarbon chain) that is a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted. Any of the above mentioned monovalent alkyl groups may be an alkylenyl by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an “alkylenyl” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 10, from 1 to 9, from 1 to 8, from 1 to 7, from 1 to 6, from 1 to 5, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 5, or from 4 to 8. A substituted alkylenyl is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.As used herein, the term “alkynyl” refers to an alkyl group, as defined herein, having one or more triple bonds. In some embodiments, the term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-20, C2-18, C2-16, C2-14, C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.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). In some embodiments, a base editor described herein alters the sequence of a TTR polynucleotide.By “ameliorate” is meant reduce, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease. In embodiments, the disease is amyloidosis, and a base editor system described herein reduces the accumulation of amyloid in a tissue of a subject.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.The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.By “base editor (BE),” or “nucleobase editor polypeptide (NBE)” is meant an agent that binds a polynucleotide and has nucleobase modifying activity. In various embodiments, the base editor comprises a nucleobase modifying polypeptide (e.g., a deaminase) and a polynucleotide programmable nucleotide binding domain (e.g., Cas9 or Cpf1). Representative nucleic acid and protein sequences of base editors include those sequences having about or at least about 85% sequence identity to any base editor sequence provided in the sequence listing, such as those corresponding to SEQ ID NOs: 2-11.By “BE4 cytidine deaminase (BE4) polypeptide,” is meant a base editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain, a cytidine deaminase domain, and two uracil glycosylase inhibitor domains (UGIs). In embodiments, the napDNAbp is a Cas9n (D10A) polypeptide. Non-limiting examples of cytidine deaminase domains include rAPOBEC, ppAPOBEC, RrA3F, AmAPOBEC1, and SsAPOBEC3B. By “BE4 cytidine deaminase (BE4) polynucleotide,” is meant a polynucleotide encoding a BE4 polypeptide. By “base editing activity” is meant acting to chemically alter a base within a polynucleotide. In one embodiment, a first base is converted to a second base. In one embodiment, the base editing activity is cytidine deaminase activity, e.g., converting target C•G to T•A. In another embodiment, the base editing activity is adenosine or adenine deaminase activity, e.g., converting A•T to G•C.The term “base editor system” or “base editing system” refers to an intermolecular complex for editing a nucleobase of a target nucleotide sequence. In various embodiments, the base editor (BE) system comprises (1) a polynucleotide programmable nucleotide binding domain, a deaminase domain (e.g., cytidine deaminase or adenosine deaminase) for deaminating nucleobases in the target nucleotide sequence; and (2) one or more guide polynucleotides (e.g., guide RNA) in conjunction with the polynucleotide programmable nucleotide binding domain. In various embodiments, the base editor (BE) system comprises a nucleobase editor domain selected from an adenosine deaminase or a cytidine deaminase, and a domain having nucleic acid sequence specific binding activity. In some embodiments, the base editor system comprises (1) a base editor (BE) comprising a polynucleotide programmable DNA binding domain and a deaminase domain for deaminating one or more nucleobases in a target nucleotide sequence; and (2) one or more guide RNAs in conjunction with the polynucleotide programmable DNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some embodiments, the base editor is a cytidine base editor (CBE). In some embodiments, the base editor is an adenine or adenosine base editor (ABE). In some embodiments, the base editor is an adenine or adenosine base editor (ABE) or a cytidine or cytosine base editor (CBE). In some embodiments, the base editor system (e.g., a base editor system comprising a cytidine deaminase) comprises a uracil glycosylase inhibitor or other agent or peptide (e.g., a uracil stabilizing protein such as provided in WO2022015969, the disclosure of which is incorporated herein by reference in its entirety for all purposes) that inhibits the inosine base excision repair system.As used herein, the term “bivalent” refers to a chemical moiety with two points of attachment. For example, a “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include but are not limited to: The terms “carbocyclyl,” “carbocycle,” and “carbocyclic ring” as used herein, refer to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having from 3 to 14 members, wherein the aliphatic ring system is optionally substituted as described herein. Carbocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to an optionally substituted monocyclic C3-C8 hydrocarbon, or an optionally substituted C6-C12 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. The term “cycloalkyl” refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. In some embodiments, cycloalkyl groups have 3–6 carbons. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.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.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 base editors described herein include the following: TAG, TAA, and TGA.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 base editor (e.g., base editor comprising a nucleic acid programmable DNA binding protein, such as Cas9, and a deaminase) 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 base editor (e.g., a deaminase, or a nucleic acid programmable DNA binding protein) may associate covalently or non-covalently. As one example, a base editor may include a deaminase covalently linked to a nucleic acid programmable DNA binding protein (e.g., by a peptide bond). Alternatively, a base editor may include a deaminase and a nucleic acid programmable DNA binding protein that associate noncovalently (e.g., where one or more components of the base editor are supplied in 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.By “cytosine” or “4-Aminopyrimidin-2(1H)-one” is meant a purine nucleobase with the molecular formula C4H5N3O, having the structure , and corresponding to CAS No. 71-30-7.By “cytidine” is meant a cytosine molecule attached to a ribose sugar via a glycosidic bond, having the structure , and corresponding to CAS No. 65-46-3. Its molecular formula is C9H13N3O5.By “Cytidine Base Editor (CBE)” is meant a base editor comprising a cytidine deaminase.By “Cytidine Base Editor (CBE) polynucleotide” is meant a polynucleotide encoding a CBE.By “cytidine deaminase” or “cytosine deaminase” is meant a polypeptide or fragment thereof capable of deaminating cytidine or cytosine. In embodiments, the cytidine or cytosine is present in a polynucleotide. In one embodiment, the cytidine deaminase converts cytosine to uracil or 5-methylcytosine to thymine. The terms “cytidine deaminase” and “cytosine deaminase” are used interchangeably throughout the application. Petromyzon marinus cytosine deaminase 1 (PmCDA1) (SEQ ID NO: 13-14), Activation-induced cytidine deaminase (AICDA) (SEQ ID NOs: 15-21), and APOBEC (SEQ ID NOs: 12-61) are exemplary cytidine deaminases. Further exemplary cytidine deaminase (CDA) sequences are provided in the Sequence Listing as SEQ ID NOs: 62-66 and SEQ ID NOs: 67-189. Non-limiting examples of cytidine deaminases include those described in PCT / US20 / 16288, PCT / US2018 / 021878, 180802-021804 / PCT, PCT / US2018 / 048969, and PCT / US2016 / 058344.By “cytosine deaminase activity” is meant catalyzing the deamination of cytosine or cytidine. In one embodiment, a polypeptide having cytosine deaminase activity converts an amino group to a carbonyl group. In an embodiment, a cytosine deaminase converts cytosine to uracil (i.e., C to U) or 5-methylcytosine to thymine (i.e., 5mC to T). In some embodiments, a cytosine deaminase as provided herein has increased cytosine deaminase activity (e.g., at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold or more) relative to a reference cytosine deaminase.The term “deaminase” or “deaminase domain,” as used herein, refers to a protein or fragment thereof that catalyzes a deamination reaction.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 using the methods and / or compositions of the present disclosure include as non-limiting examples amyloidosis, cardiomyopathy, familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), familial transthyretin amyloidosis (FTA), senile systemic amyloidosis (SSA), transthyretin amyloidosis, and the like. The disease can be any disease associated with a mutation in a transthyretin (TTR) polynucleotide sequence. By “dual editing activity” or “dual deaminase activity” is meant having adenosine deaminase and cytidine deaminase activity. In one embodiment, a base editor having dual editing activity has both AàG and CàT activity, wherein the two activities are approximately equal or are within about 10% or 20% of each other. In another embodiment, a dual editor has AàG activity that no more than about 10% or 20% greater than CàT activity. In another embodiment, a dual editor has AàG activity that is no more than about 10% or 20% less than CàT activity. In some embodiments, the adenosine deaminase variant has predominantly cytosine deaminase activity, and little, if any, adenosine deaminase activity. In some embodiments, the adenosine deaminase variant has cytosine deaminase activity, and no significant or no detectable adenosine deaminase activity.By “effective amount” is meant the amount of an agent (e.g., a base 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 base 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 base 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. In one embodiment, an effective amount of a base editor is sufficient to alter the sequence of a TTR polynucleotide in 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more cells of a tissue.The term “encapsulated” is used herein to refer to substances that are completely surrounded by another material. In an embodiment, an mRNA molecule encoding a base editor and / or a guide polynucleotide is encapsulated by a lipid nanoparticle of the disclosure.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.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.The term “haloaliphatic” refers to an aliphatic group substituted by one or more halogen atoms (e.g., one, two, three, four, five, six, or seven halo, such as fluoro, iodo, bromo, or chloro). In some embodiments, haloaliphatic groups contain 1-7 halogen atoms. In some embodiments, haloaliphatic groups contain 1-5 halogen atoms. In some embodiments, haloaliphatic groups contain 1-3 halogen atoms.The term “haloalkyl” refers to an alkyl group substituted by one or more halogen atoms (e.g., one, two, three, four, five, six, or seven halo, such as fluoro, iodo, bromo, or chloro). In some embodiments, haloalkyl groups contain 1-7 halogen atoms. In some embodiments, haloalkyl groups contain 1-5 halogen atoms. In some embodiments, haloalkyl groups contain 1-3 halogen atoms.The term “heteroalkylenyl” or “heteroalkylene”, as used herein, denotes an optionally substituted straight–chain (i.e., unbranched), or branched bivalent alkyl group (i.e., bivalent saturated hydrocarbon chain) having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” is described below. In some embodiments, heteroalkylenyl groups contain 2–10 carbon atoms wherein 1–3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur.  In some embodiments, heteroalkylenyl groups contain 2–8 carbon atoms wherein 1–3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroalkylenyl groups contain 4-8 carbon atoms, wherein 1–3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroalkylenyl groups contain 2-5 carbon atoms, wherein 1–2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur.  In yet other embodiments, heteroalkylenyl groups contain 1–3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur.  Suitable heteroalkylenyl groups include, but are not limited to -CH2O-, -(CH2)2O-, -CH2OCH2-, -O(CH2)2-, -(CH2)3O-, -(CH2)2OCH2-, -CH2O(CH2)2-, -O(CH2)3-, -(CH2)4O-, -(CH2)3OCH2-, -CH2O(CH2)3-, -(CH2)2O(CH2)2-, -O(CH2)4-. Unless otherwise specified, Cx heteroalkylenyl refers to heteroalkylenyl having x number of carbon atoms prior to replacement with heteroatoms.The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).The terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably herein, and refer to a stable 3- to 8-membered monocyclic, a 7- to 12-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiamorpholinyl, and . A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.“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 “inhibitor of base repair”, “base repair inhibitor”, “IBR” or their grammatical equivalents refer to a protein that is capable in inhibiting the activity of a nucleic acid repair enzyme, for example a base excision repair enzyme.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.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.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. For example, those of ordinary skill in the art appreciate that a polypeptide whose structure includes two or more functional or organizational domains often includes a stretch of amino acids between such domains that links them to one another. In some embodiments, a polypeptide comprising a linker element “L’” has an overall structure of the general form S1-L’-S2, wherein S1 and S2 may be the same or different and represent two domains associated with one another by the linker. In some embodiments, a polypeptide linker is at least 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, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more amino acids in length. In some embodiments, a linker is characterized in that it tends not to adopt a rigid three-dimensional structure, but rather provides flexibility to the polypeptide. A variety of different linker elements that can appropriately be used when engineering polypeptides (e.g., fusion polypeptides) known in the art (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2: 1 121-1123).As used herein, a “lipid nanoparticle (LNP) composition” is a nanoparticle composition comprising one or more ionizable lipids. Exemplary LNP compositions include, but are not limited to, phospholipids, conjugate-linker lipids (e.g., PEG-lipids), sterols, and ionizable lipids (e.g., IZ1, IZ4).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 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 (4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)).As used herein, the “N / P ratio” is the molar ratio of ionizable nitrogen atoms in a lipid(s) to phosphate groups in a nucleic acid molecular entity(ies). In some embodiments, the nitrogen atoms are ionizable within a physiological pH range. In some embodiments, the molecular entities in a nanoparticle composition include a lipid component and an RNA. Ionizable nitrogen atoms can include, for example, nitrogen atoms that can be protonated at about pH 1, about pH 2, about pH 3, about pH 4, about pH 4.5, about pH 5, about pH 5.5, about pH 6, about pH 6.5, about pH 7, about pH 7.5, or about pH 8 or higher. The physiological pH range can include, for example, the pH range of different cellular compartments (such as organs, tissues, and cells) and bodily fluids (such as blood, CSF, gastric juice, milk, bile, saliva, tears, and urine). In certain specific embodiments, the physiological pH range refers to the pH range of blood in a mammal, for example, from about 7.35 to about 7.45. Similarly, for phosphate charge neutralizers that have one or more ionizable nitrogen atoms, the N / P ratio can refer to a molar ratio of ionizable nitrogen atoms in the phosphate charge neutralizer to the phosphate groups in a nucleic acid. In some embodiments, ionizable nitrogen atoms refer to those nitrogen atoms that are ionizable within a pH range between 5 and 14.For a payload that does not contain a phosphate group, the N / P ratio can refer to a molar ratio of ionizable nitrogen atoms in a lipid to the total negative charge in the payload. For example, the N / P ratio of an LNP composition can refer to a molar ratio of the total ionizable nitrogen atoms in the LNP composition to the total negative charge in the payload that is present in the composition.As used herein, the term “nanoparticle” refers to a particle having a diameter of less than 1000 nanometers (nm). In some embodiments, a nanoparticle has a diameter of less than 300 nm, as defined by the National Science Foundation. In some embodiments, a nanoparticle has a diameter of less than 100 nm as defined by the National Institutes of Health. In some embodiments, nanoparticles are micelles in that they comprise an enclosed compartment, separated from the bulk solution by a micellar membrane, typically comprised of amphiphilic entities which surround and enclose a space or compartment (e.g., to define a lumen). In some embodiments, a micellar membrane is comprised of at least one polymer, such as for example a biocompatible and / or biodegradable polymer.In some embodiments, lipid nanoparticles described herein can have an average hydrodynamic diameter from about 30 to about 170 nm. In some embodiments, lipid nanoparticles described herein can have an average hydrodynamic diameter that is about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 205 nm, 210 nm, 215 nm, 220 nm, or any range having endpoints defined by any two of the aforementioned values. For example, in some embodiments, lipid nanoparticles described herein have an average hydrodynamic diameter from between 50 nm to 100 nm. For example, in some embodiments, compositions, preparations, nanoparticles, and / or nanomaterials described herein have an average hydrodynamic diameter from between 50 nm to 90 nm. In some embodiments, lipid nanoparticles described herein have an average hydrodynamic diameter from about 60 to about 80 nm. For example, in some embodiments, lipid nanoparticles described herein have an average hydrodynamic diameter from between 50 nm to 70 nm.As used herein, the term “nanoparticle composition” refers to a composition that contains at least one nanoparticle and at least one additional agent or ingredient. In some embodiments, a nanoparticle composition contains a substantially uniform collection of nanoparticles as described herein.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).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: 190), KRPAATKKAGQAKKKK (SEQ ID NO: 191), KKTELQTTNAENKTKKL (SEQ ID NO: 192), KRGINDRNFWRGENGRKTR (SEQ ID NO: 193), RKSGKIAAIVVKRPRK (SEQ ID NO: 194), PKKKRKV (SEQ ID NO: 195), MDSLLMNRRKFLYQFKNVRWAKGRRETYLC (SEQ ID NO: 196), PKKKRKVEGADKRTADGSEFESPKKKRKV (SEQ ID NO: 328), or RKSGKIAAIVVKRPRKPKKKRKV (SEQ ID NO: 329).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 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. Exemplary nucleic acid programmable DNA binding proteins and nucleic acid sequences encoding nucleic acid programmable DNA binding proteins are provided in the Sequence Listing as SEQ ID NOs: 197-245, 254-260, and 378. In some embodiments, the napDNAbp is a (CRISPR-associated system) Cas9 endonuclease, for example, Cas9 (Csnl) from Streptococcus pyogenes (e.g., SEQ ID NO: 197), Cas9 from Neisseria meningitidis (NmeCas9; SEQ ID NO: 208), Nme2Cas9 (SEQ ID NO: 209), Streptococcus constellatus (ScoCas9), or derivatives thereof (e.g., a sequence with at least about 85% sequence identity to a Cas9, such as Nme2Cas9 or spCas9).The terms “nucleobase editing domain” or “nucleobase editing protein,” as used herein, refers to a protein or enzyme that can catalyze a nucleobase modification in RNA or DNA, such as cytosine (or cytidine) to uracil (or uridine) or thymine (or thymidine), and adenine (or adenosine) to hypoxanthine (or inosine) deaminations, as well as non-templated nucleotide additions and insertions. In some embodiments, the nucleobase editing domain is a deaminase domain (e.g., an adenine deaminase or an adenosine deaminase; or a cytidine deaminase or a cytosine deaminase).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.).The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).As used herein, a “phospholipid” can refer to a lipid that includes a phosphate moiety and one or more carbon chains, such as unsaturated fatty acid chains. A phospholipid may include one or more multiple (e.g., double or triple) bonds. In some embodiments, a phospholipid may facilitate fusion to a membrane. For example, a cationic phospholipid may interact with one or more negatively charged phospholipids of a membrane (e.g., a cellular or intracellular membrane). Fusion of a phospholipid to a membrane may allow one or more elements of an LNP to pass through the membrane, i.e., delivery of the one or more elements to a cell.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.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. The reference can be a cell or subject with a pathogenic mutation in a transthyretin (TTR) polynucleotide sequence and / or a transthyretin (TTR) polypeptide sequence. A reference can be a subject or cell with an amyloidosis (e.g., a transthyretin amyloidosis) or a subject or cell without an amyloidosis. In one embodiment, the level of amyloidosis in a cell or tissue treated with a base editor system described herein is compared to the level of amyloidosis in a corresponding untreated cell or tissue. 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 term “sterolyl,” as used herein, refers to a 17-membered fused polycyclic ring moiety that is either saturated or partially unsaturated and substituted with at least one hydroxyl group, and has a single point of attachment to the rest of the molecule at any substitutable carbon or oxygen atom. In some embodiments, a sterolyl group is a cholesterolyl group, or a variant or derivative thereof. In some embodiments, a cholesterolyl group is modified. In some embodiments, a cholesterolyl group is an oxidized cholesterolyl group (e.g., oxidized on the beta-ring structure or on the hydrocarbon tail structure). In some embodiments, a cholesterolyl group is an esterified cholesterolyl group. In some embodiments, a sterolyl group is a phytosterolyl group. Exemplary sterolyl groups include but are not limited to 25-hydroxycholesterolyl (25-OH), 20α-hydroxycholesterolyl (20α-OH), 27-hydroxycholesterolyl, 6-keto-5α-hydroxycholesterolyl, 7-ketocholesterolyl, 7β-hydroxycholesterolyl, 7α-hydroxycholesterolyl, 7β-25-dihydroxycholesterolyl, beta-sitosterolyl, stigmasterolyl, brassicasterolyl, and campesterolyl.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 described herein, compounds of this disclosure may be described as “substituted” or “optionally substituted”. That is, compounds may contain optionally substituted and / or substituted moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., refers to at least ; and refers to at least ,,, or ). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.Suitable monovalent substituents include halogen; –(CH2)0–4R°; –(CH2)0–4OR°; –O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4Ph, which may be substituted with R°; −(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; (CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; −N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; –N(R°)N(R°)C(O)NR°2; −N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; (CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR°–, –SC(S)SR°; −(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, (CH2)0–4OC(O)NR°2; C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°;(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; –S(O)2NR°2; (CH2)0–4S(O)R°; –N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; –P(O)2R°; P(O)R°2; −OP(O)R°2; –OP(O)(OR°)2; –SiR°3; –OSiR°3; –(C1–4 straight or branched alkylene)O–N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2Rl, –(haloRl), –(CH2)0–2OH, –(CH2)0–2ORl, –(CH2)0–2CH(ORl)2; –O(haloRl), –CN, –N3, –(CH2)0–2C(O)Rl, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)ORl, –(CH2)0–2C(O)NH2, –(CH2)0–2C(O)NHRl, –(CH2)0–2C(O)NRl2, –(CH2)0–2SRl, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHRl, –(CH2)0–2NRl2, –NO2, –SiRl3, –OSiRl3, C(O)SRl, –(C1–4 straight or branched alkylene)C(O)ORl, or –SSRl wherein each Rl is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.Suitable divalent substituents include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.Suitable substituents on the aliphatic group of R* include halogen, –Rl, (haloRl), –OH, –ORl, –O(haloRl), –CN, –C(O)OH, –C(O)ORl, –NH2, –NHRl, –NRl2, or –NO2, wherein each Rl is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, suitable substituents on a substitutable nitrogen include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, –S(O)2R†, –S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.Suitable substituents on the aliphatic group of R† are independently halogen, –Rl, (haloRl), –OH, –ORl, –O(haloRl), –CN, –C(O)OH, –C(O)ORl, –NH2, –NHRl, –NRl2, or –NO2, wherein each Rl is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.The term “stable,” when applied to compositions herein, means that the compositions maintain one or more aspects of their physical structure (e.g., size range and / or distribution of particles) over a period of time. In some embodiments, a stable nanoparticle composition is one for which the average particle size, the maximum particle size, the range of particle sizes, and / or the distribution of particle sizes (i.e., the percentage of particles above a designated size and / or outside a designated range of sizes) is maintained for a period of time under specified conditions. In some embodiments, a stable provided composition is one for which a biologically relevant activity is maintained for a period of time. In some embodiments, the period of time is at least about one hour; in some embodiments the period of time is about 5 hours, about 10 hours, about one (1) day, about one (1) week, about two (2) weeks, about one (1) month, about two (2) months, about three (3) months, about four (4) months, about five (5) months, about six (6) months, about eight (8) months, about ten (10) months, about twelve (12) months, about twenty-four (24) months, about thirty-six (36) months, or longer. In some embodiments, the period of time is within the range of about one (1) day to about twenty-four (24) months, about two (2) weeks to about twelve (12) months, about two (2) months to about five (5) months, etc. For example, if a population of nanoparticles is subjected to prolonged storage, temperature changes, and / or pH changes, and a majority of the nanoparticles in the composition maintain a diameter within a stated range, the nanoparticle composition is stable. In some embodiments, a stable composition is stable at ambient conditions. In some embodiments, a stable composition is stable under biologic conditions (i.e. 37 ºC in phosphate buffered saline).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 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 deamination of a base. The deaminase can be a cytidine or an adenine deaminase. The fusion protein or base editing complex comprising a deaminase may comprise a dCas9-adenosine deaminase fusion protein, a Cas12b-adenosine deaminase fusion, or a base editor disclosed herein.By “transthyretin (TTR) polypeptide” is meant a polypeptide or fragment thereof having at least about 95% amino acid sequence identity to an amino acid sequence provided at NCBI Reference Sequence No. NP_000362.1, or a fragment thereof, that binds an anti-TTR antibody. In some embodiments, a TTR polypeptide or fragment thereof has holo-retinol-binding protein (RBP) and / or thyroxine (T4) transport activity. In embodiments, TTR is capable of forming a tetramer. An exemplary TTR polypeptide sequence follows (the signal peptide sequence is in bold; therefore, the mature TTR polypeptide corresponds to amino acids 21 to 147 of the following sequence):MASHRLLLLCLAGLVFVSEAGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE (SEQ ID NO: 464).By “transthyretin (TTR) polynucleotide” is meant a nucleic acid molecule that encodes a TTR 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, the regulatory sequence is a promoter region. In embodiments, a TTR polynucleotide is the genomic sequence, cDNA, mRNA, or gene associated with and / or required for TTR expression. An exemplary TTR polynucleotide sequence (corresponding to Consensus Coding Sequence (CCDS) No. 11899.1) is provided below. Further exemplary TTR polynucleotide sequences include Gene Ensembl ID: ENSG00000118271 and Transcript Ensembl ID: ENST00000237014.8.ATGGCTTCTCATCGTCTGCTCCTCCTCTGCCTTGCTGGACTGGTATTTGTGTCTGAGGCTGGCCCTACGGGCACCGGTGAATCCAAGTGTCCTCTGATGGTCAAAGTTCTAGATGCTGTCCGAGGCAGTCCTGCCATCAATGTGGCCGTGCATGTGTTCAGAAAGGCTGCTGATGACACCTGGGAGCCATTTGCCTCTGGGAAAACCAGTGAGTCTGGAGAGCTGCATGGGCTCACAACTGAGGAGGAATTTGTAGAAGGGATATACAAAGTGGAAATAGACACCAAATCTTACTGGAAGGCACTTGGCATCTCCCCATTCCATGAGCATGCAGAGGTGGTATTCACAGCCAACGACTCCGGCCCCCGCCGCTACACCATTGCCGCCCTGCTGAGCCCCTACTCCTATTCCACCACGGCTGTCGTCACCAATCCCAAGGAATGA (SEQ ID NO: 465).A further exemplary TTR polynucleotide sequence is provided at NCBI Reference Sequence No. NG_009490.1 and follows (where exons encoding the TTR polypeptide are in bold, introns are in italics, and exemplary promoter regions are indicated by the combined underlined and bold-underlined text (promoter positions -1 to -177) and by the bold-underlined text (promoter positions -106 to -176):TTATGTGTTTATTCAACAATGGCGGAGGAGAGGCATGCCAGATAAGGCAGACACGGGCATTCCAAACACAAGAAAGGTATGTGCTGCAGAGAAGTCAGATAACTTTCCTAGGCTCTCCTGCAGTCCGGATGAAATACTCTCAAAAAATTAGCCCGGGCCCTTTGCTCCAATTTTTCGCTTACCTAGCAACCATCTAACTATTAATTAAATTGGTATTATGGTTTTAACATGAATCTTTTATGATTTGCTTACCATTAATCAAACCCCCGAGGCTTATTCACCTCAAGGGGAGCTGACAAAGTTGAATTATTCAACCTGCAAAGATCCAGGGCCCCCAAATACTGTCATTTCCACTCTCCCCTAACCCCCACCATGAGGCCCAGTCTCAGCACTCGGCCAGCCTATGCCCAACTCGGGGTAATCAGCTTAGACATATTAATATTAGTGGGCATTTCAGTATCAACAGATCACTGTCTAGCAGCTGACAGGCACCCTCAGAAAATAAACCAAGAAGAAAGGGTTTATCTATAATATCAAAATTTTTCATAGATAAACCTGCCCATTATAAGGAAGAGGGCAGAAGAACCCTAAACTAAGAGCCAGGCAACTTGTTCATTAATCACAGCATATTCCATAGAAGGAGGAGAAATGTTGTCATCAAATTCATCTTTTTCACCTCAATTAAACATCTATGCTACAGCTCCACAGTCAGATTGAGAGGAAAAACAGTACGTAGCTAAGAAAAGACATAGACTTGTAACTGAAATGCTTCACTGGTGCTCCTTTTGTTTTAAGGCATTGGATCTTCATAGCTACTGATCGTGCCCAAGCACACAGTATCTGCAGCAACCACTTAGGCCTCCAGGAATGTGGTGACCATTGACCCTAATTCATTCCCCTTCATGGATCCTATGTAACCATCCTCCAAAAAGAGCTTTCGCAAACTCAAATAAACACAGGAAAGGAAGACCTTCTTATCTTTGAGAGTATATGTTTAGCCCTATAACCCTCTCTTATCATAAATTGCTTCTTAGGCAAGAAACACTGGATTTTTCTTGTATTTGTCATTGCCATTGGTTCCATACAAGCATTCATTTAACAAATAATACATTCCATCTCCGTTTTTTGCTTTTTCCTTCATGCTTCGGCCTTGGTTTTCTCTCACCTAAAACACTACAAGCTTCTTCTCCCAGAGCTCTCACTTTGACTCCAGACTACCTACATTTAATCTTTAATTCTCTACCAAAATTTTCTCTTATCTTTATATCTTTTTAATTTTAATTTTATTTTTTGTGGATACATAGTAGGTGTATATATTTATGGGGTACATGCAATGTTTTAATACAGGCATGCAATGTGAAATAAGGACATCATGGAGAATGGGGTATCCATCTCCTCAAGCATTTATCTTTTCAGTTACAAACAATCCAATTACACTCTTTATTTTAAAATATACAATTATTAATTATAGTCACTCTGTTGTGCTATCAAATAGTAGATCTTATTCTTTCTATTTTTTGTACCCTCTCGTCTTTTTATATTAAAAAATAATCTTTATCTCTGTAAGCTTCATCAGTGATTTTCCAATGAAATTTAGGATCTTCTCTATACCCTGAATTGCCTTACTTTCTCCCCACTTCCTTGTCTTATTCAAATGCAGATTTCATTAATGATTTCCAGATCAATGATAGTTCAGAAAGCAAGCAAGTCAAAGTGACCAAGGGCATGGCCTGAAAACTGTTCTAAGAGAGGAATTTACAGAACAACTATTAAATGATGTCAATAGGATTGTATTAGTCCGTTTTCATACGGCTATAAAGAACTGCCTGAGACTGGGTAATTTATAAAGGAAAGAGGTTTAATTGACTCACAGTTCAGCACAACTGGGCAGGCCTCAGGAAACTTACAATCATGGTAGAAGGTGAAGGGGAAGCAAAGCACCTTCCTCACAAGGCGTCAGGAAGAAGTGCCAAGCAAAGGGGGAAAAGCCCCTTGTAAAACTACCAGAACCTGTGAGAACTCAATCACTATCACAAGAACAGCATGAGGGAACCGCCCCTCGTGATTCAATTACCTCCACCTGGTCTCTCCCTTGACACATGGGGATTATGGGTGTTACAATTCAAGATGAGATTTGGGTGGGGACACAAAGCCTAACCATATCAAGGATCAAGTGGTGGGTTGAAACTAACAGGATGAGATATATCAGATACAAACACAGGGTCCCATATTTGGGTTAAAATTCATAAATGATCAAAGCACAGGATGACAGATAATATAGGTCATTTTAGATTATTGTGGCCAACAGATCACAGTGGGTAGTGTTATGACGAAGGGAGGGTCACAGTTACTACAGTTACAGATGGATTCTGGGTACAACATTTGCACTAAAGTGCCTTTGCCAAGGGAGGCAACAGTCTCGACATCCTGTGGCCTGATCTACTTCAGGGACTGTGTCTTGTTCAGAGCATCACATTTGAAGAGAACTTTGACCAAGGGGAATATGCCAGAAAAGGAAGTTCGGGATGCTGAGGATCTTAGGAACTATGTCTAAACAAGATTCATTCACAGAAGTGGGAATGTCTATTTGGCAAAAAGAAAATACTACTTACATGGCTGTTGGAAGACCAGCAATCACAAACTCAGTTTTTCAAAAGGCTGGGCAGAAACACAGATGAAAGAAACAGGCCATGTTTAAGAAAAGATAAAAGCTCACGCATGATATGCCACTAGAGAATCACCTAGCCTCAGTGTTGGCGGGGAGGCCTGGGGAGTCTTGATGTCTGAGAGTGACATTCTGATGATCACTGTCATGTGTAAATGTTGGCCTAAAGCTGCCAATATTTTTGATTTAAGAGAAGCAAGAAATGCAAATTTTTATGCAGCATGTCTCAATTTTTAATTTTGGCAACTATTACAAAATGTTTAAAGAGACTCTGTGCAGCCCAAATATAACATATCTATGGGCTGATGGCAGCCCAGCGTTGCCAGTTCACAGGGTCTACAAGAGATGATTCTTAGTTTCAACAGGGTGCAGTGCTGAAACGCGTGCACAGTAGATTTTGCTTCGGTTATGAAAGAACTTCCAAATATTTATGATTCATAGCCAGAGAAAAGGCTCTCTATCCAGGTTCTGAACAATAGGAAATCATCAAGAGGATATTGGATGACAATATATGAAAGATGTTATTTGAGAAAGGATTCTCTCCTGAGGCATAGATGTTGAACCAAATTCTATTAGTTATGCTTTTACAGCAAGATAGTGGTTTACAGCTTACAAAAGGCTTGTACATCCTCTCATATTAAAAGTTATTAGAACAGTCCTTTGAAGTAGAAAAGTAGGCATTTCTATTTTACAAACGAGTTGGCCGAGTATCTGAGATAGTAGATAACTCATAGAAGGTCATCCGGGAAACGGGGCAGCAGAACTGGGATCGAATGACTCTGGTCATCCAACTCCAAATGCAAAAGTCTTTCTGCTGCTGCTTCCTAGTTAAACTCTAAGGGTCTAAGACTCCATTCCTAGTTATGGTCTCAACTACATTTGCTCATTGCTGTGAGGGGTCAACCCACCTCCCGGAGTCCTCTCCTGCACATTCTCATGTTCCTGAAAGGCTTTTCTGTCCCTTCCACTACTCCCTGTAAGCTCCTGTGCTTCACAATTTCTTGTTGAATTTTTTCTAATCTGACTCTATCAGTTATGGGAATGTTCCCTCAATTCTTAGTGCTCCAAACCGGACTTGCTCTTGGCTTGTATTTGTCCAAAATATTTGTCTTCTCTATGTTTTCTACATGTTTGTCTTATAAGGACAAAAACCTGCCTTAGTTTATCCATGAACAAAGCCACGCATGCTAGTGGACACACACACACATGCGCGTGCGCGCGCACACACACACACACACACATACACACAGAGACTTTGTATGTGAGTAATGAATCATCAAATCATCATAATTTCTGGACTTGTATTAATAAGTCGGCCAGGAGGAAAAGAATCTGCTGTCAATCATGGCTTCTGGTTCTCACAGTCATCTCTACTTTCTTCCAGCAAGTTTGGTTCTGTCAAAAACCAGCTGTCAGCCTTGTTCCTGCATGCCCAATGCAGAAGAGTCAGTAAAGAAGATTTGGTTCTCTGTATTTCAGGGGCATCAATGCCAGGTTGAAATATGCCATTCTGGCCCAGCTCAGTGGCTCACACGTGTAATCCCAGCACTTTGGAAGGCCAAAGCGGGTGGATTGCTTGAGCTCAGGAGTTCGAGACCAGCCTGGGCAAGAGGCTGAGGTGGGAGGATGACCTGAGCCCGGGAGGTCAAGGCTGCAGCGAGCTGTGATCGTGCCACTGCACTCGAGCCAGGGCGTTGGAGTGAGACCCTGTCAAAAAAAAAAAAAAAAAGGAAGGAAAAAAGGAAGGAAGGAAGGGAGGGAGGGAAGATGCCATTCTTAGATTGAAGTGGACTTTATCTGGGCAGAACACACACACACATACACACATGCACACACACATTGTGGAGAAATTGCTGACTAAGCAAAGCTTCCAAATGACTTAGTTTGGCTAAAATGTAGGCTTTTAAAAATGTGAGCACTGCCAAGGGTTTTTCCTTGTTGACCCATGGATCCATCAAGTGCAAACATTTTCTAATGCACTATATTTAAGCCTGTGCAGCTAGATGTCATTCAACATGAAATACATTATTACAACTTGCATCTGTCTAAAATCTTGCATCTAAAATGAGAGACAAAAAATCTATAAAAATGGAAAACATGCATAGAAATATGTGAGGGAGGAAAAAATTACCCCCAAGAATGTTAGTGCACGCAGTCACACAGGGAGAAGACTATTTTTGTTTTGTTTTGATTGTTTTGTTTTGTTTTGGTTGTTTTGTTTTGGTGACCTAACTGGTCAAATGACCTATTAAGAATATTTCATAGAACGAATGTTCCGATGCTCTAATCTCTCTAGACAAGGTTCATATTTGTATGGGTTACTTATTCTCTCTTTGTTGACTAAGTCAATAATCAGAATCAGCAGGTTTGCAGTCAGATTGGCAGGGATAAGCAGCCTAGCTCAGGAGAAGTGAGTATAAAAGCCCCAGGCTGGGAGCAGCCATCACAGAAGTCCACTCATTCTTGGCAGGATGGCTTCTCATCGTCTGCTCCTCCTCTGCCTTGCTGGACTGGTATTTGTGTCTGAGGCTGGCCCTACGGTGAGTGTTTCTGTGACATCCCATTCCTACATTTAAGATTCACGCTAAATGAAGTAGAAGTGACTCCTTCCAGCTTTGCCAACCAGCTTTTATTACTAGGGCAAGGGTACCCAGCATCTATTTTTAATATAATTAATTCAAACTTCAAAAAGAATGAAGTTCCACTGAGCTTACTGAGCTGGGACTTGAACTCTGAGCATTCTACCTCATTGCTTTGGTGCATTAGGTTTGTAATATCTGGTACCTCTGTTTCCTCAGATAGATGATAGAAATAAAGATATGATATTAAGGAAGCTGTTAATACTGAATTTTCAGAAAAGTATCCCTCCATAAAATGTATTTGGGGGACAAACTGCAGGAGATTATATTCTGGCCCTATAGTTATTCAAAACGTATTTATTGATTAATCTTTAAAAGGCTTAGTGAACAATATTCTAGTCAGATATCTAATTCTTAAATCCTCTAGAAGAATTAACTAATACTATAAAATGGGTCTGGATGTAGTTCTGACATTATTTTATAACAACTGGTAAGAGGGAGTGACTATAGCAACAACTAAAATGATCTCAGGAAAACCTGTTTGGCCCTATGTATGGTACATTACATCTTTTCAGTAATTCCACTCAAATGGAGACTTTTAACAAAGCAACTGTTCTCAGGGGACCTATTTTCTCCCTTAAAATTCATTATACACATCCCTGGTTGATAGCAGTGTGTCTGGAGGCAGAAACCATTCTTGCTTTGGAAACAATTACGTCTGTGTTATACTGAGTAGGGAAGCTCATTAATTGTCGACACTTACGTTCCTGATAATGGGATCAGTGTGTAATTCTTGTTTCGCTCCAGATTTCTAATACCACAAAGAATAAATCCTTTCACTCTGATCAATTTTGTTAACTTCTCACGTGTCTTCTCTACACCCAGGGCACCGGTGAATCCAAGTGTCCTCTGATGGTCAAAGTTCTAGATGCTGTCCGAGGCAGTCCTGCCATCAATGTGGCCGTGCATGTGTTCAGAAAGGCTGCTGATGACACCTGGGAGCCATTTGCCTCTGGGTAAGTTGCCAAAGAACCCTCCCACAGGACTTGGTTTTATCTTCCCGTTTGCCCCTCACTTGGTAGAGAGAGGCTCACATCATCTGCTAAAGAATTTACAAGTAGATTGAAAAACGTAGGCAGAGGTCAAGTATGCCCTCTGAAGGATGCCCTCTTTTTGTTTTGCTTAGCTAGGAAGTGACCAGGAACCTGAGCATCATTTAGGGGCAGACAGTAGAGAAAAGAAGGAATCAGAACTCCTCTCCTCTAGCTGTGGTTTGCAACCCTTTTGGGTCACAGAACACTTTATGTAGGTGATGAAAAGTAAACATTCTATGCCCAGAAAAAATGCACAGATACACACACATACAAAATCATATATGTGATTTTAGGAGTTTCACAGATTCCCTGGTGTCCCTGGGTAACACCAAAGCTAAGTGTCCTTGTCTTAGAATTTTAGGAAAAGGTATAATGTGTATTAACCCATTAACAAAAGGAAAGGAATTCAGAAATATTATTAACCAGGCATCTGTCTGTAGTTAATATGGATCACCCAAAACCCAAGGCTTTTGCCTAATGAACACTTTGGGGCACCTACTGTGTGCAAGGCTGGGGGCTGTCAAGCTCAGTTAAAAAAAAAAAGATAGAAGAGATGGATCCATGAGGCAAAGTACAGCCCCAGGCTAATCCCACGATCACCCGACTTCATGTCCAAGAGTGGCTTCTCACCTTCATTAGCCAGTTCACAATTTTCATGGAGTTTTTCTACCTGCACTAGCAAAAACTTCAAGGAAAATACATATTAATAAATCTAAGCAAAGTGACCAGAAGACAGAGCAATCAGGAGACCCTTTGCATCCAGCAGAAGAGGAACTGCTAAGTATTTACATCTCCACAGAGAAGAATTTCTGTTGGGTTTTAATTGAACCCCAAGAACCACATGATTCTTCAACCATTATTGGGAAGATCATTTTCTTAGGTCTGGTTTTAACTGGCTTTTTATTTGGGAATTCATTTATGTTTATATAAAATGCCAAGCATAACATGAAAAGTGGTTACAGGACTATTCTAAGGGAGAGACAGAATGGACACCAAAAATATTCCAATGTTCTTGTGAATCTTTTCCTTGCACCAGGACAAAAAAAAAAAGAAGTGAAAAGAAGAAAGGAGGAGGGGCATAATCAGAGTCAGTAAAGACAACTGCTATTTTTATCTATCGTAGCTGTTGCAGTCAAATGGGAAGCAATTTCCAACATTCAACTATGGAGCTGGTACTTACATGGAAATAGAAGTTGCCTAGTGTTTGTTGCTGGCAAAGAGTTATCAGAGAGGTTAAATATATAAAAGGGAAAAGAGTCAGATACAGGTTCTTCTTCCTACTTTAGGTTTTCCACTGTGTGTGCAAATGATACTCCCTGGTGGTGTGCAGATGCCTCAAAGCTATCCTCACACCACAAGGGAGAGGAGCGAGATCCTGCTGTCCTGGAGAAGTGCAGAGTTAGAACAGCTGTGGCCACTTGCATCCAATCATCAATCTTGAATCACAGGGACTCTTTCTTAAGTAAACATTATACCTGGCCGGGCACGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGATGCCAAAGTGGGCATATCATCTGAGGTCAGGAGTTCAAGACCAGCCTGGCCAACATGGCAAAACTCCGTCTTTATGAAAAATACAAAAATTAGCCAGGCATGGTGGCAGGCGCCTGTAATCCCAGCTAATTGGGAGGCTGAGGCTGGAGAATCCCTTGAATCTAGGAGGCAGAGGTTGCAGTGAGCTGAGATCGTGCCATTGCACTCCAGCCTGGGTGACAAGAGTAAAACTCTGTCTCAAAAAAAAAAAATTATACCTACATTCTCTTCTTATCAGAGAAAAAAATCTACAGTGAGCTTTTCAAAAAGTTTTTACAAACTTTTTGCCATTTAATTTCAGTTAGGAGTTTTCCCTACTTCTGACTTAGTTGAGGGGAAATGTTCATAACATGTTTATAACATGTTTATGTGTGTTAGTTGGTGGGGGTGTATTACTTTGCCATGCCATTTGTTTCCTCCATGCGTAACTTAATCCAGACTTTCACACCTTATAGGAAAACCAGTGAGTCTGGAGAGCTGCATGGGCTCACAACTGAGGAGGAATTTGTAGAAGGGATATACAAAGTGGAAATAGACACCAAATCTTACTGGAAGGCACTTGGCATCTCCCCATTCCATGAGCATGCAGAGGTGAGTATACAGACCTTCGAGGGTTGTTTTGGTTTTGGTTTTTGCTTTTGGCATTCCAGGAAATGCACAGTTTTACTCAGTGTACCACAGAAATGTCCTAAGGAAGGTGATGAATGACCAAAGGTTCCCTTTCCTATTATACAAGAAAAAATTCACAACACTCTGAGAAGCAAATTTCTTTTTGACTTTGATGAAAATCCACTTAGTAACATGACTTGAACTTACATGAAACTACTCATAGTCTATTCATTCCACTTTATATGAATATTGATGTATCTGCTGTTGAAATAATAGTTTATGAGGCAGCCCTCCAGACCCCACGTAGAGTGTATGTAACAAGAGATGCACCATTTTATTTCTCGAAAACCCGTAACATTCTTCATTCCAAAACACATCTGGCTTCTCGGAGGTCTGGACAAGTGATTCTTGGCAACACATACCTATAGAGACAATAAAATCAAAGTAATAATGGCAACACAATAGATAACATTTACCAAGCATACACCATGTGGCAGACACAATTATAAGTGTTTTCCATATTTAACCTACTTAATCCTCAGGAATAAGCCACTGAGGTCAGTCCTATTATTATCCCCATCTTATAGATGAAGAAAATGAGGCACCAGGAAGTCAAATAACTTGTCAAAGGTCACAAGACTAGGAAATACACAAGTAGAAATGTTTACAATTAAGGCCCAGGCTGGGTTTGCCCTCAGTTCTGCTATGCCTCGCATTATGCCCCAGGAAACTTTTTCCCTTGTGAAAGCCAAGCTTAAAAAAAGAAAAGCCACATTTGTAACGTGCTCTGTTCCCCTGCCTATGGTGAGGATCTTCAAACAGTTATACATGGACCCAGTCCCCCTGCCTTCTCCTTAATTTCTTAAGTCATTTGAAACAGATGGCTGTCATGGAAATAGAATCCAGACATGTTGGTCAGAGTTAAAGATCAACTAATTCCATCAAAAATAGCTCGGCATGAAAGGGAACTATTCTCTGGCTTAGTCATGGATGAGACTTTCAATTGCTATAAAGTGGTTCCTTTATTAGACAATGTTACCAGGGAAACAACAGGGGTTTGTTTGACTTCTGGGGCCCACAAGTCAACAAGAGAGCCCCATCTACCAAGGAGCATGTCCCTGACTACCCCTCAGCCAGCAGCAAGACATGGACCCCAGTCAGGGCAGGAGCAGGGTTTCGGCGGCGCCCAGCACAAGACATTGCCCCTAGAGTCTCAGCCCCTACCCTCGAGTAATAGATCTGCCTACCTGAGACTGTTGTTTGCCCAAGAGCTGGGTCTCAGCCTGATGGGAACCATATAAAAAGGTTCACTGACATACTGCCCACATGTTGTTCTCTTTCATTAGATCTTAGCTTCCTTGTCTGCTCTTCATTCTTGCAGTATTCATTCAACAAACATTAAAAAAAAAAAAAAGCATTCTATGTGTGGAACACTCTGCTAGATGCTGTGGATTTAGAAATGAAAATACATCCCGACCCTTGGAATGGAAGGGAAAGGACTGAAGTAAGACAGATTAAGCAGGACCGTCAGCCCAGCTTGAAGCCCAGATAAATACGGAGAACAAGAGAGAGCGAGTAGTGAGAGATGAGTCCCAATGCCTCACTTTGGTGACGGGTGCGTGGTGGGCTTCATGCAGCTTCTTCTGATAAATGCCTCCTTCAGAACTGGTCAACTCTACCTTGGCCAGTGACCCAGGTGGTCATAGTAGATTTACCAAGGGAAAATGGAAACTTTTATTAGGAGCTCTTAGGCCTCTTCACTTCATGGATTTTTTTTTCCTTTTTTTTTGAGATGGAGTTTTGCCCTGTCACCCAGGCTGGAATGCAGTGGTGCAATCTCAGCTCACTGCAACCTCCGCCTCCCAGGTTCAAGCAATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTACAGGTGTGCGCCACCACACCAGGCTAATTTTTGTATTTTTTGTAAAGACAGGTTTTCACCACGTTGGCCAGGCTGGTCTGAACTCCAGACCTCAGGTGATTCACCTGTCTCAGCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACCGTGCCCGGCTACTTCATGGATTTTTGATTACAGATTATGCCTCTTACAATTTTTAAGAAGAATCAAGTGGGCTGAAGGTCAATGTCACCATAAGACAAAAGACATTTTTATTAGTTGATTCTAGGGAATTGGCCTTAAGGGGAGCCCTTTCTTCCTAAGAGATTCTTAGGTGATTCTCACTTCCTCTTGCCCCAGTATTATTTTTGTTTTTGGTATGGCTCACTCAGATCCTTTTTTCCTCCTATCCCTAAGTAATCCGGGTTTCTTTTTCCCATATTTAGAACAAAATGTATTTATGCAGAGTGTGTCCAAACCTCAACCCAAGGCCTGTATACAAAATAAATCAAATTAAACACATCTTTACTGTCTTCTACCTCTTTCCTGACCTCAATATATCCCAACTTGCCTCACTCTGAGAACCAAGGCTGTCCCAGCACCTGAGTCGCAGATATTCTACTGATTTGACAGAACTGTGTGACTATCTGGAACAGCATTTTGATCCACAATTTGCCCAGTTACAAAGCTTAAATGAGCTCTAGTGCATGCATATATATTTCAAAATTCCACCATGATCTTCCACACTCTGTATTGTAAATAGAGCCCTGTAATGCTTTTACTTCGTATTTCATTGCTTGTTATACATAAAAATATACTTTTCTTCTTCATGTTAGAAAATGCAAAGAATAGGAGGGTGGGGGAATCTCTGGGCTTGGAGACAGGAGACTTGCCTTCCTACTATGGTTCCATCAGAATGTAGACTGGGACAATACAATAATTCAAGTCTGGTTTGCTCATCTGTAAATTGGGAAGAATGTTTCCAGCTCCAGAATGCTAAATCTCTAAGTCTGTGGTTGGCAGCCACTATTGCAGCAGCTCTTCAATGACTCAATGCAGTTTTGCATTCTCCCTACCTTTTTTTTCTAAAACCAATAAAATAGATACAGCCTTTAGGCTTTCTGGGATTTCCCTTAGTCAAGCTAGGGTCATCCTGACTTTCGGCGTGAATTTGCAAAACAAGACCTGACTCTGTACTCCTGCTCTAAGGACTGTGCATGGTTCCAAAGGCTTAGCTTGCCAGCATATTTGAGCTTTTTCCTTCTGTTCAAACTGTTCCAAAATATAAAAGAATAAAATTAATTAAGTTGGCACTGGACTTCCGGTGGTCAGTCATGTGTGTCATCTGTCACGTTTTTCGGGCTCTGGTGGAAATGGATCTGTCTGTCTTCTCTCATAGGTGGTATTCACAGCCAACGACTCCGGCCCCCGCCGCTACACCATTGCCGCCCTGCTGAGCCCCTACTCCTATTCCACCACGGCTGTCGTCACCAATCCCAAGGAATGAGGGACTTCTCCTCCAGTGGACCTGAAGGACGAGGGATGGGATTTCATGTAACCAAGAGTATTCCATTTTTACTAAAGCAGTGTTTTCACCTCATATGCTATGTTAGAAGTCCAGGCAGAGACAATAAAACATTCCTGTGAAAGGCACTTTTCATTCCACTTTAACTTGATTTTTTAAATTCCCTTATTGTCCCTTCCAAAAAAAAGAGAATCAAAATTTTACAAAGAATCAAAGGAATTCTAGAAAGTATCTGGGCAGAACGCTAGGAGAGATCCAAATTTCCATTGTCTTGCAAGCAAAGCACGTATTAAATATGATCTGCAGCCATTAAAAAGACACATTCTGTAAATGAGAGAGCCTTATTTTCCTGTAACCTTCAGCAAATAGCAAAAGACACATTCCAAGGGCCCACTTCTTTACTGTGGGCATTTCTTTTTTTTTCTTTTTTTCTTTTTTCCTTTTTTGAGACAAAGTCTCACTCTGTTGCCCAGGCTAGAATGCAGTGGTGTAATCTCAGCTCACTGCAACCTCTGCTTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCCAAGTAACTGGGATTACAGGCGCATGCCACCACGCCTAGCTCATTTTTGTATTTTTAGTAGAGATGGGATTTTGCCATGTTGGCTAGGCTGGTCTACGAACTCCTGACCTCAGGTGATCCACCTGCCTCAGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACTACACCCGGCCCCTACTCTGGGCATTTCTTTGATTAAAGAGAAGGGGAGCTCCAACAAGATACACCTGCAGCAACTCAGGCCGTCTGATCAGTTCAGGCCAGATCTACACTGCAACCAGCCAGGTCAGGGGAAAACCAAAGAACCCCACACACCCAATTTACTTAGGCTGATCCAAAATCCATGTATGGAGAACTCACATGCACCAGGCACTATTTTAGGTGAACTGAATATAAAGAATAGGACCCAGTACCTGCATTTACTTAAAGAACTCACAATCTTTTGAGAACATAACTGTTTCATCATGGTTTGGCAGGAGGCTATGGTACAAGGCACAGCAAGGGTAAGAAGGAGGAAGAAACCAACACCCTACAGAAATCAGGGAATGACTCTGAATAGGTGTCACTTAATCTGAGTGTTGGTAATTTGTCAGATAGACAAGGGAAAAGGTATTCTAGGTAGAGAGAATACAGTTTGCAAGGCCCAGCCAAGTGAAACAATTTGATAAGTTGAGAGAGCAGACGACGATTCAGAATGTTGAAGGGCAAAGGTATTGAGGTGGGATGGGTTATGCTGCTATCACAAATAACCCCAAATCTCGGGGGCTTAACAAAGTAAAAGTTTAGTCTCAGTTGTGCCAGGTCCAATGTAGAACTCTTTGCTCTAGAGACTCTTTAGGGTGGCTTTCCTTCTAATGGTGACTGTTTGAGACAGTTTGATTTAGTCTTGTGGCTTCAAGGTCACTCTGGTGATATTTAGCCAGCAGACTGAGGGAACATAGTATGGTATTAGACCCCTCTGTGCTGAAGTGTCACACATGAGTCCCATTGACTTCTCACTGGCCAGAGCTAGTTACATGCCCCCATCTAGATGTGCTGAGAAATGTGGCCCCTGGCTGGGAGCCATTTCCCAGAACAACTAACTCTATGCTCTGGAAGAGGAGCACTAATCTGAGTTGGCCAACAACCATCTCTACCACAGTAGGGTTGGGACTGGTGGGGCATGAGGCTGGAGTGAAGGTTGGTTTTATCTGCCACGCGTTACAGCTGTGAATTTGTCTTGAAAGCAACATGGGTCCATTGAAGGGAACCTTGACATCAGTCATGTGGCTGGGACAAGAATAGTTACCACTTGCCCGTAATCTCCAACCAGGATTCTCCAGGAGAACCTGAGTTAGACACATGGCTTAGGCCTAAACCTACCTGAGTGGTCTTTCTATTTTCCTCCAAATTCAAATCTCAAATCTTGCTACCCTCTAACTGGCTATGTTGAGAGAGGAAAAAACTTGAAGAGAATGCAGTGTAGCTTTGGAGTTTTTCACATGCACTTTTCCCAAGATACATAGCAAAATCAATGTCTCCAATTCTATTAATGTTGTTAGCAAGTCCTTGTTCCATGCATATTGGTTAATCCATAGCAAATTGCCATTTTTATAGACTAAATGGTCAAATATTGGCAATTTCATAAGGTTCAGTCTATTACCTACCATGATTGTATTGGTCACTAACCTGCCTATTTTTAGAATGCTACATATTCATTTGGCTGTTGTTAAATAGCTATGGATTTTTATAATCAAAACAGGTTGAAAATATGAATCAGTTTAAAACCACATACA (SEQ ID NO: 466).In the above TTR polynucleotide sequence provided at NCBI Reference Sequence No. NG_009490.1, exons encoding the TTR polypeptide correspond to the union of nucleotides 5137..5205, 6130..6260, 8354..8489, and 11802..11909, and the intervening sequences correspond to intron sequences. The union of nucleotides 5137..5205, 6130..6260, 8354..8489, and 11802..11909 corresponds to Consensus Coding Sequence (CCDS) No. 11899.1.By “transthyretin amyloidosis” is meant a disease associated with an accumulation of amyloid in a tissue of a subject.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.By “uracil glycosylase inhibitor” or “UGI” is meant an agent that inhibits the uracil-excision repair system. Base editors comprising a cytidine deaminase convert cytosine to uracil, which is then converted to thymine through DNA replication or repair. In various embodiments, a uracil DNA glycosylase (UGI) prevent base excision repair which changes the U back to a C. In some instances, contacting a cell and / or polynucleotide with a UGI and a base editor prevents base excision repair which changes the U back to a C. An exemplary UGI comprises an amino acid sequence as follows:>splP14739IUNGI_BPPB2 Uracil-DNA glycosylase inhibitorMTNLSDIIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTSDAPEYKPWALVIQDSNGENKIKML (SEQ ID NO: 231).In some embodiments, the agent inhibiting the uracil-excision repair system is a uracil stabilizing protein (USP). See, e.g., WO 2022015969 A1, incorporated herein by reference.As used herein, the term "vector" refers to a means of introducing a nucleic acid molecule into a cell, resulting in a transformed cell. Vectors include plasmids, transposons, phages, viruses, liposomes, lipid nanoparticles, and episomes.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, 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 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 pertainsIn 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 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 DRAWINGSFIGs. 1A and 1B provide plots and charts showing that, under similar conditions, base editor systems containing a guide RNA targeting a human TTR polynucleotide sequence for base editing (i.e., human gRNA or “human”) and administered to primary human hepatocytes were associated with higher levels of base editing than base editor systems containing a guide RNA targeting a non-human primate TTR polynucleotide sequence (i.e., cyno gRNA or “cyno”) and administered to primary cyno hepatocytes. The base editor systems contained mRNA encoding an adenosine deaminase base editor containing a TadA*8.20 adenosine deaminase domain with a V82T amino acid alteration (referred to throughout the figures as “ABE9.51”). FIG. 1A provides a plot and chart showing base editing rates measured for base editing of a synthetic polynucleotide sequence (“AAVS1 Cassette”) in human embryonic kidney (HEK293) cells that contained a polynucleotide having the target sites for both the human gRNA and for the cyno gRNA. The base editor systems were delivered to the HEK293T cells using a commercially available lipid transfection reagent, Lipofectamine® MessengerMAX mRNA Transfection Reagent (LipoMM). FIG. 1B provides plots and a chart showing base editing rates measured in primary human hepatocytes (PHH) and primary cyno hepatocytes (PCH) at the TTR gene (left panel) or at the ALAS1 gene control (right panel). The ALAS1 gene (right panel) was base edited using a base editor system containing the control guide RNA sg23 known to be effective for use in targeting base editors to alter a nucleobase within the ALAS1 gene and an mRNA molecule encoding a base editor containing a TadA*8.8 adenosine deaminase domain. The base editor systems of FIG. 1B were delivered using lipid nanoparticles containing the ionizable lipid IZ1. In FIGs. 1A and 1B, the terms PHH-A, PHH-B, and PHH-C indicate three different human donors from which primary human hepatocytes (PHH) were obtained, “cTTR” indicates a cyno TTR gene, and “Conserved” indicates the ALAS1 gene.FIGs. 2A and 2B provide plots and charts showing that, under similar conditions, base editor systems containing a guide RNA targeting a human TTR polynucleotide sequence for base editing (i.e., human gRNA or “human”) and administered to primary human hepatocytes were associated with higher levels of base editing than base editor systems containing a guide RNA targeting a non-human primate TTR polynucleotide sequence (i.e., cyno gRNA or “cyno”) and administered to primary cyno hepatocytes (PCH). The base editor systems were administered to the cells using lipid nanoparticles containing the ionizable lipid IZ4. FIG. 2A provides a plot and a chart showing base editing rates measured in primary human hepatocytes (PHH) and primary cyno hepatocytes (PCH) at the TTR gene. The base editor systems administered to the PHH contained the guide RNA gRNA2944, and the base editor systems administered to the PCH contained the guide RNA gRNA2945. The base editor systems contained mRNA encoding a base editor containing a TadA*8.20 adenosine deaminase domain with a V82T amino acid alteration (referred to throughout the figures as “ABE9.51”). FIG. 2B provides a plot and a chart showing base editing rates measured for base editing measured in primary human hepatocytes (PHH) and primary cyno hepatocytes (PCH) at the ALAS1 gene. The ALAS1 gene was base edited using a base editor system containing the control guide RNA sg23 known to be effective for use in targeting base editors to alter a nucleobase within the ALAS1 gene and an mRNA molecule encoding a base editor containing a TadA*8.8 adenosine deaminase domain. In FIGs. 2A and 2B, the terms PHH1, PHH2, and PHH3 indicate primary human hepatocytes (PHH) from three different human donors. Throughout the figures the term “surrogacy” refers to evaluating or using base editing measurements for a non-human primate polynucleotide sequence or cell to infer base editing rates achieved under similar or analogous conditions (e.g., using a base editor system containing a guide RNA targeting a human polynucleotide rather than a non-human primate polynucleotide for base editing) in a human polynucleotide sequence or cell.FIGs. 3A to 3F provide bar graphs showing liver enzyme data for male (FIGs. 3A-3C) and female (FIGs. 3D-3F) non-human primates administered the indicated doses of lipid nanoparticles containing the lipid IZ1 and a base editor system containing a guide RNA targeting the TTR gene for base editing at the HM17 target site and an mRNA molecule encoding an adenosine deaminase base editor containing a TadA*8.20 adenosine deaminase domain variant with a V82T amino acid alteration. The groupings of bars from left-to-right in FIGs. 3A to 3F correspond to Control, 0.5 mg / kg, 1 mg / kg, and 2 mg / kg, respectively. In FIGs. 3A to 3F, the term “AST” represents “aspartate transaminase,” the term “ALT” represents “alanine transaminase,” and the term “ALP” represents “alkaline phosphatase.” The x-axes in FIGs. 3A to 3F represent the number of days following lipid nanoparticle administration (day 0). This experiment indicates that LNP administration of a base editor system had no sustained deleterious effect.FIG. 4 provides bar graphs showing rates of on-target (TTR gene A>G nucleotide alterations) and off-target (EIF3E gene A>G nucleotide alteration) base editing measured in primary human hepatocytes from donors PHH Donor 1 (PHH1 of FIGs. 2A and 2B) and PHH Donor 2 (PHH2 of FIGs. 2A and 2B) administered lipid nanoparticles containing base editor systems containing a guide RNA targeting the TTR gene for base editing at the HM17 target site and mRNA encoding an adenosine deaminase base editor containing a TadA*8.20 adenosine deaminase domain with a V82T amino acid alteration (referred to throughout the figures as “ABE9.51”) or a TadA*8.20 adenosine deaminase domain with the amino acid alterations V82T, Y147T, and Q154S (referred to throughout the figures as “ABE9.52”). For each pair of bars of FIG. 4, the left bar corresponds to “TTR, A>G” and the right bar represents “EIF3E, A>G.”FIGs. 5A and 5B provide images of primary human hepatocyte cells. FIG. 5A provides an image of primary cyno hepatocyte cells that have not been administered any base editor system. FIG. 5B provides an image of primary cyno hepatocyte cells one day after having been administered lipid nanoparticles containing a base editor system containing a guide RNA targeting a non-human primate TTR gene for base editing and mRNA encoding an adenosine deaminase base editor containing a TadA*8.20 adenosine deaminase domain with a V82T amino acid alteration (referred to throughout the figures as “ABE9.51”).FIGs. 6A and 6B provide plots and charts showing that, under similar conditions, base editor systems containing a guide RNA targeting a human TTR polynucleotide sequence for base editing (i.e., human gRNA or “human”) and administered to primary human hepatocytes were associated with higher levels of base editing than base editor systems containing a guide RNA targeting a non-human primate TTR polynucleotide sequence (i.e., cyno gRNA or “cyno”) and administered to primary cyno hepatocytes (PCH). The base editor systems were administered to the cells using lipid nanoparticles containing the ionizable lipid IZ4. FIG. 6A provides a plot and a chart showing base editing rates measured in primary human hepatocytes (PHH) and primary cyno hepatocytes (PCH) at the TTR gene. The base editor systems administered to the PHH contained the guide RNA gRNA2944, and the base editor systems administered to the PCH contained the guide RNA gRNA2945. The base editor systems contained mRNA encoding a base editor containing a TadA*8.20 adenosine deaminase domain with a V82T amino acid alteration (referred to throughout the figures as “ABE9.51”). FIG. 6B provides a plot and a chart showing base editing rates measured for base editing measured in primary human hepatocytes (PHH) and primary cyno hepatocytes (PCH) at the ALAS1 gene. The ALAS1 gene was base edited using a base editor system containing the control guide RNA sg23 known to be effective for use in targeting base editors to alter a nucleobase within the ALAS1 gene and an mRNA molecule encoding a base editor containing a TadA*8.8 adenosine deaminase domain. In FIGs. 6A and 6B, the terms PHH1, PHH2, and PHH3 indicate primary human hepatocytes (PHH) from three different human donors, where the three donors were the same donors as those of FIGs. 2A and 2B. DETAILED DESCRIPTIONProvided herein are compositions for polynucleotide (e.g., a gene) modification or editing and methods of using the same to treat or prevent conditions associated with the extracellular deposition in various tissues of amyloid fibrils formed by the aggregation of misfolded transthyretin (TTR) proteins. Such conditions include, but are not limited to, polyneuropathy due to hereditary transthyretin amyloidosis (hATTR-PN) and hereditary cardiomyopathy due to transthyretin amyloidosis (hATTR-CM), both associated with autosomal dominant mutations of the TTR gene, and an age-related cardiomyopathy associated with wild-type TTR proteins (ATTRwt), also known as senile cardiac amyloidosis. Compositions and methods directed to editing a TTR polynucleotide using an editing system, such as one comprising a base editor and guide RNAs are disclosed.The invention is based, at least in part, on the discovery that base editor systems can be used to disrupt expression of a transthyretin polypeptide or to edit a pathogenic mutation in a transthyretin polypeptide and that the base editor systems can be effectively delivered to cells using lipid nanoparticles of the disclosure. In one embodiment, the disclosure provides guide RNA sequences that are effective for use in conjunction with a base editing system for editing a transthyretin (TTR) gene sequence to disrupt splicing or correct a pathogenic mutation. In another embodiment, the invention provides guide RNA sequences that target a Cas12b nuclease to edit a TTR gene sequence, thereby disrupting TTR polypeptide expression.Accordingly, the disclosure provides guide RNA sequences suitable for use with an ABE and / or a BE4 for transthyretin (TTR) gene splice site disruption and guide RNA sequences suitable for use with bhCas12b nucleases for disruption of the transthyretin (TTR) gene. In embodiments, the compositions and methods of the present invention can be used for editing a TTR gene in a hepatocyte. The methods provided herein can include reducing or eliminating expression of TTR in a hepatocyte cell to treat an amyloidosis. TRANSTHYRETIN PROTEIN AND GENE Transthyretin (TTR), originally known as prealbumin, is a 55-kDa transport protein for both thyroxine (T4) and retinol-binding protein, that circulates in soluble form in the serum and cerebrospinal fluid (CSF) of healthy humans. TTR is understood to be primarily synthesized in the liver. Under normal conditions, TTR circulates as a homotetramer with a central channel. An exemplary wild-type TTR monomer is 147 amino acids in length and has the amino acid sequence below: MASHRLLLLCLAGLVFVSEAGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE (SEQ ID NO: 464).The TTR gene, composed of four exons, is located on chromosome 18 at 18q12.1. The full sequence of the human TTR gene is available at UniProtKB - P02766 (TTHY_HUMAN). Over 120 TTR variants have so far been identified, the great majority of which are pathogenic. The most common pathogenic variant consists of a point mutation leading to replacement of valine by methionine at position 30 of the mature protein. This Val30Met mutation is responsible for hATTR amyloidosis and is the most frequent amyloidogenic mutation worldwide, accounting for about 50% of TTR variants.Hereditary transthyretin amyloidosis (hATTR) is a disease caused by mutations in the TTR gene. Autosomal dominant mutations destabilize the TTR tetramer and enhance dissociation into monomers, resulting in misfolding, aggregation, and the subsequent extracellular deposition of TTR amyloid fibrils in different tissue sites. This multisystem extracellular deposition of amyloid (amyloidosis) results in dysfunction of different organs and tissues. In particular, polyneuropathy due to transthyretin amyloidosis (ATTR-PN) and cardiomyopathy due to transthyretin amyloidosis (ATTR-CM) are severe disorders associated with significant morbidity and mortality.When there is clinical suspicion for hATTR-PN, diagnosis is typically done by tissue biopsy with staining for amyloid, amyloid typing (using immunohistochemistry or mass spectrometry), and / or TTR gene sequencing. When there is clinical suspicion for ATTR-CM, the key diagnostic tools are either endomyocardial biopsy (with tissue staining and amyloid typing by immunohistochemistry or mass spectrometry) or 99m technetium-pyrophosphate scan. Both of these approaches can provide a diagnosis of ATTR-CM. TTR gene sequencing can be used to differentiate between the hATTR-CM (mutation positive) and ATTRwt-CM (mutation negative).In some embodiments, the compositions described herein include guide polynucleotides containing a spacer having a nucleotide sequence that functions as a guide to direct a gene editing protein (e.g., a base editor) to alter a TTR gene, for example by introducing one or more nucleobase alterations in the TTR gene. These point mutations may be used to disrupt gene function, by the introduction of a missense mutation(s) that results in production of a less functional, or non-functional protein, thus silencing the TTR gene. Alternatively, it is contemplated herein that corrections to one or more point mutation(s) may be made using a gene editing protein to alter a mutated gene to correct the underlying mutation causing the dysfunction in the TTR gene or otherwise mitigate against dysfunction of the gene. AMYLOIDOSISAmyloidosis is a disorder that involves extracellular deposition of amyloid in an organ or tissue (e.g., the liver). Amyloidosis may occur when mutant transthyretin polypeptides aggregate (e.g., as fibrils). An amyloidosis caused by a mutation to the transthyretin gene can be referred to as a “transthyretin amyloidosis”. Some forms of transthyretin amyloidosis are not associated with a mutation to the transthyretin gene. Non-limiting examples of mutations to the mature transthyretin (TTR) protein that can lead to amyloidosis include the alterations T60A, V30M, V30A, V30G, V30L, V122I, V122A, and V122(-). One method for treatment of transthyretin amyloidosis includes disrupting expression or activity of transthyretin in a cell of a subject, optionally a hepatocyte cell. Accordingly, provided herein are methods for reducing or eliminating expression of transthyretin in a cell. The transthyretin in the cell can be a pathogenic variant. Expression of transthyretin in a cell can be disrupted by disrupting splicing of a transthyretin transcript.Transthyretin amyloidosis is a progressive condition characterized by the buildup of protein deposits in organs and / or tissues. These protein deposits can occur in the peripheral nervous system, which is made up of nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound. Protein deposits in these nerves result in a loss of sensation in the extremities (peripheral neuropathy). The autonomic nervous system, which controls involuntary body functions such as blood pressure, heart rate, and digestion, may also be affected by amyloidosis. In some cases, the brain and spinal cord (i.e., central nervous system) are affected. Other areas of amyloidosis include the heart, kidneys, eyes, liver, and gastrointestinal tract. The age at which symptoms begin to develop can be between the ages of 20 and 70.There are three major forms of transthyretin amyloidosis, which are distinguished by their symptoms and the body systems they effect: neuropathic, leptomeningeal, and cardiac.The neuropathic form of transthyretin amyloidosis primarily affects the peripheral and autonomic nervous systems, resulting in peripheral neuropathy and difficulty controlling bodily functions. Impairments in bodily functions can include sexual impotence, diarrhea, constipation, problems with urination, and a sharp drop in blood pressure upon standing (orthostatic hypotension). Some people experience heart and kidney problems as well. Various eye problems may occur, such as cloudiness of the clear gel that fills the eyeball (vitreous opacity), dry eyes, increased pressure in the eyes (glaucoma), or pupils with an irregular or ”scalloped” appearance. Some people with this form of transthyretin amyloidosis develop carpal tunnel syndrome, which can involve numbness, tingling, and weakness in the hands and fingers.The leptomeningeal form of transthyretin amyloidosis primarily affects the central nervous system. In people with this form, amyloidosis occurs in the leptomeninges, which are two thin layers of tissue that cover the brain and spinal cord. A buildup of protein in this tissue can cause stroke and bleeding in the brain, an accumulation of fluid in the brain (hydrocephalus), difficulty coordinating movements (ataxia), muscle stiffness and weakness (spastic paralysis), seizures, and loss of intellectual function (dementia). Eye problems similar to those in the neuropathic form may also occur. When people with leptomeningeal transthyretin amyloidosis have associated eye problems, they are said to have the oculoleptomeningeal form.The cardiac form of transthyretin amyloidosis affects the heart. People with cardiac amyloidosis may have an abnormal heartbeat (arrhythmia), an enlarged heart (cardiomegaly), or orthostatic hypertension. These abnormalities can lead to progressive heart failure and death. Occasionally, people with the cardiac form of transthyretin amyloidosis have mild peripheral neuropathy.Mutations in the transthyretin (TTR) gene cause transthyretin amyloidosis. Transthyretin transports vitamin A (retinol) and a hormone called thyroxine throughout the body. Not being bound by theory, to transport retinol and thyroxine, transthyretin must form a tetramer. Transthyretin is produced primarily in the liver (i.e., in hepatic cells). A small amount of transthyretin (TTR) is produced in an area of the brain called the choroid plexus and in the retina.TTR gene mutations can alter the structure of transthyretin, impairing its ability to bind to other transthyretin proteins. The TTR gene mutation can be autosomal dominant. SPLICE SITESGene splice sites and splice site motifs are well known in the art and it is within the skill of a practitioner to identify splice sites in sequence (see, e.g., Sheth, et al., “Comprehensive splice-site analysis using comparative genomics”, Nucleic Acids Research, 34:3955-3967 (2006); Dogan, et al., “AplicePort – an interactive splice-site analysis tool”, Nucleic Acids Research, 35:W285-W291 (2007); and Zuallaert, et al., “SpliceRover: interpretable convolutional neural networks for improved splice site prediction”, Bioinformatics, 34:4180-4188 (2018)).Canonical splice donors contain the DNA sequence GT on the sense strand, whereas canonical splice acceptors comprise the DNA sequence AG. Alteration of the sequence disrupts normal splicing. Splice donors can be disrupted by adenine base editing of the complementary base in the second position in the antisense strand (GT→GC), and splice acceptors can be disrupted by adenine base editing of the first position in the sense strand (AG→GG). EDITING OF TARGET GENESTo edit the transthyretin (TTR) gene, a cell (e.g., a hepatocyte) is contacted with a guide RNA and a nucleobase editor polypeptide comprising a nucleic acid programmable DNA binding protein (napDNAbp) and a cytidine deaminase or adenosine deaminase to edit a base of a gene sequence. Editing of the base can result in disruption of a splice site (e.g., through alteration of a splice-site motif nucleobase). Editing of the base can result in replacement of a pathogenic variant amino acid with a non-pathogenic variant amino acid. As a non-limiting example, editing of the base can result in replacing a T60A, V30M, V30A, V30G, V30L, V122I, V122A, or a V122(-) alteration in the mature transthyretin (TTR) polypeptide with a non-pathogenic variant or the wild-type valine residue. The cytidine deaminase can be BE4 (e.g., saBE4). The adenosine deaminase can be ABE (e.g., saABE.8.8). In some embodiments, multiple target sites are edited simultaneously. In some embodiments, the TTR gene is edited by contacting a cell with a nuclease and a guide RNA to introduce an indel into a gene sequence. The indel can be associated with a reduction or elimination of expression of the gene. The nuclease can be Cas12b (e.g., bhCas12b). The cells can be edited in vivo or ex vivo. The guide RNA can be a single guide or a dual guide. In some embodiments, cells to be edited are contacted with at least one nucleic acid, wherein at least one nucleic acid encodes a guide RNA, or two or more guide RNAs, and a nucleobase editor polypeptide comprising a nucleic acid programmable DNA binding protein (napDNAbp) and a deaminase, e.g., an adenosine or a cytidine deaminase. In some embodiments, the gRNA comprises nucleotide analogs. These nucleotide analogs can inhibit degradation of the gRNA by cellular processes. Exemplary single guide RNA (sgRNA) sequences are provided in Tables 1A to 1E and exemplary spacer sequences and target sequences (e.g., protospacer sequences) are provided in Tables 1B, 1C, and 2A to 2E.With the present disclosure, guide polynucleotides and spacer sequences suitable for use therein for targeting a base editor to alter a nucleobase within the human TTR gene to either disrupt the start codon, or disrupt splice sites, whether donors or acceptors, via A→G editing within an editing window (roughly positions 4 to 7 in the 20-nt protospacer region corresponding to the spacer of the guide polynucleotide).Protospacer, corresponding to guide RNA GA457, has the sequence 5’-GCCATCCTGCCAAGAATGAG-3’ (SEQ ID NO: 467) and is located at 34,879 to 34,898 bp of the human TTR gene.Protospacer, corresponding to guide RNA GA459, has the sequence 5’-GCAACTTACCCAGAGGCAAA-3’ (SEQ ID NO: 468) and is located at 36,007 to 36,026 bp of the human TTR gene.Protospacer, corresponding to guide RNA GA460, has the sequence 5’-TATAGGAAAACCAGTGAGTC-3’ (SEQ ID NO: 469) and is located at 38,106-38,125 bp of the human TTR gene.Protospacer, corresponding to guide RNA GA461, has the sequence 5’-TACTCACCTCTGCATGCTCA-3’ (SEQ ID NO: 470) and is located at 38,234-38253 of the human TTR gene.Protospacer, corresponding to guide RNA GA458, has the sequence 5’-GCCATCCTGCCAAGAACGAG-3’ (SEQ ID NO: 471) represents the sequence within the cynomolgus macaque TTR gene corresponding to the human protospacer sequence corresponding to guide RNA GA459.The present disclosure includes a guide polynucleotide having a sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% identical to the sequence 5’-GCCAUCCUGCCAAGAAUGAG-3’ (SEQ ID NO: 472) (GA457). The present disclosure includes a guide polynucleotide having the sequence 5’-GCCAUCCUGCCAAGAAUGAG-3’ (SEQ ID NO: 472) (GA457).The present disclosure includes a modified guide polynucleotide having a sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% identical to the sequence 5’-GCCAUCCUGCCAAGAAUGAG-3’ (SEQ ID NO: 472), wherein the nucleotides GCC shown in bold are modified by methylation (GA521) (C is modified to 2’-O-methylcytidine, G is modified to 2’-O-methylguanosine). The present disclosure includes a modified guide polynucleotide having the sequence 5’-mGsmCsmCAUCCUGCCAAGAAUGAG-3’ (SEQ ID NO: 472) (GA521), wherein mC: 2’-O-methylcytidine, mG: 2’-O-methylguanosine and s: phosphorothioate (PS) backbone linkage.The present disclosure includes a guide polynucleotide having a sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% identical to the sequence 5’-GCCAUCCUGCCAAGAACGAG-3’ (SEQ ID NO: 473) (GA458). The present disclosure includes a guide polynucleotide having the sequence 5’-GCCAUCCUGCCAAGAACGAG-3’ (SEQ ID NO: 473) (GA458).The present disclosure includes a guide polynucleotide having a sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% identical to the sequence 5’-GCAACUUACCCAGAGGCAAA-3’ (SEQ ID NO: 474) (GA459). The present disclosure includes a guide polynucleotide having the sequence 5’-GCAACUUACCCAGAGGCAAA-3’ (SEQ ID NO: 474) (GA459).The present disclosure includes a guide polynucleotide having a sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% identical to the sequence 5’-UAUAGGAAAACCAGUGAGUC-3’ (SEQ ID NO: 475) (GA460). The present disclosure includes a guide polynucleotide having the sequence 5’-UAUAGGAAAACCAGUGAGUC-3’ (SEQ ID NO: 475) (GA460).The present disclosure includes a guide polynucleotide having a sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% identical to the sequence 5’-UACUCACCUCUGCAUGCUCA-3’ (SEQ ID NO: 476) (GA461). The present disclosure includes a guide polynucleotide having the sequence 5’-UACUCACCUCUGCAUGCUCA-3’ (SEQ ID NO: 476) (GA461).In some aspects, provided herein is a guide RNA, comprising a sequence defined by mG*mC*mC*AUCCUGCCAAGAAUGAGmGUUUUAGmAmGmCmUmAGmAmAmAmUmAmGmCmAmAGUUmAAmAAmUAmAmGmGmCmUmAGUmCmCGUUAmUmCAAmCmUmUGmAmAmAmAmAmGmUmGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmU*mU*mU*mU (GA521, (SEQ ID NO: 477), wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, mA* is 2’-O-methyladenosine, mC* is 2’-O-methylcytidine, mG* is 2’-O-methylguanosine, mU* is 2’-O-methyluridine, and wherein nucleotides represented in bold are linked by a phosphorothioate (PS) backbone linkage.Alternatively, GA521 is represented asmG*smC*smC*AUCCUGCCAAGAAUGAGmGsUsUsUsUsAsGsmAsmGsmCsmUsmAsGsmAsmAsmAsmUsmAsmGsmCssmAsmAsGsUsUsmAsAsmAsAsmUsAsmAsmGsmGsmCsmUsmAsGsUsmCsmCsGsUsUsAsmUsmCsAsAsmCsmUsmUsGsmAsmAsmAsmAsmAsmGsmUsmGsGsmCsmAsmCsmCsmGsmAsmGsmUsmCsmGsmGsmUsmGsmCsmU*smU*smU*smU (GA521, SEQ ID NO: 477), wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, mA* is 2’-O-methyladenosine, mC* is 2’-O-methylcytidine, mG* is 2’-O-methylguanosine, mU* is 2’-O-methyluridine, and wherein nucleotides are linked by a phosphorothioate (PS) backbone linkage represented by the letter ‘s’.In some embodiments, mG*mC*mC*AUCCUGCCAAGAAUGAGmGUUUUAGmAmGmCmUmAGmAmAmAmUmAmGmCmAmAGUUmAAmAAmUAmAmGmGmCmUmAGUmCmCGUUAmUmCAAmCmUmUGmAmAmAmAmAmGmUmGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmU*mU*mU*mU (GA521, SEQ ID NO: 477), wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, mA* is 2’-O-methyladenosine, mC* is 2’-O-methylcytidine, mG* is 2’-O-methylguanosine, mU* is 2’-O-methyluridine, and wherein nucleotides represented in bold are linked by a phosphorothioate (PS) backbone linkage.Alternatively, GA521 is represented asmG*mC*mC*AUCCUGCCAAGAAUGAGmGsUsUsUsUsAsGsmAsmsGsmCsmUsmAsGsmAsmAsmAsmUsmAsmGsmCssmAsmAsGsUsUsmAsAsmAsAsmUsAsmAsmGsmGsmCsmUsmAsGsUsmCsmCsGsUsUsAsmUsmCsAsAsmCsmUsmUsGsmAsmAsmAsmAsmAsmGsmUsmGsGsmCsmAsmCsmCsmGsmAsmGsmUsmCsmGsmGsmUsmGsmCsmU*mU*mU*mU (GA521, SEQ ID NO: 477), wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, mA* is 2’-O-methyladenosine, mC* is 2’-O-methylcytidine, mG* is 2’-O-methylguanosine, mU* is 2’-O-methyluridine, and wherein nucleotides represented in bold are linked by a phosphorothioate (PS) backbone linkage represented by the letter ‘s’.Exemplary guide RNAs, spacer sequences, and target sequences are provided in Tables 1A to 1E and Tables 2A to 2E. In various instances, it is advantageous for a spacer sequence to include a 5′ and / or a 3′ “G” nucleotide. In some cases, for example, any spacer sequence or guide polynucleotide provided herein comprises or further comprises a 5′ “G”, where, in some embodiments, the 5′ “G” is or is not complementary to a target sequence. In some embodiments, the 5′ “G” is added to a spacer sequence that does not already contain a 5′ “G.” For example, it can be advantageous for a guide RNA to include a 5′ terminal “G” when the guide RNA is expressed under the control of a U6 promoter or the like because the U6 promoter prefers a “G” at the transcription start site (see Cong, L. et al. “Multiplex genome engineering using CRISPR / Cas systems. Science 339:819-823 (2013) doi: 10.1126 / science.1231143). In some cases, a 5′ terminal “G” is added to a guide polynucleotide that is to be expressed under the control of a promoter, but is optionally not added to the guide polynucleotide if or when the guide polynucleotide is not expressed under the control of a promoter.Variants of the spacer sequences provided herein comprising 1, 2, 3, 4, or 5 nucleobase alterations are contemplated. For example, variation of a target polynucleotide sequence within a population (e.g., single nucleotide polymorphisms) may require said alterations to a spacer sequence to allow the spacer to better bind a variant of a target sequence in a subject.In embodiments, a guide RNA comprises a sequence complementary to a promoter region of a TTR polynucleotide sequence. In embodiments, the promoter region spans from positions +10, +5, +1, -1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -15, -20, -25, -30, -35, -40, -45, -50, -55, -60, -65, -70, -75, -80, -85, -90, -95, -100, -105, -110, -115, -120, -125, -130, -135, -140, -145, -150, -155, -160, -165, -170, -175, -180, -185, -190, -195, -200, -250, or -300 to position +5, +1, -1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -15, -20, -25, -30, -35, -40, -45, -50, -55, -60, -65, -70, -75, -80, -85, -90, -95, -100, -105, -110, -115, -120, -125, -130, -135, -140, -145, -150, -155, -160, -165, -170, -175, -180, -185, -190, -195, -200, -250, -300, or -400, where position +1 corresponds to the first A of the start codon (ATG) of the TTR polynucleotide sequence. In various embodiments of the disclosure, a guide RNA contains the following polynucleotide sequence, where the sequence may be modified by adding or removing one or more of the “Ns” (i.e., the spacer sequence, shown in bold, can be extended or truncated by, e.g., 1, 2, 3, 4, or 5 nucleotides):nsnsnsNNNNNNNNNNNNNNNNNgUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugGcaccgagucggugcuususus (SEQ ID NO: 1235). Where, “n” is a, c, g, or u; “N” is A, C, G, or U; A is adenosine; C is cytidine; G is guanosine; U is uridine; a is 2’-O-methyladenosine; c is 2’-O-methylcytidine; g is 2’-O-methylguanosine; u is 2’-O-methyluridine and s is a phosphorothioate (PS) backbone linkage and wherein bold type represents the spacer sequence. Table 1A. Exemplary guide RNAs for editing transthyretin (TTR) splice sites and / or introducing indels into the TTR gene (e.g., using bhCas12b)sgRNA IDSequenceSEQ ID NOsgRNA_361mUsmAsmUsAGGAAAACCAGTGAGTCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmUsmUsmUsU484sgRNA_362mUsmAsmCsUCACCUCUGCAUGCUCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmUsmUsmUsU485sgRNA_363mAsmCsmUsCACCUCUGCAUGCUCAUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmUsmUsmUsU486sgRNA_364mUsmAsmCsCACCUAUGAGAGAAGACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCmUsmUsmUsU487sgRNA_365mAsmUsmAsCUCACCUCUGCAUGCUCAGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAmUsmUsmUsU488sgRNA_366mAsmCsmUsGGUUUUCCUAUAAGGUGUGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAmUsmUsmUsU489sgRNA_367mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUUGGCAGGAUGGCUUCUCmAsmUsmCsG490sgRNA_368mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUCCUAUAAGGUGUGAAAGmUsmCsmUsG491sgRNA_369mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUGAGCCCAUGCAGCUCUCmCsmAsmGsA492sgRNA_370mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACCUCCUCAGUUGUGAGCCCmAsmUsmGsC493sgRNA_371mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACGUAGAAGGGAUAUACAAAmGsmUsmGsG494sgRNA_372mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACCCACUUUGUAUAUCCCUUmCsmUsmAsC495sgRNA_373mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACGGUGUCUAUUUCCACUUUmGsmUsmAsU496sgRNA_374mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACCAUGAGCAUGCAGAGGUGmAsmGsmUsA497gRNA1594mCsmAsmAsCUUACCCAGAGGCAAAUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU498gRNA1595mAsmAsmUsGGCUCCCAGGUGUCAUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU499gRNA1596mGsmGsmCsUCCCAGGUGUCAUCAGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU500gRNA1597mCsmUsmCsUCAUAGGUGGUAUUCACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU501gRNA1598mUsmAsmUsAGGAAAACCAGUGAGUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU628gRNA1599mUsmAsmCsUCACCUCUGCAUGCUCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU629gRNA1600mGsmCsmAsACUUACCCAGAGGCAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU502gRNA1601mUsmCsmUsGUAUACUCACCUCUGCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU503gRNA1602mGsmAsmAsACACUCACCGUAGGGCCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU504gRNA1603mCsmUsmCsUACACCCAGGGCACCGGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU505gRNA1604mAsmCsmAsCCUUAUAGGAAAACCAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU506gRNA1605mAsmUsmAsGGAAAACCAGUGAGUCUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU507gRNA1606mAsmCsmUsCACCUCUGCAUGCUCAUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU508gRNA1607mCsmUsmCsACCGUAGGGCCAGCCUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU509gRNA1746mAsmAsmCsCUGCUGAUUCUGAUUAUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU510gRNA1747mAsmAsmGsAGAGAAUAAGUAACCCAUGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU511gRNA1748mAsmAsmGsCAGCCUAGCUCAGGAGAAGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU512gRNA1749mAsmAsmGsUCCACUCAUUCUUGGCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU513gRNA1750mAsmCsmGsAUGAGAAGCCAUCCUGCCGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU514gRNA1751mAsmGsmAsCAAGGUUCAUAUUUGUAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU515gRNA1752mAsmGsmGsCUGGGAGCAGCCAUCACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU516gRNA1753mAsmUsmAsAGUAACCCAUACAAAUAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU517gRNA1754mAsmUsmAsCUCACUUCUCCUGAGCUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU518gRNA1755mAsmUsmUsAUUGACUUAGUCAACAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU519gRNA1756mCsmAsmAsAUAUGAACCUUGUCUAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU520gRNA1757mCsmAsmGsAAGUCCACUCAUUCUUGGGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU521gRNA1758mCsmAsmGsGCUGGGAGCAGCCAUCACGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU522gRNA1759mCsmCsmAsUCCUGCCAAGAAUGAGUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU523gRNA1760mCsmCsmUsGCUGAUUCUGAUUAUUGAGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU524gRNA1761mCsmGsmAsUGCUCUAAUCUCUCUAGAGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU525gRNA1762mCsmUsmAsAGUCAAUAAUCAGAAUCAGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU526gRNA1763mCsmUsmAsGACAAGGUUCAUAUUUGUGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU527gRNA1764mGsmAsmAsCCUUGUCUAGAGAGAUUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU528gRNA1765mGsmAsmAsGUCCACUCAUUCUUGGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU529gRNA1766mGsmAsmAsUCAGCAGGUUUGCAGUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU530gRNA1767mGsmAsmAsUGAGUGGACUUCUGUGAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU531gRNA1768mGsmAsmCsUGCAAACCUGCUGAUUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU532gRNA1769mGsmAsmCsUUAGUCAACAAAGAGAGAGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU533gRNA1770mGsmAsmUsAAGCAGCCUAGCUCAGGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU534gRNA1771mGsmAsmUsGAGAAGCCAUCCUGCCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU535gRNA1772mGsmCsmCsAUCCUGCCAAGAAUGAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU630gRNA1773mGsmCsmUsUUUAUACUCACUUCUCCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU536gRNA1774mGsmGsmAsUAAGCAGCCUAGCUCAGGGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU537gRNA1775mGsmUsmCsUAGAGAGAUUAGAGCAUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU538gRNA1776mGsmUsmGsAUGGCUGCUCCCAGCCUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU539gRNA1777mUsmAsmCsUUAUUCUCUCUUUGUUGAGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU540gRNA1778mUsmAsmUsUCUCUCUUUGUUGACUAAGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU541gRNA1779mUsmAsmUsUGACUUAGUCAACAAAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU542 gRNA1780mUsmAsmUsUGACUUAGUCAACAAAGAGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU543gRNA1781mUsmCsmAsGAAUCAGCAGGUUUGCAGGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU544gRNA1782mUsmCsmCsACUCAUUCUUGGCAGGAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU545gRNA1783mUsmCsmUsCUCUUUGUUGACUAAGUCGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU546gRNA1784mUsmGsmAsGAAGCCAUCCUGCCAAGAGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU547gRNA1785mUsmGsmAsGCUAGGCUGCUUAUCCCUGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU548 gRNA1786mUsmGsmAsGUAUAAAAGCCCCAGGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU549gRNA1787mUsmGsmAsUGGCUGCUCCCAGCCUGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU550gRNA1788mUsmGsmCsCAAGAAUGAGUGGACUUCGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU551gRNA1789mUsmGsmCsCAAUCUGACUGCAAACCUGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU552gRNA1790mUsmGsmUsUGACUAAGUCAAUAAUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU553gRNA1791mUsmUsmGsACUUAGUCAACAAAGAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU554gRNA1792mUsmUsmUsGUUGACUAAGUCAAUAAUGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU555gRNA-#1mAsmAsmAsAGCCCCAGGCUGGGAGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU556gRNA-#2mAsmAsmGsUGAGUAUAAAAGCCCCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU557gRNA-#3mAsmAsmUsAAUCAGAAUCAGCAGGUUGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU558gRNA-#4mAsmAsmUsAUGAACCUUGUCUAGAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU559gRNA-#5mAsmAsmUsGAGUGGACUUCUGUGAUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU560gRNA-#6mAsmCsmAsAAUAUGAACCUUGUCUAGGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU561gRNA-#7mAsmCsmAsGAAGUCCACUCAUUCUUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU562gRNA-#8mAsmCsmCsUUGUCUAGAGAGAUUAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU563gRNA-#9mAsmGsmAsAGCCAUCCUGCCAAGAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU564gRNA-#10mAsmGsmCsAGGUUUGCAGUCAGAUUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU565gRNA-#11mAsmGsmGsGAUAAGCAGCCUAGCUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU566gRNA-#12mAsmGsmGsUUUGCAGUCAGAUUGGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU567gRNA-#13mAsmGsmUsAUAAAAGCCCCAGGCUGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU568gRNA-#14mAsmGsmUsCAAUAAUCAGAAUCAGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU569gRNA-#15mAsmUsmAsAUCAGAAUCAGCAGGUUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU570gRNA-#16mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUUGACUUAGUCAACAAAGAsmGsmAsmG571gRNA-#17mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUCUCUUUGUUGACUAAGUCsmAsmAsmU572gRNA-#18mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUGAUUAUUGACUUAGUCAAsmCsmAsmA573gRNA-#19mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUUGGCAGGAUGGCUUCUCAsmUsmCsmG574gRNA-#20mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACACUUAGUCAACAAAGAGAGsmAsmAsmU575gRNA-#21mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACGCAGGGAUAAGCAGCCUAGsmCsmUsmC576gRNA-#22mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACGUAUGGGUUACUUAUUCUCsmUsmCsmU577gRNA-#23mCsmAsmAsGAAUGAGUGGACUUCUGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU578gRNA-#24mCsmAsmAsUCUGACUGCAAACCUGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU579gRNA-#25mCsmAsmCsAGAAGUCCACUCAUUCUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU580gRNA-#26mCsmAsmGsACGAUGAGAAGCCAUCCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU581gRNA-#27mCsmAsmGsCAGGUUUGCAGUCAGAUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU582gRNA-#28mCsmAsmGsGAUGGCUUCUCAUCGUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU583gRNA-#29mCsmAsmGsGUUUGCAGUCAGAUUGGCGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU584gRNA-#30mCsmAsmGsUCAGAUUGGCAGGGAUAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU585gRNA-#31mCsmCsmAsCUCAUUCUUGGCAGGAUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU586gRNA-#32mCsmUsmAsAGUCAAUAAUCAGAAUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU587gRNA-#33mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACGUCAACAAAGAGAGAAUAAsmGsmUsmA588gRNA-#34mCsmUsmUsAUCCCUGCCAAUCUGACGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU589gRNA-#35mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUCCCUGCCAAUCUGACUGCsmAsmAsmA590gRNA-#36mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUUCUCUCUUUGUUGACUAAsmGsmUsmC591gRNA-#37mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUCCUGAGCUAGGCUGCUUAsmUsmCsmC592gRNA-#38mCsmUsmUsCUGUGAUGGCUGCUCCCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU593gRNA-#39mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUGUGAUGGCUGCUCCCAGCsmCsmUsmG594gRNA-#40mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACGCAGGAUGGCUUCUCAUCGsmUsmCsmU595gRNA-#41mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUCUAGAGAGAUUAGAGCAUsmCsmGsmG596gRNA-#42mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACGUUGACUAAGUCAAUAAUCsmAsmGsmA597gRNA-#43mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACUAUACUCACUUCUCCUGAGsmCsmUsmA598gRNA-#44mGsmAsmAsGUGAGUAUAAAAGCCCCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU599gRNA-#45mGsmAsmCsAAGGUUCAUAUUUGUAUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU600gRNA-#46mGsmAsmGsUAUAAAAGCCCCAGGCUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU601gRNA-#47mGsmAsmGsUGGACUUCUGUGAUGGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU602gRNA-#48mGsmAsmUsGGCUGCUCCCAGCCUGGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU603gRNA-#49mGsmCsmAsGCCUAGCUCAGGAGAAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU604gRNA-#50mGsmCsmUsGCUUAUCCCUGCCAAUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU605gRNA-#51mGsmGsmGsAUAAGCAGCCUAGCUCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU606gRNA-#52mGsmGsmUsUUGCAGUCAGAUUGGCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU607gRNA-#53mGsmUsmUsACUUAUUCUCUCUUUGUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU608gRNA-#54mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACCUUAUUCUCUCUUUGUUGAsmCsmUsmA609gRNA-#55mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACAUAUUUGUAUGGGUUACUUsmAsmUsmU610gRNA-#56mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACACUAAGUCAAUAAUCAGAAsmUsmCsmA611gRNA-#57mGsmUsmUsUGCAGUCAGAUUGGCAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU612gRNA-#58mGsmUsmUsCUGUCUUUUGGUCAGGACAACCGUCUAGCUAUAAGUGCUGCAGGGUGUGAGAAACUCCUAUUGCUGGACGAUGUCUCUUACGAGGCAUUAGCACGCAGUCAGAUUGGCAGGGAsmUsmAsmA613gRNA-#59mUsmAsmCsAAAUAUGAACCUUGUCUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU614gRNA-#60mUsmAsmCsUCACUUCUCCUGAGCUAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU615gRNA-#61mUsmAsmUsAAAAGCCCCAGGCUGGGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU616gRNA-#62mUsmCsmAsCUUCUCCUGAGCUAGGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU617gRNA-#63mUsmCsmAsGAUUGGCAGGGAUAAGCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU618gRNA-#64mUsmCsmAsGGAGAAGUGAGUAUAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU619gRNA-#65mUsmCsmUsGACUGCAAACCUGCUGAUGUUUUAGUACUCUGUAAUGAAAAUUACAGAAUCUACUAAAACAAGGCAAAAUGCCGUGUUUAUCUCGUCAACUUGUUGGCGAGAUsmUsmUsmU620gRNA-#66mUsmGsmAsGCUAGGCUGCUUAUCCCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU621gRNA-#67mUsmGsmCsCAAUCUGACUGCAAACCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU622gRNA-#68mUsmGsmCsUCUAAUCUCUCUAGACAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU623gRNA-#69mUsmGsmUsGAUGGCUGCUCCCAGCCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU624gRNA-#70mUsmUsmGsGCAGGGAUAAGCAGCCUGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU625gRNA-#71mUsmUsmUsUAUACUCACUUCUCCUGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsmUsmUsmU626Lowercase m indicates 2’-O-methylated nucleobases (e.g., mA, mC, mG, mU), and “s” indicates phosphorothioates. Table 1B. Exemplary guide RNAs for editing a TTR polynucleotide (spacer sequences within a gRNA sequence are in bold)gRNA IDSpeciesSpacer Sequence (5’-3’)SEQ ID NOgRNA sequence (5’-3’)SEQ ID NOGA457HumanGCCAUCCUGCCAAGAAUGAG  472gscscsAUCCUGCCAAGAAUGAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsususu  627GA519 (gRNA2945)CynoGCCAUCCUGCCAAGAACGAG  473gscscsAUCCUGCCAAGAACGAGgUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugGcaccgagucggugcuususus  631GA458CynoGCCAUCCUGCCAAGAACGAG  473gscscsAUCCUGCCAAGAACGAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsususu  632GA459HumanGCAACUUACCCAGAGGCAAA  474gscsasACUUACCCAGAGGCAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsususu  633GA460Human / CynoUAUAGGAAAACCAGUGAGUC  475usasusAGGAAAACCAGUGAGUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsususu  634GA520Human / CynoUAUAGGAAAACCAGUGAGUC  475usasusAGGAAAACCAGUGAGUCgUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugGcaccgagucggugcuususus  635GA461Human / CynoUACUCACCUCUGCAUGCUCA  476usascsUCACCUCUGCAUGCUCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsususu  636GA521 (gRNA2944)HumanGCCAUCCUGCCAAGAAUGAG   472mG*mC*mC*ATCCTGCCAAGAATGAGmGUUUUAGmAmGmCmUmAGmAmAmAmUmAmGmCmAmAGUUmAAmAAmUAmAmGmGmCmUmAGUmCmCGUUAmUmCAAmCmUmUGmAmAmAmAmAmGmUmGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmU*mU*mU*mU    637Letters in the sequences:- A: adenosine; C: cytidine; G: guanosine; U: uridine; a or mA: 2’-O-methyladenosine; c or mC: 2’-O-methylcytidine; g or mG: 2’-O-methylguanosine; u or mU: 2’-O-methyluridine; and s or *: phosphorothioate (PS) backbone linkage. Bold type in gRNA sequence denotes spacer sequence corresponding to Protospacer. GA460 and GA520 have the same protospacer sequence but have different chemical modifications in the gRNA sequence. Table 1C. Exemplary guide RNAs for editing a TTR polynucleotide (spacer sequences within gRNA sequences are shown in bold)LNP gRNA IDSpeciesSpacer Sequence(5’-3’)Equivalent Human gRNAgRNA Sequence (5’-3’)1GA519CynoGCCAUCCUGCCAAGAACGAG (SEQ ID NO: 473 )GA457gscscsAUCCUGCCAAGAACGAGgUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugGcaccgagucggugcuususus (SEQ ID NO: 631 )2GA520CynoUAUAGGAAAACCAGUGAGUC (SEQ ID NO: 475 ) GA460usasusAGGAAAACCAGUGAGUCgUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugGcaccgagucggugcuususus (SEQ ID NO: 635 )Letters in the sequences: A = adenosine; C = cytidine; G = guanosine; U = uridine; a = 2’-O-methyladenosine; c = 2’-O-methylcytidine; g = 2’-O-methylguanosine; u = 2’-O-methyluridine; s = phosphorothioate (PS) backbone linkage. C = nucleotide that differs in NHP from human TTR sequence. Bold type in gRNA sequence denotes spacer sequence corresponding to Protospacer. Table 1D. Exemplary guide RNA sequences (spacer sequences are in bold)Guide RNA sequence (5’-3’)SEQ ID NOgscscsAUCCUGCCAAGAAUGAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsususu 627AUCCUGCCAAGAACGAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsususu 638gscsasACUUACCCAGAGGCAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsususu 633usasusAGGAAAACCAGUGAGUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsususu 634usascsUCACCUCUGCAUGCUCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUsususu 636gscscsAUCCUGCCAAGAACGAGgUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugGcaccgagucggugcuususus 631usasusAGGAAAACCAGUGAGUCgUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugGcaccgagucggugcuususus 635A is adenosine; C is cytidine; G is guanosine; U is uridine; a is 2’-O-methyladenosine; c is 2’-O-methylcytidine; g is 2’-O-methylguanosine; u is 2’-O-methyluridine and s is phosphorothioate (PS) backbone linkage and wherein bold type represents the spacer sequence. Table 1E. Exemplary guide RNA sequences (spacer sequences are in bold)gRNA sequence (5’-3’)SEQ ID NOGCCAUCCUGCCAAGAAUGAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUUUU 639GCCAUCCUGCCAAGAACGAGGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUUUU 640GCAACUUACCCAGAGGCAAAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUUUU 641UAUAGGAAAACCAGUGAGUCGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUUUU 642UACUCACCUCUGCAUGCUCAGUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUUUU 643gccAUCCUGCCAAGAACGAGgUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugGcaccgagucggugcuuuu 640 Table 2A. Exemplary Spacer and Target Site Sequences.sgRNASpacer sequenceSEQ ID NOTarget site IDTarget site sequence (target bases for base editing are in bold and underlined)SEQ ID NOTarget Base(s)sgRNA_361UAUAGGAAAACCAGUGAGUC475TSBTx2602TATAGGAAAACCAGTGAGTC4694AsgRNA_362UACUCACCUCUGCAUGCUCA476TSBTx2603TACTCACCTCTGCATGCTCA4706A, 7CsgRNA_363ACUCACCUCUGCAUGCUCAU644TSBTx2604ACTCACCTCTGCATGCTCAT6585A, 6CsgRNA_364UACCACCUAUGAGAGAAGAC645TSBTx2605TACCACCTATGAGAGAAGAC6597CsgRNA_365AUACUCACCUCUGCAUGCUCA646TSBTx2606ATACTCACCTCTGCATGCTCA6607A, 8CsgRNA_366ACUGGUUUUCCUAUAAGGUGU647TSBTx2607ACTGGTTTTCCTATAAGGTGT661 11CsgRNA_367UUGGCAGGAUGGCUUCUCAUCG648TSBTx2608TTGGCAGGATGGCTTCTCATCG6626A, 9AsgRNA_368UCCUAUAAGGUGUGAAAGUCUG649TSBTx2609GTTTTCCTATAAGGTGTGAAAGTCTG663 sgRNA_369UGAGCCCAUGCAGCUCUCCAGA650TSBTx2610GTTGTGAGCCCATGCAGCTCTCCAGA664 sgRNA_370CUCCUCAGUUGUGAGCCCAUGC651TSBTx2611ATTCCTCCTCAGTTGTGAGCCCATGC665 sgRNA_371GUAGAAGGGAUAUACAAAGUGG652TSBTx2612ATTTGTAGAAGGGATATACAAAGTGG666 sgRNA_372CCACUUUGUAUAUCCCUUCUAC653TSBTx2613ATTTCCACTTTGTATATCCCTTCTAC667 sgRNA_373GGUGUCUAUUUCCACUUUGUAU654TSBTx2614ATTTGGTGTCTATTTCCACTTTGTAT668 sgRNA_374CAUGAGCAUGCAGAGGUGAGUA655TSBTx2615ATTCCATGAGCATGCAGAGGTGAGTA669 sgRNA_375GGCUAUCGUCACCAAUCCCA656 GGCTATCGTCACCAATCCCA6705AsgRNA_376GCUAUCGUCACCAAUCCCAA657 GCTATCGTCACCAATCCCAA6714AsgRNA_377GGCUAUCGUCACCAAUCCCA656 GGCTATCGTCACCAATCCCA6705A Table 2B. Exemplary Spacer and Target Site Sequences.gRNA_NameSpacer SequenceSEQ ID NO: Target Site / Protospacer SequenceSEQ ID NO: gRNA1747AAGAGAGAAUAAGUAACCCAU672AAGAGAGAATAAGTAACCCAT689gRNA1748AAGCAGCCUAGCUCAGGAGAA673AAGCAGCCTAGCTCAGGAGAA690gRNA1749AAGUCCACUCAUUCUUGGCA674AAGTCCACTCATTCTTGGCA691gRNA1750ACGAUGAGAAGCCAUCCUGCC675ACGATGAGAAGCCATCCTGCC692gRNA1751AGACAAGGUUCAUAUUUGUA676AGACAAGGTTCATATTTGTA693gRNA1752AGGCUGGGAGCAGCCAUCAC677AGGCTGGGAGCAGCCATCAC694gRNA1753AUAAGUAACCCAUACAAAUA678ATAAGTAACCCATACAAATA695gRNA1754AUACUCACUUCUCCUGAGCU679ATACTCACTTCTCCTGAGCT696gRNA1755AUUAUUGACUUAGUCAACAA680ATTATTGACTTAGTCAACAA697gRNA1756CAAAUAUGAACCUUGUCUAG681CAAATATGAACCTTGTCTAG698gRNA1757CAGAAGUCCACUCAUUCUUGG682CAGAAGTCCACTCATTCTTGG699gRNA1758CAGGCUGGGAGCAGCCAUCAC683CAGGCTGGGAGCAGCCATCAC700gRNA1759CCAUCCUGCCAAGAAUGAGU684CCATCCTGCCAAGAATGAGT701gRNA1760CCUGCUGAUUCUGAUUAUUGA685CCTGCTGATTCTGATTATTGA702gRNA1761CGAUGCUCUAAUCUCUCUAGA686CGATGCTCTAATCTCTCTAGA703 gRNA1762CUAAGUCAAUAAUCAGAAUCA687CTAAGTCAATAATCAGAATCA704gRNA1763CUAGACAAGGUUCAUAUUUGU688CTAGACAAGGTTCATATTTGT705gRNA1764GAACCUUGUCUAGAGAGAUU706GAACCTTGTCTAGAGAGATT1218gRNA1765GAAGUCCACUCAUUCUUGGC707GAAGTCCACTCATTCTTGGC1219gRNA1766GAAUCAGCAGGUUUGCAGUC708GAATCAGCAGGTTTGCAGTC1220gRNA1767GAAUGAGUGGACUUCUGUGA709GAATGAGTGGACTTCTGTGA1221gRNA1768GACUGCAAACCUGCUGAUUC710GACTGCAAACCTGCTGATTC1222gRNA1769GACUUAGUCAACAAAGAGAGA711GACTTAGTCAACAAAGAGAGA1223gRNA1770GAUAAGCAGCCUAGCUCAGG712GATAAGCAGCCTAGCTCAGG1224gRNA1771GAUGAGAAGCCAUCCUGCCA713GATGAGAAGCCATCCTGCCA1225gRNA1772GCCAUCCUGCCAAGAAUGAG472GCCATCCTGCCAAGAATGAG467gRNA1773GCUUUUAUACUCACUUCUCC714GCTTTTATACTCACTTCTCC1226gRNA1774GGAUAAGCAGCCUAGCUCAGG715GGATAAGCAGCCTAGCTCAGG1227gRNA1775GUCUAGAGAGAUUAGAGCAU716GTCTAGAGAGATTAGAGCAT1228gRNA1776GUGAUGGCUGCUCCCAGCCU717GTGATGGCTGCTCCCAGCCT1229gRNA1777UACUUAUUCUCUCUUUGUUGA718TACTTATTCTCTCTTTGTTGA1230gRNA1778UAUUCUCUCUUUGUUGACUAA719TATTCTCTCTTTGTTGACTAA1231gRNA1779UAUUGACUUAGUCAACAAAG720TATTGACTTAGTCAACAAAG1232gRNA1780UAUUGACUUAGUCAACAAAGA721TATTGACTTAGTCAACAAAGA1233gRNA1781UCAGAAUCAGCAGGUUUGCAG722TCAGAATCAGCAGGTTTGCAG1234gRNA1782UCCACUCAUUCUUGGCAGGA723TCCACTCATTCTTGGCAGGA741gRNA1783UCUCUCUUUGUUGACUAAGUC724TCTCTCTTTGTTGACTAAGTC742gRNA1784UGAGAAGCCAUCCUGCCAAGA725TGAGAAGCCATCCTGCCAAGA743gRNA1785UGAGCUAGGCUGCUUAUCCCU726TGAGCTAGGCTGCTTATCCCT744gRNA1786UGAGUAUAAAAGCCCCAGGC727TGAGTATAAAAGCCCCAGGC745gRNA1787UGAUGGCUGCUCCCAGCCUG728TGATGGCTGCTCCCAGCCTG746gRNA1788UGCCAAGAAUGAGUGGACUUC729TGCCAAGAATGAGTGGACTTC747gRNA1789UGCCAAUCUGACUGCAAACCU730TGCCAATCTGACTGCAAACCT748gRNA1790UGUUGACUAAGUCAAUAAUC731TGTTGACTAAGTCAATAATC749gRNA1791UUGACUUAGUCAACAAAGAG732TTGACTTAGTCAACAAAGAG750gRNA1792UUUGUUGACUAAGUCAAUAAU733TTTGTTGACTAAGTCAATAAT751gRNA1746AACCUGCUGAUUCUGAUUAU734AACCTGCTGATTCTGATTAT752gRNA1594CAACUUACCCAGAGGCAAAU735CAACTTACCCAGAGGCAAAT753gRNA1595AAUGGCUCCCAGGUGUCAUC736AATGGCTCCCAGGTGTCATC754gRNA1596GGCUCCCAGGUGUCAUCAGC737GGCTCCCAGGTGTCATCAGC755gRNA1597CUCUCAUAGGUGGUAUUCAC738CTCTCATAGGTGGTATTCAC756gRNA1598UAUAGGAAAACCAGUGAGUC475TATAGGAAAACCAGTGAGTC469gRNA1599UACUCACCUCUGCAUGCUCA476TACTCACCTCTGCATGCTCA470gRNA1600GCAACUUACCCAGAGGCAAA474GCAACTTACCCAGAGGCAAA468gRNA1601UCUGUAUACUCACCUCUGCA739TCTGTATACTCACCTCTGCA757gRNA1602GAAACACUCACCGUAGGGCC740GAAACACTCACCGTAGGGCC758gRNA1603CUCUACACCCAGGGCACCGG759CTCTACACCCAGGGCACCGG779gRNA1604ACACCUUAUAGGAAAACCAG760ACACCTTATAGGAAAACCAG780gRNA1605AUAGGAAAACCAGUGAGUCU761ATAGGAAAACCAGTGAGTCT781gRNA1606ACUCACCUCUGCAUGCUCAU644ACTCACCTCTGCATGCTCAT658gRNA1607CUCACCGUAGGGCCAGCCUC762CTCACCGTAGGGCCAGCCTC782gRNA-#1AAAAGCCCCAGGCUGGGAGC763AAAAGCCCCAGGCTGGGAGC783gRNA-#2AAGUGAGUAUAAAAGCCCCA764AAGTGAGTATAAAAGCCCCA784gRNA-#3AAUAAUCAGAAUCAGCAGGUU765AATAATCAGAATCAGCAGGTT785gRNA-#4AAUAUGAACCUUGUCUAGAG766AATATGAACCTTGTCTAGAG786gRNA-#5AAUGAGUGGACUUCUGUGAU767AATGAGTGGACTTCTGTGAT787gRNA-#6ACAAAUAUGAACCUUGUCUAG768ACAAATATGAACCTTGTCTAG788gRNA-#7ACAGAAGUCCACUCAUUCUU769ACAGAAGTCCACTCATTCTT789gRNA-#8ACCUUGUCUAGAGAGAUUAG770ACCTTGTCTAGAGAGATTAG790gRNA-#9AGAAGCCAUCCUGCCAAGAA771AGAAGCCATCCTGCCAAGAA791gRNA-#10AGCAGGUUUGCAGUCAGAUU772AGCAGGTTTGCAGTCAGATT792gRNA-#11AGGGAUAAGCAGCCUAGCUC773AGGGATAAGCAGCCTAGCTC793gRNA-#12AGGUUUGCAGUCAGAUUGGC774AGGTTTGCAGTCAGATTGGC794gRNA-#13AGUAUAAAAGCCCCAGGCUG775AGTATAAAAGCCCCAGGCTG795gRNA-#14AGUCAAUAAUCAGAAUCAGC776AGTCAATAATCAGAATCAGC796gRNA-#15AUAAUCAGAAUCAGCAGGUU777ATAATCAGAATCAGCAGGTT797gRNA-#16UUGACUUAGUCAACAAAGAGAG778TTGACTTAGTCAACAAAGAGAG798gRNA-#17UCUCUUUGUUGACUAAGUCAAU799TCTCTTTGTTGACTAAGTCAAT820gRNA-#18UGAUUAUUGACUUAGUCAACAA800TGATTATTGACTTAGTCAACAA821gRNA-#19 (sgRNA_367)UUGGCAGGAUGGCUUCUCAUCG648TTGGCAGGATGGCTTCTCATCG662gRNA-#20ACUUAGUCAACAAAGAGAGAAU801ACTTAGTCAACAAAGAGAGAAT822gRNA-#21GCAGGGAUAAGCAGCCUAGCUC802GCAGGGATAAGCAGCCTAGCTC823gRNA-#22GUAUGGGUUACUUAUUCUCUCU803GTATGGGTTACTTATTCTCTCT824gRNA-#23CAAGAAUGAGUGGACUUCUG804CAAGAATGAGTGGACTTCTG825gRNA-#24CAAUCUGACUGCAAACCUGC805CAATCTGACTGCAAACCTGC826gRNA-#25CACAGAAGUCCACUCAUUCU806CACAGAAGTCCACTCATTCT827gRNA-#26CAGACGAUGAGAAGCCAUCC807CAGACGATGAGAAGCCATCC828gRNA-#27CAGCAGGUUUGCAGUCAGAU808CAGCAGGTTTGCAGTCAGAT829gRNA-#28CAGGAUGGCUUCUCAUCGUC809CAGGATGGCTTCTCATCGTC830gRNA-#29CAGGUUUGCAGUCAGAUUGGC810CAGGTTTGCAGTCAGATTGGC831gRNA-#30CAGUCAGAUUGGCAGGGAUA811CAGTCAGATTGGCAGGGATA832gRNA-#31CCACUCAUUCUUGGCAGGAU812CCACTCATTCTTGGCAGGAT833gRNA-#32CUAAGUCAAUAAUCAGAAUC813CTAAGTCAATAATCAGAATC834gRNA-#33GUCAACAAAGAGAGAAUAAGUA814GTCAACAAAGAGAGAATAAGTA835gRNA-#34CUUAUCCCUGCCAAUCUGAC815CTTATCCCTGCCAATCTGAC836gRNA-#35UCCCUGCCAAUCUGACUGCAAA816TCCCTGCCAATCTGACTGCAAA837gRNA-#36UUCUCUCUUUGUUGACUAAGUC817TTCTCTCTTTGTTGACTAAGTC838gRNA-#37UCCUGAGCUAGGCUGCUUAUCC818TCCTGAGCTAGGCTGCTTATCC839gRNA-#38CUUCUGUGAUGGCUGCUCCC819CTTCTGTGATGGCTGCTCCC860gRNA-#39UGUGAUGGCUGCUCCCAGCCUG840TGTGATGGCTGCTCCCAGCCTG861gRNA-#40GCAGGAUGGCUUCUCAUCGUCU841GCAGGATGGCTTCTCATCGTCT862gRNA-#41UCUAGAGAGAUUAGAGCAUCGG842TCTAGAGAGATTAGAGCATCGG863gRNA-#42GUUGACUAAGUCAAUAAUCAGA843GTTGACTAAGTCAATAATCAGA864gRNA-#43UAUACUCACUUCUCCUGAGCUA844TATACTCACTTCTCCTGAGCTA865gRNA-#44GAAGUGAGUAUAAAAGCCCC845GAAGTGAGTATAAAAGCCCC866gRNA-#45GACAAGGUUCAUAUUUGUAU846GACAAGGTTCATATTTGTAT867gRNA-#46GAGUAUAAAAGCCCCAGGCU847GAGTATAAAAGCCCCAGGCT868gRNA-#47GAGUGGACUUCUGUGAUGGC848GAGTGGACTTCTGTGATGGC869gRNA-#48GAUGGCUGCUCCCAGCCUGG849GATGGCTGCTCCCAGCCTGG870gRNA-#49GCAGCCUAGCUCAGGAGAAG850GCAGCCTAGCTCAGGAGAAG871gRNA-#50GCUGCUUAUCCCUGCCAAUC851GCTGCTTATCCCTGCCAATC872gRNA-#51GGGAUAAGCAGCCUAGCUCA852GGGATAAGCAGCCTAGCTCA873gRNA-#52GGUUUGCAGUCAGAUUGGCA853GGTTTGCAGTCAGATTGGCA874gRNA-#53GUUACUUAUUCUCUCUUUGU854GTTACTTATTCTCTCTTTGT875gRNA-#54CUUAUUCUCUCUUUGUUGACUA855CTTATTCTCTCTTTGTTGACTA876gRNA-#55AUAUUUGUAUGGGUUACUUAUU856ATATTTGTATGGGTTACTTATT877gRNA-#56ACUAAGUCAAUAAUCAGAAUCA857ACTAAGTCAATAATCAGAATCA878gRNA-#57GUUUGCAGUCAGAUUGGCAG858GTTTGCAGTCAGATTGGCAG879gRNA-#58GCAGUCAGAUUGGCAGGGAUAA859GCAGTCAGATTGGCAGGGATAA880gRNA-#59UACAAAUAUGAACCUUGUCU881TACAAATATGAACCTTGTCT894gRNA-#60UACUCACUUCUCCUGAGCUA882TACTCACTTCTCCTGAGCTA895gRNA-#61UAUAAAAGCCCCAGGCUGGG883TATAAAAGCCCCAGGCTGGG896gRNA-#62UCACUUCUCCUGAGCUAGGC884TCACTTCTCCTGAGCTAGGC897gRNA-#63UCAGAUUGGCAGGGAUAAGC885TCAGATTGGCAGGGATAAGC898gRNA-#64UCAGGAGAAGUGAGUAUAAA886TCAGGAGAAGTGAGTATAAA899gRNA-#65UCUGACUGCAAACCUGCUGAU887TCTGACTGCAAACCTGCTGAT900gRNA-#66UGAGCUAGGCUGCUUAUCCC888TGAGCTAGGCTGCTTATCCC901gRNA-#67UGCCAAUCUGACUGCAAACC889TGCCAATCTGACTGCAAACC902gRNA-#68UGCUCUAAUCUCUCUAGACA890TGCTCTAATCTCTCTAGACA903gRNA-#69UGUGAUGGCUGCUCCCAGCC891TGTGATGGCTGCTCCCAGCC904gRNA-#70UUGGCAGGGAUAAGCAGCCU892TTGGCAGGGATAAGCAGCCT905gRNA-#71UUUUAUACUCACUUCUCCUG893TTTTATACTCACTTCTCCTG906 Table 2C. Exemplary human TTR target site sequences and base editor + guide RNA combinations.gRNA NameEditor NameCas NameEditor AliasEditing StrategyTarget Site / Protospacer + PAM SequenceSEQ ID NOgRNA1594CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBESplice SiteCAACTTACCCAGAGGCAAATGGC907gRNA1594ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABESplice SiteCAACTTACCCAGAGGCAAATGGC908gRNA1594ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBESplice SiteCAACTTACCCAGAGGCAAATGGC909gRNA1595CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBEStop CodonAATGGCTCCCAGGTGTCATCAGC910gRNA1596CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBEStop CodonGGCTCCCAGGTGTCATCAGCAGC911gRNA1597ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABESplice SiteCTCTCATAGGTGGTATTCACAGC912gRNA1597ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBESplice SiteCTCTCATAGGTGGTATTCACAGC913gRNA1598ABE_NGG_20nt_3-12_018spCas9spCas9 IBESplice SiteTATAGGAAAACCAGTGAGTCTGG914gRNA1599ABE_NGG_20nt_3-12_018spCas9spCas9 IBESplice SiteTACTCACCTCTGCATGCTCATGG915gRNA1600ABE_NGG_20nt_3-12_018spCas9spCas9 IBESplice SiteGCAACTTACCCAGAGGCAAATGG916gRNA1601ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBESplice SiteTCTGTATACTCACCTCTGCATGC917gRNA1602ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBESplice SiteGAAACACTCACCGTAGGGCCAGC918gRNA1603ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBESplice SiteCTCTACACCCAGGGCACCGGTGA919gRNA1604ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBESplice SiteACACCTTATAGGAAAACCAGTGA920gRNA1605ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBESplice SiteATAGGAAAACCAGTGAGTCTGGA921gRNA1606ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBESplice SiteACTCACCTCTGCATGCTCATGGA922gRNA1607ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBESplice SiteCTCACCGTAGGGCCAGCCTCAGA923gRNA1746ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterAACCTGCTGATTCTGATTATTGA924gRNA1746CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterAACCTGCTGATTCTGATTATTGA925gRNA1746ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterAACCTGCTGATTCTGATTATTGA926gRNA1747ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterAAGAGAGAATAAGTAACCCATACAAAT927gRNA1747CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterAAGAGAGAATAAGTAACCCATACAAAT928gRNA1748ABE_NNGRRT_21nt_5-14_011saCas9saCas9 ABETTR PromoterAAGCAGCCTAGCTCAGGAGAAGTGAGT929gRNA1748CBE_NNGRRT_21nt_3-12_012saCas9saCas9 CBETTR PromoterAAGCAGCCTAGCTCAGGAGAAGTGAGT930gRNA1749ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterAAGTCCACTCATTCTTGGCAGGA931gRNA1749CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterAAGTCCACTCATTCTTGGCAGGA932gRNA1749ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterAAGTCCACTCATTCTTGGCAGGA933gRNA1750ABE_NNGRRT_21nt_5-14_011saCas9saCas9 ABETTR PromoterACGATGAGAAGCCATCCTGCCAAGAAT934gRNA1750CBE_NNGRRT_21nt_3-12_012saCas9saCas9 CBETTR PromoterACGATGAGAAGCCATCCTGCCAAGAAT935gRNA1751ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterAGACAAGGTTCATATTTGTATGG936gRNA1751CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterAGACAAGGTTCATATTTGTATGG937gRNA1751ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterAGACAAGGTTCATATTTGTATGG938gRNA1752ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterAGGCTGGGAGCAGCCATCACAGA939gRNA1752CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterAGGCTGGGAGCAGCCATCACAGA940gRNA1752ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterAGGCTGGGAGCAGCCATCACAGA941gRNA1753ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterATAAGTAACCCATACAAATATGA942gRNA1753CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterATAAGTAACCCATACAAATATGA943gRNA1753ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterATAAGTAACCCATACAAATATGA944gRNA1754ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterATACTCACTTCTCCTGAGCTAGG945gRNA1754CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterATACTCACTTCTCCTGAGCTAGG946gRNA1754ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterATACTCACTTCTCCTGAGCTAGG947gRNA1755ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterATTATTGACTTAGTCAACAAAGA948gRNA1755CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterATTATTGACTTAGTCAACAAAGA949gRNA1755ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterATTATTGACTTAGTCAACAAAGA950gRNA1756ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterCAAATATGAACCTTGTCTAGAGA951gRNA1756CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterCAAATATGAACCTTGTCTAGAGA952gRNA1756ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterCAAATATGAACCTTGTCTAGAGA953gRNA1757ABE_NNGRRT_21nt_5-14_011saCas9saCas9 ABETTR PromoterCAGAAGTCCACTCATTCTTGGCAGGAT954gRNA1757CBE_NNGRRT_21nt_3-12_012saCas9saCas9 CBETTR PromoterCAGAAGTCCACTCATTCTTGGCAGGAT955gRNA1758ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterCAGGCTGGGAGCAGCCATCACAGAAGT956gRNA1758CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterCAGGCTGGGAGCAGCCATCACAGAAGT957gRNA1759ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterCCATCCTGCCAAGAATGAGTGGA958gRNA1759CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterCCATCCTGCCAAGAATGAGTGGA959gRNA1759ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterCCATCCTGCCAAGAATGAGTGGA960gRNA1760ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterCCTGCTGATTCTGATTATTGACTTAGT961gRNA1760CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterCCTGCTGATTCTGATTATTGACTTAGT962gRNA1761ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterCGATGCTCTAATCTCTCTAGACAAGGT963gRNA1761CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterCGATGCTCTAATCTCTCTAGACAAGGT964gRNA1762ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterCTAAGTCAATAATCAGAATCAGCAGGT965gRNA1762CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterCTAAGTCAATAATCAGAATCAGCAGGT966gRNA1763ABE_NNGRRT_21nt_5-14_011saCas9saCas9 ABETTR PromoterCTAGACAAGGTTCATATTTGTATGGGT967gRNA1763CBE_NNGRRT_21nt_3-12_012saCas9saCas9 CBETTR PromoterCTAGACAAGGTTCATATTTGTATGGGT968gRNA1764ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGAACCTTGTCTAGAGAGATTAGA969gRNA1764CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGAACCTTGTCTAGAGAGATTAGA970gRNA1764ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGAACCTTGTCTAGAGAGATTAGA971gRNA1765ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterGAAGTCCACTCATTCTTGGCAGG972gRNA1765CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterGAAGTCCACTCATTCTTGGCAGG973gRNA1765ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterGAAGTCCACTCATTCTTGGCAGG974gRNA1766ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGAATCAGCAGGTTTGCAGTCAGA975gRNA1766CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGAATCAGCAGGTTTGCAGTCAGA976gRNA1766ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGAATCAGCAGGTTTGCAGTCAGA977gRNA1767ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterGAATGAGTGGACTTCTGTGATGG978gRNA1767CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterGAATGAGTGGACTTCTGTGATGG979gRNA1767ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterGAATGAGTGGACTTCTGTGATGG980gRNA1768ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGACTGCAAACCTGCTGATTCTGA981gRNA1768CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGACTGCAAACCTGCTGATTCTGA982gRNA1768ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGACTGCAAACCTGCTGATTCTGA983gRNA1769ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterGACTTAGTCAACAAAGAGAGAATAAGT984gRNA1769CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterGACTTAGTCAACAAAGAGAGAATAAGT985gRNA1770ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGATAAGCAGCCTAGCTCAGGAGA986gRNA1770CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGATAAGCAGCCTAGCTCAGGAGA987gRNA1770ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGATAAGCAGCCTAGCTCAGGAGA988gRNA1771ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGATGAGAAGCCATCCTGCCAAGA989gRNA1771CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGATGAGAAGCCATCCTGCCAAGA990gRNA1771ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGATGAGAAGCCATCCTGCCAAGA991gRNA1772ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterGCCATCCTGCCAAGAATGAGTGG992gRNA1772CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterGCCATCCTGCCAAGAATGAGTGG993gRNA1772ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterGCCATCCTGCCAAGAATGAGTGG994gRNA1773ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGCTTTTATACTCACTTCTCCTGA995gRNA1773CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGCTTTTATACTCACTTCTCCTGA996gRNA1773ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGCTTTTATACTCACTTCTCCTGA997gRNA1774ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterGGATAAGCAGCCTAGCTCAGGAGAAGT998gRNA1774CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterGGATAAGCAGCCTAGCTCAGGAGAAGT999gRNA1775ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterGTCTAGAGAGATTAGAGCATCGG1000gRNA1775CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterGTCTAGAGAGATTAGAGCATCGG1001gRNA1775ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterGTCTAGAGAGATTAGAGCATCGG1002gRNA1776ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterGTGATGGCTGCTCCCAGCCTGGG1003gRNA1776CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterGTGATGGCTGCTCCCAGCCTGGG1004gRNA1776ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterGTGATGGCTGCTCCCAGCCTGGG1005gRNA1777ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterTACTTATTCTCTCTTTGTTGACTAAGT1006gRNA1777CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterTACTTATTCTCTCTTTGTTGACTAAGT1007gRNA1778ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterTATTCTCTCTTTGTTGACTAAGTCAAT1008gRNA1778CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterTATTCTCTCTTTGTTGACTAAGTCAAT1009gRNA1779ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterTATTGACTTAGTCAACAAAGAGA1010gRNA1779CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterTATTGACTTAGTCAACAAAGAGA1011gRNA1779ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterTATTGACTTAGTCAACAAAGAGA1012gRNA1780ABE_NNGRRT_21nt_5-14_011saCas9saCas9 ABETTR PromoterTATTGACTTAGTCAACAAAGAGAGAAT1013gRNA1780CBE_NNGRRT_21nt_3-12_012saCas9saCas9 CBETTR PromoterTATTGACTTAGTCAACAAAGAGAGAAT1014gRNA1781ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterTCAGAATCAGCAGGTTTGCAGTCAGAT1015gRNA1781CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterTCAGAATCAGCAGGTTTGCAGTCAGAT1016gRNA1782ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterTCCACTCATTCTTGGCAGGATGG1017gRNA1782CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterTCCACTCATTCTTGGCAGGATGG1018gRNA1782ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterTCCACTCATTCTTGGCAGGATGG1019gRNA1783ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterTCTCTCTTTGTTGACTAAGTCAATAAT1020gRNA1783CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterTCTCTCTTTGTTGACTAAGTCAATAAT1021gRNA1784ABE_NNGRRT_21nt_5-14_011saCas9saCas9 ABETTR PromoterTGAGAAGCCATCCTGCCAAGAATGAGT1022gRNA1784CBE_NNGRRT_21nt_3-12_012saCas9saCas9 CBETTR PromoterTGAGAAGCCATCCTGCCAAGAATGAGT1023gRNA1785ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterTGAGCTAGGCTGCTTATCCCTGCCAAT1024gRNA1785CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterTGAGCTAGGCTGCTTATCCCTGCCAAT1025gRNA1786ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterTGAGTATAAAAGCCCCAGGCTGG1026gRNA1786CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterTGAGTATAAAAGCCCCAGGCTGG1027gRNA1786ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterTGAGTATAAAAGCCCCAGGCTGG1028gRNA1787ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterTGATGGCTGCTCCCAGCCTGGGG1029gRNA1787CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterTGATGGCTGCTCCCAGCCTGGGG1030gRNA1787ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterTGATGGCTGCTCCCAGCCTGGGG1031gRNA1788ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterTGCCAAGAATGAGTGGACTTCTGTGAT1032gRNA1788CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterTGCCAAGAATGAGTGGACTTCTGTGAT1033gRNA1789ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterTGCCAATCTGACTGCAAACCTGCTGAT1034gRNA1789CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterTGCCAATCTGACTGCAAACCTGCTGAT1035gRNA1790ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterTGTTGACTAAGTCAATAATCAGA1036gRNA1790CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterTGTTGACTAAGTCAATAATCAGA1037gRNA1790ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterTGTTGACTAAGTCAATAATCAGA1038gRNA1791ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterTTGACTTAGTCAACAAAGAGAGA1039gRNA1791CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterTTGACTTAGTCAACAAAGAGAGA1040gRNA1791ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterTTGACTTAGTCAACAAAGAGAGA1041gRNA1792ABE_NNGRRT_21nt_5-14_011saCas9saCas9 ABETTR PromoterTTTGTTGACTAAGTCAATAATCAGAAT1042gRNA1792CBE_NNGRRT_21nt_3-12_012saCas9saCas9 CBETTR PromoterTTTGTTGACTAAGTCAATAATCAGAAT104gRNA-#1ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterAAAAGCCCCAGGCTGGGAGCAGC1044gRNA-#1CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterAAAAGCCCCAGGCTGGGAGCAGC1045gRNA-#1ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterAAAAGCCCCAGGCTGGGAGCAGC1046gRNA-#2ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterAAGTGAGTATAAAAGCCCCAGGC1047gRNA-#2CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterAAGTGAGTATAAAAGCCCCAGGC1048gRNA-#2ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterAAGTGAGTATAAAAGCCCCAGGC1049gRNA-#3ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterAATAATCAGAATCAGCAGGTTTGCAGT1050gRNA-#3CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterAATAATCAGAATCAGCAGGTTTGCAGT1051gRNA-#4CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterAATATGAACCTTGTCTAGAGAGA1052gRNA-#4ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterAATATGAACCTTGTCTAGAGAGA1053gRNA-#4ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterAATATGAACCTTGTCTAGAGAGA1054gRNA-#5ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterAATGAGTGGACTTCTGTGATGGC1055gRNA-#5CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterAATGAGTGGACTTCTGTGATGGC1056gRNA-#5ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterAATGAGTGGACTTCTGTGATGGC1057gRNA-#6ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterACAAATATGAACCTTGTCTAGAGAGAT1058gRNA-#6CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterACAAATATGAACCTTGTCTAGAGAGAT1059gRNA-#7ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterACAGAAGTCCACTCATTCTTGGC1060gRNA-#7CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterACAGAAGTCCACTCATTCTTGGC1061gRNA-#7ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterACAGAAGTCCACTCATTCTTGGC1062gRNA-#8ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterACCTTGTCTAGAGAGATTAGAGC1063gRNA-#8CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterACCTTGTCTAGAGAGATTAGAGC1064gRNA-#8ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterACCTTGTCTAGAGAGATTAGAGC1065gRNA-#9CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterAGAAGCCATCCTGCCAAGAATGA1066gRNA-#9ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterAGAAGCCATCCTGCCAAGAATGA1067gRNA-#9ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterAGAAGCCATCCTGCCAAGAATGA1068gRNA-#10ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterAGCAGGTTTGCAGTCAGATTGGC1069gRNA-#10CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterAGCAGGTTTGCAGTCAGATTGGC1070gRNA-#10ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterAGCAGGTTTGCAGTCAGATTGGC1071gRNA-#11ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterAGGGATAAGCAGCCTAGCTCAGG1072gRNA-#11CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterAGGGATAAGCAGCCTAGCTCAGG1073gRNA-#11ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterAGGGATAAGCAGCCTAGCTCAGG1074gRNA-#12ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterAGGTTTGCAGTCAGATTGGCAGG1075gRNA-#12CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterAGGTTTGCAGTCAGATTGGCAGG1076gRNA-#12ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterAGGTTTGCAGTCAGATTGGCAGG1077gRNA-#13CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterAGTATAAAAGCCCCAGGCTGGGA1078gRNA-#13ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterAGTATAAAAGCCCCAGGCTGGGA1079gRNA-#13ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterAGTATAAAAGCCCCAGGCTGGGA1080gRNA-#14ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterAGTCAATAATCAGAATCAGCAGG1081gRNA-#14CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterAGTCAATAATCAGAATCAGCAGG1082gRNA-#14ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterAGTCAATAATCAGAATCAGCAGG1083gRNA-#15ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterATAATCAGAATCAGCAGGTTTGC1084gRNA-#15CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterATAATCAGAATCAGCAGGTTTGC1085gRNA-#15ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterATAATCAGAATCAGCAGGTTTGC1086gRNA-#16ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterATTATTGACTTAGTCAACAAAGAGAG1087gRNA-#17ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterATTCTCTCTTTGTTGACTAAGTCAAT1088gRNA-#18ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterATTCTGATTATTGACTTAGTCAACAA1089gRNA-#19 (sgRNA_367)ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterATTCTTGGCAGGATGGCTTCTCATCG1090gRNA-#20ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterATTGACTTAGTCAACAAAGAGAGAAT1091gRNA-#21ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterATTGGCAGGGATAAGCAGCCTAGCTC1092gRNA-#22ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterATTTGTATGGGTTACTTATTCTCTCT1093gRNA-#23CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterCAAGAATGAGTGGACTTCTGTGA1094gRNA-#23ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterCAAGAATGAGTGGACTTCTGTGA1095gRNA-#23ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterCAAGAATGAGTGGACTTCTGTGA1096gRNA-#24CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterCAATCTGACTGCAAACCTGCTGA1097gRNA-#24ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterCAATCTGACTGCAAACCTGCTGA1098gRNA-#24ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterCAATCTGACTGCAAACCTGCTGA1099gRNA-#25ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterCACAGAAGTCCACTCATTCTTGG1100gRNA-#25CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterCACAGAAGTCCACTCATTCTTGG1101gRNA-#25ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterCACAGAAGTCCACTCATTCTTGG1102gRNA-#26ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterCAGACGATGAGAAGCCATCCTGC1103gRNA-#26CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterCAGACGATGAGAAGCCATCCTGC1104gRNA-#26ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterCAGACGATGAGAAGCCATCCTGC1105gRNA-#27ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterCAGCAGGTTTGCAGTCAGATTGG1106gRNA-#27CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterCAGCAGGTTTGCAGTCAGATTGG1107gRNA-#27ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterCAGCAGGTTTGCAGTCAGATTGG1108gRNA-#28ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterCAGGATGGCTTCTCATCGTCTGC1109gRNA-#28CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterCAGGATGGCTTCTCATCGTCTGC1110gRNA-#28ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterCAGGATGGCTTCTCATCGTCTGC1111gRNA-#29ABE_NNGRRT_21nt_5-14_011saCas9saCas9 ABETTR PromoterCAGGTTTGCAGTCAGATTGGCAGGGAT1112gRNA-#29CBE_NNGRRT_21nt_3-12_012saCas9saCas9 CBETTR PromoterCAGGTTTGCAGTCAGATTGGCAGGGAT1113gRNA-#30ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterCAGTCAGATTGGCAGGGATAAGC1114gRNA-#30CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterCAGTCAGATTGGCAGGGATAAGC1115gRNA-#30ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterCAGTCAGATTGGCAGGGATAAGC1116gRNA-#31ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterCCACTCATTCTTGGCAGGATGGC1117gRNA-#31CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterCCACTCATTCTTGGCAGGATGGC1118gRNA-#31ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterCCACTCATTCTTGGCAGGATGGC1119gRNA-#32ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterCTAAGTCAATAATCAGAATCAGC1120gRNA-#32CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterCTAAGTCAATAATCAGAATCAGC1121gRNA-#32ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterCTAAGTCAATAATCAGAATCAGC1122gRNA-#33ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterCTTAGTCAACAAAGAGAGAATAAGTA1123gRNA-#34ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterCTTATCCCTGCCAATCTGACTGC1124gRNA-#34CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterCTTATCCCTGCCAATCTGACTGC1125gRNA-#34ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterCTTATCCCTGCCAATCTGACTGC1126gRNA-#35ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterCTTATCCCTGCCAATCTGACTGCAAA1127gRNA-#36ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterCTTATTCTCTCTTTGTTGACTAAGTC1128gRNA-#37ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterCTTCTCCTGAGCTAGGCTGCTTATCC1129gRNA-#38ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterCTTCTGTGATGGCTGCTCCCAGC1130gRNA-#38CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterCTTCTGTGATGGCTGCTCCCAGC1131gRNA-#38ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterCTTCTGTGATGGCTGCTCCCAGC1132gRNA-#39ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterCTTCTGTGATGGCTGCTCCCAGCCTG1133gRNA-#40ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterCTTGGCAGGATGGCTTCTCATCGTCT1134gRNA-#41ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterCTTGTCTAGAGAGATTAGAGCATCGG1135gRNA-#42ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterCTTTGTTGACTAAGTCAATAATCAGA1136gRNA-#43ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterCTTTTATACTCACTTCTCCTGAGCTA1137gRNA-#44ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterGAAGTGAGTATAAAAGCCCCAGG1138gRNA-#44CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterGAAGTGAGTATAAAAGCCCCAGG1139gRNA-#44ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterGAAGTGAGTATAAAAGCCCCAGG1140gRNA-#45ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterGACAAGGTTCATATTTGTATGGG1141gRNA-#45CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterGACAAGGTTCATATTTGTATGGG1142gRNA-#45ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterGACAAGGTTCATATTTGTATGGG1143gRNA-#46ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterGAGTATAAAAGCCCCAGGCTGGG1144gRNA-#46CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterGAGTATAAAAGCCCCAGGCTGGG1145gRNA-#46ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterGAGTATAAAAGCCCCAGGCTGGG1146gRNA-#47ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterGAGTGGACTTCTGTGATGGCTGC1147gRNA-#47CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterGAGTGGACTTCTGTGATGGCTGC1148gRNA-#47ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterGAGTGGACTTCTGTGATGGCTGC1149gRNA-#48ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterGATGGCTGCTCCCAGCCTGGGGC1150gRNA-#48CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterGATGGCTGCTCCCAGCCTGGGGC1151gRNA-#48ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterGATGGCTGCTCCCAGCCTGGGGC1152gRNA-#48CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGCAGCCTAGCTCAGGAGAAGTGA1153gRNA-#48ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGCAGCCTAGCTCAGGAGAAGTGA1154gRNA-#48ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGCAGCCTAGCTCAGGAGAAGTGA1155gRNA-#50CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGCTGCTTATCCCTGCCAATCTGA1156gRNA-#50ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGCTGCTTATCCCTGCCAATCTGA1157gRNA-#50ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGCTGCTTATCCCTGCCAATCTGA1158gRNA-#51CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGGGATAAGCAGCCTAGCTCAGGA1159gRNA-#51ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGGGATAAGCAGCCTAGCTCAGGA1160gRNA-#51ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGGGATAAGCAGCCTAGCTCAGGA1161gRNA-#52ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterGGTTTGCAGTCAGATTGGCAGGG1162gRNA-#52CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterGGTTTGCAGTCAGATTGGCAGGG1163gRNA-#52ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterGGTTTGCAGTCAGATTGGCAGGG1164gRNA-#53CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGTTACTTATTCTCTCTTTGTTGA1165gRNA-#53ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGTTACTTATTCTCTCTTTGTTGA1166gRNA-#53ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGTTACTTATTCTCTCTTTGTTGA1167gRNA-#54ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterGTTACTTATTCTCTCTTTGTTGACTA1168gRNA-#55ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterGTTCATATTTGTATGGGTTACTTATT1169gRNA-#56ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterGTTGACTAAGTCAATAATCAGAATCA1170gRNA-#57CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterGTTTGCAGTCAGATTGGCAGGGA1171gRNA-#57ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterGTTTGCAGTCAGATTGGCAGGGA1172gRNA-#57ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterGTTTGCAGTCAGATTGGCAGGGA1173gRNA-#58ABE_VTTN_22nt_5-9_017cas12bcas12b ABETTR PromoterGTTTGCAGTCAGATTGGCAGGGATAA1174gRNA-#59CBE_NGA_20nt_4-9_006spCas9spCas9 VRQR CBETTR PromoterTACAAATATGAACCTTGTCTAGA1175gRNA-#59ABE_NGA_20nt_3-9_005spCas9spCas9 VRQR ABETTR PromoterTACAAATATGAACCTTGTCTAGA1176gRNA-#59ABE_NGA_20nt_3-12_019spCas9spCas9 VRQR IBETTR PromoterTACAAATATGAACCTTGTCTAGA1177gRNA-#60ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterTACTCACTTCTCCTGAGCTAGGC1178gRNA-#60CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterTACTCACTTCTCCTGAGCTAGGC1179gRNA-#60ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterTACTCACTTCTCCTGAGCTAGGC1180gRNA-#61ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterTATAAAAGCCCCAGGCTGGGAGC1181gRNA-#61CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterTATAAAAGCCCCAGGCTGGGAGC1182gRNA-#61ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterTATAAAAGCCCCAGGCTGGGAGC1183gRNA-#62ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterTCACTTCTCCTGAGCTAGGCTGC1184gRNA-#62CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterTCACTTCTCCTGAGCTAGGCTGC1185gRNA-#62ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterTCACTTCTCCTGAGCTAGGCTGC1186gRNA-#63ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterTCAGATTGGCAGGGATAAGCAGC1187gRNA-#63CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterTCAGATTGGCAGGGATAAGCAGC1188gRNA-#63ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterTCAGATTGGCAGGGATAAGCAGC1189gRNA-#64ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterTCAGGAGAAGTGAGTATAAAAGC1190gRNA-#64CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterTCAGGAGAAGTGAGTATAAAAGC1191gRNA-#64ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterTCAGGAGAAGTGAGTATAAAAGC1192gRNA-#65ABE_NNNRRT_21nt_5-14_014saCas9saCas9 KKH ABETTR PromoterTCTGACTGCAAACCTGCTGATTCTGAT1193gRNA-#65CBE_NNNRRT_21nt_3-12_015saCas9saCas9 KKH CBETTR PromoterTCTGACTGCAAACCTGCTGATTCTGAT1194gRNA-#66ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterTGAGCTAGGCTGCTTATCCCTGC1195gRNA-#66CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterTGAGCTAGGCTGCTTATCCCTGC1196gRNA-#66ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterTGAGCTAGGCTGCTTATCCCTGC1197gRNA-#67ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterTGCCAATCTGACTGCAAACCTGC1198gRNA-#67CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterTGCCAATCTGACTGCAAACCTGC1199gRNA-#67ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterTGCCAATCTGACTGCAAACCTGC1200gRNA-#68ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterTGCTCTAATCTCTCTAGACAAGG1201gRNA-#68CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterTGCTCTAATCTCTCTAGACAAGG1202gRNA-#68ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterTGCTCTAATCTCTCTAGACAAGG1203gRNA-#69ABE_NGG_20nt_3-9_002spCas9spCas9 ABETTR PromoterTGTGATGGCTGCTCCCAGCCTGG1204gRNA-#69CBE_NGG_20nt_4-9_003spCas9spCas9 CBETTR PromoterTGTGATGGCTGCTCCCAGCCTGG1205gRNA-#69ABE_NGG_20nt_3-12_018spCas9spCas9 IBETTR PromoterTGTGATGGCTGCTCCCAGCCTGG1206gRNA-#70ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterTTGGCAGGGATAAGCAGCCTAGC1207gRNA-#70CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterTTGGCAGGGATAAGCAGCCTAGC1208gRNA-#70ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterTTGGCAGGGATAAGCAGCCTAGC1209gRNA-#71ABE_NGC_20nt_3-9_008spCas9spCas9 NGC ABETTR PromoterTTTTATACTCACTTCTCCTGAGC1210gRNA-#71CBE_NGC_20nt_4-9_009spCas9spCas9 NGC CBETTR PromoterTTTTATACTCACTTCTCCTGAGC1211gRNA-#71ABE_NGC_20nt_3-12_020spCas9spCas9 NGC IBETTR PromoterTTTTATACTCACTTCTCCTGAGC1212 Table 2C (CONTINUED)gRNA NamePAMHuman Chromosome LocationStart SiteEnd SiteStrandTarget Base Position(s)gRNA1594GGCchr183159301131593034-8gRNA1594GGCchr183159301131593034-7gRNA1594GGCchr183159301131593034-7gRNA1595AGCchr183159299431593017-9gRNA1596AGCchr183159299131593014-7,6gRNA1597AGCchr183159855831598581+8gRNA1597AGCchr183159855831598581+8gRNA1598TGGchr183159511431595137+4gRNA1599TGGchr183159523931595262-6gRNA1600TGGchr183159301231593035-8gRNA1601TGCchr183159524531595268-12gRNA1602AGCchr183159195931591982-10gRNA1603TGAchr183159288331592906+11gRNA1604TGAchr183159510831595131+10gRNA1605GGAchr183159511531595138+3gRNA1606GGAchr183159523831595261-5gRNA1607AGAchr183159195331591976-4gRNA1746TGAchr183159177631591799- gRNA1746TGAchr183159177631591799- gRNA1746TGAchr183159177631591799- gRNA1747ACAAATchr183159173831591765- gRNA1747ACAAATchr183159173831591765- gRNA1748GTGAGTchr183159182031591847+ gRNA1748GTGAGTchr183159182031591847+ gRNA1749GGAchr183159188031591903+ gRNA1749GGAchr183159188031591903+ gRNA1749GGAchr183159188031591903+ gRNA1750AAGAATchr183159189031591917- gRNA1750AAGAATchr183159189031591917- gRNA1751TGGchr183159172531591748+ gRNA1751TGGchr183159172531591748+ gRNA1751TGGchr183159172531591748+ gRNA1752AGAchr183159185831591881+ gRNA1752AGAchr183159185831591881+ gRNA1752AGAchr183159185831591881+ gRNA1753TGAchr183159173431591757- gRNA1753TGAchr183159173431591757- gRNA1753TGAchr183159173431591757- gRNA1754AGGchr183159182631591849- gRNA1754AGGchr183159182631591849- gRNA1754AGGchr183159182631591849- gRNA1755AGAchr183159176131591784- gRNA1755AGAchr183159176131591784- gRNA1755AGAchr183159176131591784- gRNA1756AGAchr183159172031591743- gRNA1756AGAchr183159172031591743- gRNA1756AGAchr183159172031591743- gRNA1757CAGGATchr183159187731591904+ gRNA1757CAGGATchr183159187731591904+ gRNA1758AGAAGTchr183159185731591884+ gRNA1758AGAAGTchr183159185731591884+ gRNA1759GGAchr183159188331591906- gRNA1759GGAchr183159188331591906- gRNA1759GGAchr183159188331591906- gRNA1760CTTAGTchr183159177031591797- gRNA1760CTTAGTchr183159177031591797- gRNA1761CAAGGTchr183159170731591734+ gRNA1761CAAGGTchr183159170731591734+ gRNA1762GCAGGTchr183159177131591798+ gRNA1762GCAGGTchr183159177131591798+ gRNA1763ATGGGTchr183159172331591750+ gRNA1763ATGGGTchr183159172331591750+ gRNA1764AGAchr183159171331591736- gRNA1764AGAchr183159171331591736- gRNA1764AGAchr183159171331591736- gRNA1765AGGchr183159187931591902+ gRNA1765AGGchr183159187931591902+ gRNA1765AGGchr183159187931591902+ gRNA1766AGAchr183159178631591809+ gRNA1766AGAchr183159178631591809+ gRNA1766AGAchr183159178631591809+ gRNA1767TGGchr183159187131591894- gRNA1767TGGchr183159187131591894- gRNA1767TGGchr183159187131591894- gRNA1768TGAchr183159178331591806- gRNA1768TGAchr183159178331591806- gRNA1768TGAchr183159178331591806- gRNA1769ATAAGTchr183159175131591778- gRNA1769ATAAGTchr183159175131591778- gRNA1770AGAchr183159181731591840+ gRNA1770AGAchr183159181731591840+ gRNA1770AGAchr183159181731591840+ gRNA1771AGAchr183159189231591915- gRNA1771AGAchr183159189231591915- gRNA1771AGAchr183159189231591915- gRNA1772TGGchr183159188431591907- gRNA1772TGGchr183159188431591907- gRNA1772TGGchr183159188431591907- gRNA1773TGAchr183159183231591855- gRNA1773TGAchr183159183231591855- gRNA1773TGAchr183159183231591855- gRNA1774AGAAGTchr183159181631591843+ gRNA1774AGAAGTchr183159181631591843+ gRNA1775CGGchr183159170631591729- gRNA1775CGGchr183159170631591729- gRNA1775CGGchr183159170631591729- gRNA1776GGGchr183159185531591878- gRNA1776GGGchr183159185531591878- gRNA1776GGGchr183159185531591878- gRNA1777CTAAGTchr183159175031591777+ gRNA1777CTAAGTchr183159175031591777+ gRNA1778GTCAATchr183159175431591781+ gRNA1778GTCAATchr183159175431591781+ gRNA1779AGAchr183159175931591782- gRNA1779AGAchr183159175931591782- gRNA1779AGAchr183159175931591782- gRNA1780GAGAATchr183159175531591782- gRNA1780GAGAATchr183159175531591782- gRNA1781TCAGATchr183159178331591810+ gRNA1781TCAGATchr183159178331591810+ gRNA1782TGGchr183159188331591906+ gRNA1782TGGchr183159188331591906+ gRNA1782TGGchr183159188331591906+ gRNA1783AATAATchr183159175731591784+ gRNA1783AATAATchr183159175731591784+ gRNA1784ATGAGTchr183159188631591913- gRNA1784ATGAGTchr183159188631591913- gRNA1785GCCAATchr183159180831591835- gRNA1785GCCAATchr183159180831591835- gRNA1786TGGchr183159184231591865+ gRNA1786TGGchr183159184231591865+ gRNA1786TGGchr183159184231591865+ gRNA1787GGGchr183159185431591877- gRNA1787GGGchr183159185431591877- gRNA1787GGGchr183159185431591877- gRNA1788TGTGATchr183159187331591900- gRNA1788TGTGATchr183159187331591900- gRNA1789GCTGATchr183159178831591815- gRNA1789GCTGATchr183159178831591815- gRNA1790AGAchr183159176531591788+ gRNA1790AGAchr183159176531591788+ gRNA1790AGAchr183159176531591788+ gRNA1791AGAchr183159175731591780- gRNA1791AGAchr183159175731591780- gRNA1791AGAchr183159175731591780- gRNA1792CAGAATchr183159176331591790+ gRNA1792CAGAATchr183159176331591790+ gRNA-#1AGCchr183159184931591872+ gRNA-#1AGCchr183159184931591872+ gRNA-#1AGCchr183159184931591872+ gRNA-#2GGCchr183159183931591862+ gRNA-#2GGCchr183159183931591862+ gRNA-#2GGCchr183159183931591862+ gRNA-#3TGCAGTchr183159177831591805+ gRNA-#3TGCAGTchr183159177831591805+ gRNA-#4AGAchr183159171831591741- gRNA-#4AGAchr183159171831591741- gRNA-#4AGAchr183159171831591741- gRNA-#5GGCchr183159187031591893- gRNA-#5GGCchr183159187031591893- gRNA-#5GGCchr183159187031591893- gRNA-#6AGAGATchr183159171731591744- gRNA-#6AGAGATchr183159171731591744- gRNA-#7GGCchr183159187631591899+ gRNA-#7GGCchr183159187631591899+ gRNA-#7GGCchr183159187631591899+ gRNA-#8AGCchr183159171131591734- gRNA-#8AGCchr183159171131591734- gRNA-#8AGCchr183159171131591734- gRNA-#9TGAchr183159188831591911- gRNA-#9TGAchr183159188831591911- gRNA-#9TGAchr183159188831591911- gRNA-#10GGCchr183159179131591814+ gRNA-#10GGCchr183159179131591814+ gRNA-#10GGCchr183159179131591814+ gRNA-#11AGGchr183159181431591837+ gRNA-#11AGGchr183159181431591837+ gRNA-#11AGGchr183159181431591837+ gRNA-#12AGGchr183159179431591817+ gRNA-#12AGGchr183159179431591817+ gRNA-#12AGGchr183159179431591817+ gRNA-#13GGAchr183159184431591867+ gRNA-#13GGAchr183159184431591867+ gRNA-#13GGAchr183159184431591867+ gRNA-#14AGGchr183159177431591797+ gRNA-#14AGGchr183159177431591797+ gRNA-#14AGGchr183159177431591797+ gRNA-#15TGCchr183159177931591802+ gRNA-#15TGCchr183159177931591802+ gRNA-#15TGCchr183159177931591802+ gRNA-#16ATTAchr183159175831591784- gRNA-#17ATTCchr183159175531591781+ gRNA-#18ATTCchr183159176431591790- gRNA-#19ATTCchr183159189031591916+ gRNA-#20ATTGchr183159175531591781- gRNA-#21ATTGchr183159180831591834+ gRNA-#22ATTTchr183159173831591764+ gRNA-#23TGAchr183159187431591897- gRNA-#23TGAchr183159187431591897- gRNA-#23TGAchr183159187431591897- gRNA-#24TGAchr183159178931591812- gRNA-#24TGAchr183159178931591812- gRNA-#24TGAchr183159178931591812- gRNA-#25TGGchr183159187531591898+ gRNA-#25TGGchr183159187531591898+ gRNA-#25TGGchr183159187531591898+ gRNA-#26TGCchr183159189731591920- gRNA-#26TGCchr183159189731591920- gRNA-#26TGCchr183159189731591920- gRNA-#27TGGchr183159179031591813+ gRNA-#27TGGchr183159179031591813+ gRNA-#27TGGchr183159179031591813+ gRNA-#28TGCchr183159189831591921+ gRNA-#28TGCchr183159189831591921+ gRNA-#28TGCchr183159189831591921+ gRNA-#29AGGGATchr183159179331591820+ gRNA-#29AGGGATchr183159179331591820+ gRNA-#30AGCchr183159180131591824+ gRNA-#30AGCchr183159180131591824+ gRNA-#30AGCchr183159180131591824+ gRNA-#31GGCchr183159188431591907+ gRNA-#31GGCchr183159188431591907+ gRNA-#31GGCchr183159188431591907+ gRNA-#32AGCchr183159177131591794+ gRNA-#32AGCchr183159177131591794+ gRNA-#32AGCchr183159177131591794+ gRNA-#33CTTAchr183159175031591776- gRNA-#34TGCchr183159180031591823- gRNA-#34TGCchr183159180031591823- gRNA-#34TGCchr183159180031591823- gRNA-#35CTTAchr183159179731591823- gRNA-#36CTTAchr183159175231591778+ gRNA-#37CTTCchr183159181631591842- gRNA-#38AGCchr183159186031591883- gRNA-#38AGCchr183159186031591883- gRNA-#38AGCchr183159186031591883- gRNA-#39CTTCchr183159185731591883- gRNA-#40CTTGchr183159189331591919+ gRNA-#41CTTGchr183159170631591732- gRNA-#42CTTTchr183159176231591788+ gRNA-#43CTTTchr183159182831591854- gRNA-#44AGGchr183159183831591861+ gRNA-#44AGGchr183159183831591861+ gRNA-#44AGGchr183159183831591861+ gRNA-#45GGGchr183159172631591749+ gRNA-#45GGGchr183159172631591749+ gRNA-#45GGGchr183159172631591749+ gRNA-#46GGGchr183159184331591866+ gRNA-#46GGGchr183159184331591866+ gRNA-#46GGGchr183159184331591866+ gRNA-#47TGCchr183159186731591890- gRNA-#47TGCchr183159186731591890- gRNA-#47TGCchr183159186731591890- gRNA-#48GGCchr183159185331591876- gRNA-#48GGCchr183159185331591876- gRNA-#48GGCchr183159185331591876- gRNA-#48TGAchr183159182231591845+ gRNA-#48TGAchr183159182231591845+ gRNA-#48TGAchr183159182231591845+ gRNA-#50TGAchr183159180431591827- gRNA-#50TGAchr183159180431591827- gRNA-#50TGAchr183159180431591827- gRNA-#51GGAchr183159181531591838+ gRNA-#51GGAchr183159181531591838+ gRNA-#51GGAchr183159181531591838+ gRNA-#52GGGchr183159179531591818+ gRNA-#52GGGchr183159179531591818+ gRNA-#52GGGchr183159179531591818+ gRNA-#53TGAchr183159174831591771+ gRNA-#53TGAchr183159174831591771+ gRNA-#53TGAchr183159174831591771+ gRNA-#54GTTAchr183159174831591774+ gRNA-#55GTTCchr183159173231591758+ gRNA-#56GTTGchr183159176631591792+ gRNA-#57GGAchr183159179631591819+ gRNA-#57GGAchr183159179631591819+ gRNA-#57GGAchr183159179631591819+ gRNA-#58GTTTchr183159179631591822+ gRNA-#59AGAchr183159172231591745- gRNA-#59AGAchr183159172231591745- gRNA-#59AGAchr183159172231591745- gRNA-#60GGCchr183159182531591848- gRNA-#60GGCchr183159182531591848- gRNA-#60GGCchr183159182531591848- gRNA-#61AGCchr183159184631591869+ gRNA-#61AGCchr183159184631591869+ gRNA-#61AGCchr183159184631591869+ gRNA-#62TGCchr183159182231591845- gRNA-#62TGCchr183159182231591845- gRNA-#62TGCchr183159182231591845- gRNA-#63AGCchr183159180431591827+ gRNA-#63AGCchr183159180431591827+ gRNA-#63AGCchr183159180431591827+ gRNA-#64AGCchr183159183231591855+ gRNA-#64AGCchr183159183231591855+ gRNA-#64AGCchr183159183231591855+ gRNA-#65TCTGATchr183159178231591809- gRNA-#65TCTGATchr183159178231591809- gRNA-#66TGCchr183159181231591835- gRNA-#66TGCchr183159181231591835- gRNA-#66TGCchr183159181231591835- gRNA-#67TGCchr183159179231591815- gRNA-#67TGCchr183159179231591815- gRNA-#67TGCchr183159179231591815- gRNA-#68AGGchr183159171031591733+ gRNA-#68AGGchr183159171031591733+ gRNA-#68AGGchr183159171031591733+ gRNA-#69TGGchr183159185631591879- gRNA-#69TGGchr183159185631591879- gRNA-#69TGGchr183159185631591879- gRNA-#70AGCchr183159180931591832+ gRNA-#70AGCchr183159180931591832+ gRNA-#70AGCchr183159180931591832+ gRNA-#71AGCchr183159183031591853- gRNA-#71AGCchr183159183031591853- gRNA-#71AGCchr183159183031591853-  Table 2D. Exemplary gRNA spacer sequences with PS linkage at 5’ endgRNA spacer sequence (5’-3’)SEQ ID NOgscscsAUCCUGCCAAGAAUGAG1213gscscsAUCCUGCCAAGAACGAG1214gscsasACUUACCCAGAGGCAAA1215usasusAGGAAAACCAGUGAGUC1216usascsUCACCUCUGCAUGCUCA1217gscscsAUCCUGCCAAGAACGAG1214A is adenosine; C is cytidine; G is guanosine; U is uridine; a is 2’-O-methyladenosine; c is 2’-O-methylcytidine; g is 2’-O-methylguanosine; u is 2’-O-methyluridine and s is phosphorothioate (PS) backbone linkage. Table 2E. Exemplary gRNA spacer sequence without PS linkagegRNA spacer sequence (5’-3’)SEQ ID NOGCCAUCCUGCCAAGAAUGAG 472GCCAUCCUGCCAAGAACGAG 473GCAACUUACCCAGAGGCAAA 474UAUAGGAAAACCAGUGAGUC 475UACUCACCUCUGCAUGCUCA 476GCCAUCCUGCCAAGAACGAG 473A is a modified or unmodified adenosine; C is a modified or unmodified cytidine; G is modified or unmodified guanosine; and U is a modified or unmodified uridine. The guide polynucleotide sg23 was used throughout the disclosure as a control guide RNA known to be effective in targeting base editor systems to alter a nucleobase in an ALAS1 gene. The sg23 guide RNA contained the following spacer sequence: CAGGAUCCGCACAGACUCCA (SEQ ID NO: 480). The sg23 guide RNA targeted the following sequence for base editing, where the PAM sequence is shown in bold: CAGGATCCGCACAGACTCCAGGG(SEQ ID NO: 481).The spacer sequences in Table 2A corresponding to sgRNAs sgRNA_361, sgRNA_362, sgRNA_363, sgRNA_364, sgRNA_365, sgRNA_366, and sgRNA_367 may be used for targeting a base editor to alter a nucleobase of a splice site of the transthyretin polynucleotide. The spacer sequences in Table 2A corresponding to sgRNAs sgRNA_368, sgRNA_369, sgRNA_370, sgRNA_371, sgRNA_372, sgRNA_373, and sgRNA_374 may be used for targeting an endonuclease to a transthyretin (TTR) polynucleotide sequence. The three spacer sequences in Table 2A corresponding to sgRNA_375, sgRNA_376, and sgRNA_377 may be used to alter a nucleobase of a transthyretin (TTR) polynucleotide. The alteration of the nucleobase may result in an alteration of an isoleucine (I) to a valine (V) (e.g., to correct a V122I mutation in a transthyretin polypeptide encoded by the transthyretin polynucleotide). In embodiments, a transthyretin polynucleotide may be edited using the following combinations of base editors and sgRNA sequences (see Tables 1A and 2A): ABE8.8 and sgRNA_361; ABE8.8 and sgRNA_362; ABE8.8-VRQR and sgRNA_363; BE4-VRQR and sgRNA_363; BE4-VRQR and sgRNA_364; saABE8.8 and sgRNA_365; saBE4 and sgRNA_365; saBE4-KKH and sgRNA_366, ABE-bhCas12b and sgRNA_367; spCas9-ABE and sgRNA_375; spCas9-VRQR-ABE and sgRNA_376; or saCas9-ABE and sgRNA_377. The PAM sequence of spCas9-ABE can be AGG. The PAM sequence of spCas9-VRQR-ABE can be GGA. The PAM sequence of saCas9-ABE can be AGGAAT.In certain embodiments, the fusion proteins provided herein comprise one or more features that improve the base editing activity of the fusion proteins. For example, any of the fusion proteins provided herein may comprise a Cas9 domain that has reduced nuclease activity. In some embodiments, any of the fusion proteins provided herein may have a Cas9 domain that does not have nuclease activity (dCas9), or a Cas9 domain that cuts one strand of a duplexed DNA molecule, referred to as a Cas9 nickase (nCas9). Without wishing to be bound by any particular theory, the presence of the catalytic residue (e.g., H840) maintains the activity of the Cas9 to cleave the non-edited (e.g., non-methylated) strand opposite the targeted nucleobase. Mutation of the catalytic residue (e.g., D10 to A10) prevents cleavage of the edited strand containing the targeted A residue. Such Cas9 variants can generate a single-strand DNA break (nick) at a specific location based on the gRNA-defined target sequence, leading to repair of the non-edited strand, ultimately resulting in a nucleobase change on the non-edited strand.  NUCLEOBASE EDITORSUseful in the methods and compositions described herein are nucleobase editors that edit, modify or alter a target nucleotide sequence of a polynucleotide. Nucleobase editors described herein typically include a polynucleotide programmable nucleotide binding domain and a nucleobase editing domain (e.g., adenosine deaminase, cytidine deaminase, or a dual deaminase). A polynucleotide programmable nucleotide binding domain, when in conjunction with a bound guide polynucleotide (e.g., gRNA), can specifically bind to a target polynucleotide sequence and thereby localize the base editor to the target nucleic acid sequence desired to be edited. Polynucleotide Programmable Nucleotide Binding DomainPolynucleotide programmable nucleotide binding domains bind polynucleotides (e.g., RNA, DNA). A polynucleotide programmable nucleotide binding domain of a base editor can itself comprise one or more domains (e.g., one or more nuclease domains). In some embodiments, the nuclease domain of a polynucleotide programmable nucleotide binding domain comprises an endonuclease or an exonuclease.Disclosed herein are base editors comprising a polynucleotide programmable nucleotide binding domain comprising all or a portion (e.g., a functional portion) of a CRISPR protein (i.e., a base editor comprising as a domain all or a portion (e.g., a functional portion) of a CRISPR protein (e.g., a Cas protein), also referred to as a “CRISPR protein-derived domain” of the base editor). A CRISPR protein-derived domain incorporated into a base editor can be modified compared to a wild-type or natural version of the CRISPR protein. A CRISPR protein-derived domain can comprise one or more mutations, insertions, deletions, rearrangements and / or recombinations relative to a wild-type or natural version of the CRISPR protein.Cas proteins that can be used herein include class 1 and class 2. Non-limiting examples of Cas proteins include Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas9 (also known as Csn1 or Csx12), Cas10, 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, Csf1, Csf2, CsO, Csf4, Csd1, Csd2, Cst1, Cst2, Csh1, Csh2, Csa1, Csa2, Csa3, Csa4, Csa5, Cas12a / Cpf1, Cas12b / C2c1 (e.g., SEQ ID NO: 232), Cas12c / C2c3, Cas12d / CasY, Cas12e / CasX, Cas12g, Cas12h, Cas12i, and Cas12j / CasΦ, CARF, DinG, homologues thereof, or modified versions thereof. A CRISPR enzyme can direct cleavage of one or both strands at a target sequence, such as within a target sequence and / or within a complement of a target sequence. For example, a CRISPR enzyme can direct cleavage of one or both strands within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence.A vector that encodes a CRISPR enzyme that is mutated to with respect to a corresponding wild-type enzyme such that the mutated CRISPR enzyme lacks the ability to cleave one or both strands of a target polynucleotide containing a target sequence can be used. A Cas protein (e.g., Cas9, Cas12) or a Cas domain (e.g., Cas9, Cas12) can refer to a polypeptide or domain with at least or at least about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity and / or sequence homology to a wild-type exemplary Cas polypeptide or Cas domain. Cas (e.g., Cas9, Cas12) can refer to the wild-type or a modified form of the Cas protein that can comprise an amino acid change such as a deletion, insertion, substitution, variant, mutation, fusion, chimera, or any combination thereof.In some embodiments, a CRISPR protein-derived domain of a base editor can include all or a portion (e.g., a functional portion) of Cas9 from Corynebacterium ulcerans (NCBI Refs: NC_015683.1, NC_017317.1); Corynebacterium diphtheria (NCBI Refs: NC_016782.1, NC_016786.1); Spiroplasma syrphidicola (NCBI Ref: NC_021284.1); Prevotella intermedia (NCBI Ref: NC_017861.1); Spiroplasma taiwanense (NCBI Ref: NC_021846.1); Streptococcus iniae (NCBI Ref: NC_021314.1); Belliella baltica (NCBI Ref: NC_018010.1); Psychroflexus torquis (NCBI Ref: NC_018721.1); Streptococcus thermophilus (NCBI Ref: YP_820832.1); Listeria innocua (NCBI Ref: NP_472073.1); Campylobacter jejuni (NCBI Ref: YP_002344900.1); Neisseria meningitidis (NCBI Ref: YP_002342100.1), Streptococcus pyogenes, or Staphylococcus aureus.Some aspects of the disclosure provide high fidelity Cas9 domains. High fidelity Cas9 domains are known in the art and described, for example, in Kleinstiver, B.P., et al. “High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects.” Nature 529, 490-495 (2016); and Slaymaker, I.M., et al. “Rationally engineered Cas9 nucleases with improved specificity.” Science 351, 84-88 (2015); the entire contents of each of which are incorporated herein by reference. An Exemplary high fidelity Cas9 domain is provided in the Sequence Listing as SEQ ID NO: 233.In some embodiments, any of the Cas9 fusion proteins or complexes provided herein comprise one or more of a D10A, N497X, a R661X, a Q695X, and / or a Q926X mutation, or a corresponding mutation in any of the amino acid sequences provided herein, wherein X is any amino acid. .Typically, Cas9 proteins, such as Cas9 from S. pyogenes (spCas9), require a “protospacer adjacent motif (PAM)” or PAM-like motif, which is a 2-6 base pair DNA sequence immediately following the DNA sequence targeted by the Cas9 nuclease in the CRISPR bacterial adaptive immune system. The presence of an NGG PAM sequence is required to bind a particular nucleic acid region, where the “N” in “NGG” is adenosine (A), thymidine (T), or cytosine (C), and the G is guanosine. In some embodiments, any of the fusion proteins or complexes provided herein may contain a Cas9 domain that is capable of binding a nucleotide sequence that does not contain a canonical (e.g., NGG) PAM sequence. Cas9 domains that bind to non-canonical PAM sequences have been described in the art and would be apparent to the skilled artisan. For example, Cas9 domains that bind non-canonical PAM sequences have been described in Kleinstiver, B. P., et al., “Engineered CRISPR-Cas9 nucleases with altered PAM specificities” Nature 523, 481-485 (2015); and Kleinstiver, B. P., et al., “Broadening the targeting range of Staphylococcus aureus CRISPR-Cas9 by modifying PAM recognition” Nature Biotechnology 33, 1293-1298 (2015); the entire contents of each are hereby incorporated by reference.In some embodiments, the napDNAbp is a circular permutant (e.g., SEQ ID NO: 238).In some embodiments, the polynucleotide programmable nucleotide binding domain comprises a nickase domain. Herein the term “nickase” refers to a polynucleotide programmable nucleotide binding domain comprising a nuclease domain that is capable of cleaving only one strand of the two strands in a duplexed nucleic acid molecule (e.g., DNA). For example, where a polynucleotide programmable nucleotide binding domain comprises a nickase domain derived from Cas9, the Cas9-derived nickase domain can include a D10A mutation and a histidine at position 840. In another example, a Cas9-derived nickase domain comprises an H840A mutation, while the amino acid residue at position 10 remains a D.In some embodiments, a Cas9 nuclease has an inactive (e.g., an inactivated) DNA cleavage domain, that is, the Cas9 is a nickase, referred to as an “nCas9” protein (for “nickase” Cas9; SEQ ID NO: 201). The Cas9 nickase may be a Cas9 protein that is capable of cleaving only one strand of a duplexed nucleic acid molecule (e.g., a duplexed DNA molecule). In some embodiments the Cas9 nickase comprises an amino acid sequence that is 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 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to any one of the Cas9 nickases provided herein. Additional suitable Cas9 nickases will be apparent to those of skill in the art based on this disclosure and knowledge in the field and are within the scope of this disclosure.Also provided herein are base editors comprising a polynucleotide programmable nucleotide binding domain which is catalytically dead (i.e., incapable of cleaving a target polynucleotide sequence). For example, in the case of a base editor comprising a Cas9 domain, the Cas9 can comprise both a D10A mutation and an H840A mutation. In further embodiments, a catalytically dead polynucleotide programmable nucleotide binding domain comprises a point mutation (e.g., D10A or H840A) as well as a deletion of all or a portion (e.g., a functional portion) of a nuclease domain. dCas9 domains are known in the art and described, for example, in Qi et al., “Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression.” Cell. 2013; 152(5):1173-83, the entire contents of which are incorporated herein by reference.The term “protospacer adjacent motif (PAM)” or PAM-like motif refers to a 2-6 base pair DNA sequence immediately following the DNA sequence targeted by a nucleic acid programmable DNA binding protein. In some embodiments, the PAM can be a 5′ PAM (i.e., located upstream of the 5′ end of the protospacer). In other embodiments, the PAM can be a 3′ PAM (i.e., located downstream of the 5′ end of the protospacer). The PAM sequence can be any PAM sequence known in the art. Suitable PAM sequences include, but are not limited to, NGG, NGA, NGC, NGN, NGT, NGTT, NGCG, NGAG, NGAN, NGNG, NGCN, NGCG, NGTN, NNGRRT, NNNRRT, NNGRR(N), TTTV, TYCV, TYCV, TATV, NNNNGATT, NNAGAAW, or NAAAAC. Y is a pyrimidine; N is any nucleotide base; W is A or T.A base editor provided herein can comprise a CRISPR protein-derived domain that is capable of binding a nucleotide sequence that contains a canonical or non-canonical protospacer adjacent motif (PAM) sequence.In some embodiments, the PAM is an “NRN” PAM where the “N” in “NRN” is adenine (A), thymine (T), guanine (G), or cytosine (C), and the R is adenine (A) or guanine (G); or the PAM is an “NYN” PAM, wherein the “N” in NYN is adenine (A), thymine (T), guanine (G), or cytosine (C), and the Y is cytidine (C) or thymine (T), for example, as described in R.T. Walton et al., 2020, Science, 10.1126 / science.aba8853 (2020), the entire contents of which are incorporated herein by reference.Several PAM variants are described in Table 3 below. Table 3. Cas9 proteins and corresponding PAM sequences. N is A, C, T, or G; and V is A, C, or G. VariantPAMspCas9NGGspCas9-VRQRNGAspCas9-VRERNGCGxCas9 (sp)NGNsaCas9NNGRRTsaCas9-KKHNNNRRTspCas9-MQKSERNGCGspCas9-MQKSERNGCNspCas9-LRKIQKNGTNspCas9-LRVSQKNGTNspCas9-LRVSQLNGTNspCas9-MQKFRAERNGCCpf15′ (TTTV)SpyMac5′-NAA-3′ In some embodiments, the PAM is NGC. In some embodiments, the NGC PAM is recognized by a Cas9 variant. In some embodiments, the NGC PAM Cas9 variant includes one or more amino acid substitutions selected from D1135M, S1136Q, G1218K, E1219F, A1322R, D1332A, R1335E, and T1337R (collectively termed “MQKFRAER”) of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, the Cas9 variant contains one or more amino acid substitutions selected from D1135V, G1218R, R1335Q, and T1337R (collectively termed VRQR) of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, the Cas9 variant contains one or more amino acid substitutions selected from D1135V, G1218R, R1335E, and T1337R (collectively termed VRER) of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, the Cas9 variant contains one or more amino acid substitutions selected from E782K, N968K, and R1015H (collectively termed KHH) of saCas9 (SEQ ID NO: 218). In some embodiments, the Cas9 variant includes one or more amino acid substitutions selected from D1135M, S1136Q, G1218K, E1219S, R1335E, and T1337R (collectively termed “MQKSER”) of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9. In some embodiments, the Cas9 variant includes one or more amino acid substitutions selected from D1135M, S1136Q, G1218K, E1219S, R1335E, and T1337R (collectively termed “MQKSER”) of spCas9 (SEQ ID No: 197), or a corresponding mutation in another Cas9.In some embodiments, a CRISPR protein-derived domain of a base editor comprises all or a portion (e.g., a functional portion) of a Cas9 protein with a canonical PAM sequence (NGG). In other embodiments, a Cas9-derived domain of a base editor can employ a non-canonical PAM sequence. Such sequences have been described in the art and would be apparent to the skilled artisan. For example, Cas9 domains that bind non-canonical PAM sequences have been described in Kleinstiver, B. P., et al., “Engineered CRISPR-Cas9 nucleases with altered PAM specificities” Nature 523, 481-485 (2015); and Kleinstiver, B. P., et al., “Broadening the targeting range of Staphylococcus aureus CRISPR-Cas9 by modifying PAM recognition” Nature Biotechnology 33, 1293-1298 (2015); R.T. Walton et al. “Unconstrained genome targeting with near-PAMless engineered CRISPR-Cas9 variants” Science 10.1126 / science.aba8853 (2020); Hu et al. “Evolved Cas9 variants with broad PAM compatibility and high DNA specificity,” Nature, 2018 Apr. 5, 556(7699), 57-63; Miller et al., “Continuous evolution of SpCas9 variants compatible with non-G PAMs” Nat. Biotechnol., 2020 Apr;38(4):471-481; the entire contents of each are hereby incorporated by reference. Fusion Proteins or Complexes Comprising a NapDNAbp and a Cytidine Deaminase and / or Adenosine DeaminaseSome aspects of the disclosure provide fusion proteins or complexes comprising a Cas9 domain or other nucleic acid programmable DNA binding protein (e.g., Cas12) and one or more cytidine deaminase, adenosine deaminase, or cytidine adenosine deaminase domains. It should be appreciated that the Cas9 domain may be any of the Cas9 domains or Cas9 proteins (e.g., dCas9 or nCas9) provided herein. In some embodiments, any of the Cas9 domains or Cas9 proteins (e.g., dCas9 or nCas9) provided herein may be fused with any of the cytidine deaminases and / or adenosine deaminases provided herein. The domains of the base editors disclosed herein can be arranged in any order.In some embodiments, the fusion proteins or complexes comprising a cytidine deaminase or adenosine deaminase and a napDNAbp (e.g., Cas9 or Cas12 domain) do not include a linker sequence. In some embodiments, a linker is present between the cytidine or adenosine deaminase and the napDNAbp. In some embodiments, cytidine or adenosine deaminase and the napDNAbp are fused via any of the linkers provided herein. For example, in some embodiments the cytidine or adenosine deaminase and the napDNAbp are fused via any of the linkers provided herein.It should be appreciated that the fusion proteins or complexes of the present disclosure may comprise one or more additional features. For example, in some embodiments, the fusion protein or complex may comprise inhibitors, cytoplasmic localization sequences, export sequences, such as nuclear export sequences, or other localization sequences, as well as sequence tags that are useful for solubilization, purification, or detection of the fusion proteins or complexes. Suitable protein tags provided herein include, but are not limited to, biotin carboxylase carrier protein (BCCP) tags, myc-tags, calmodulin-tags, FLAG-tags, hemagglutinin (HA)-tags, polyhistidine tags, also referred to as histidine tags or His-tags, maltose binding protein (MBP)-tags, nus-tags, glutathione-S-transferase (GST)-tags, green fluorescent protein (GFP)-tags, thioredoxin-tags, S-tags, Softags (e.g., Softag 1, Softag 3), strep-tags , biotin ligase tags, FlAsH tags, V5 tags, and SBP-tags. Additional suitable sequences will be apparent to those of skill in the art. In some embodiments, the fusion protein or complex comprises one or more His tags.Exemplary, yet nonlimiting, fusion proteins are described in International PCT Application Nos. PCT / US2017 / 045381, PCT / US2019 / 044935, and PCT / US2020 / 016288, each of which is incorporated herein by reference for its entirety. Fusion Proteins or Complexes with Internal InsertionsProvided herein are fusion proteins or complexes comprising a heterologous polypeptide fused to a nucleic acid programmable nucleic acid binding protein, for example, a napDNAbp. The heterologous polypeptide can be fused to the napDNAbp at a C-terminal end of the napDNAbp, an N-terminal end of the napDNAbp, or inserted at an internal location of the napDNAbp. In some embodiments, the heterologous polypeptide is a deaminase (e.g., cytidine or adenosine deaminase) or a functional fragment thereof. For example, a fusion protein can comprise a deaminase flanked by an N- terminal fragment and a C-terminal fragment of a Cas9 or Cas12 (e.g., Cas12b / C2c1), polypeptide.The deaminase can be a circular permutant deaminase. In some embodiments, the deaminase is a circular permutant TadA, circularly permutated at amino acid residue 116, 136, or 65 as numbered in a TadA reference sequence.The fusion protein or complexes can comprise more than one deaminase. The fusion protein or complex can comprise, for example, 1, 2, 3, 4, 5 or more deaminases. The deaminases in a fusion protein or complex can be adenosine deaminases, cytidine deaminases, or a combination thereof.In some embodiments, the napDNAbp in the fusion protein or complex contains a Cas9 polypeptide or a fragment thereof. The Cas9 polypeptide can be a variant Cas9 polypeptide. The Cas9 polypeptide can be a circularly permuted Cas9 protein.The heterologous polypeptide (e.g., deaminase) can be inserted in the napDNAbp (e.g., Cas9 or Cas12 (e.g., Cas12b / C2c1)) at a suitable location, for example, such that the napDNAbp retains its ability to bind the target polynucleotide and a guide nucleic acid. A deaminase (e.g., adenosine deaminase, cytidine deaminase, or adenosine deaminase and cytidine deaminase (dual deaminase)) can be inserted into a napDNAbp without compromising function of the deaminase (e.g., base editing activity) or the napDNAbp (e.g., ability to bind to target nucleic acid and guide nucleic acid).In some embodiments, the deaminase (e.g., adenosine deaminase, cytidine deaminase, or adenosine deaminase and cytidine deaminase) is inserted in regions of the Cas9 polypeptide comprising higher than average B-factors (e.g., higher B factors compared to the total protein or the protein domain comprising the disordered region). Cas9 polypeptide positions comprising a higher than average B-factor can include, for example, residues 768, 792, 1052, 1015, 1022, 1026, 1029, 1067, 1040, 1054, 1068, 1246, 1247, and 1248 as numbered in the above Cas9 reference sequence. Cas9 polypeptide regions comprising a higher than average B-factor can include, for example, residues 792-872, 792-906, and 2-791 as numbered in the above Cas9 reference sequence.In some embodiments, a heterologous polypeptide (e.g., deaminase) is inserted in a flexible loop of a Cas9 polypeptide. The flexible loop portions can be selected from the group consisting of 530-537, 569-570, 686-691, 943-947, 1002-1025, 1052-1077, 1232-1247, or 1298-1300 as numbered in the above Cas9 reference sequence, or a corresponding amino acid residue in another Cas9 polypeptide. The flexible loop portions can be selected from the group consisting of: 1-529, 538-568, 580-685, 692-942, 948-1001, 1026-1051, 1078-1231, or 1248-1297 as numbered in the above Cas9 reference sequence, or a corresponding amino acid residue in another Cas9 polypeptide.A heterologous polypeptide (e.g., adenine deaminase) can be inserted into a Cas9 polypeptide region corresponding to amino acid residues: 1017-1069, 1242-1247, 1052-1056, 1060-1077, 1002 – 1003, 943-947, 530-537, 568-579, 686-691, 1242-1247, 1298 – 1300, 1066-1077, 1052-1056, or 1060-1077 as numbered in the above Cas9 reference sequence, or a corresponding amino acid residue in another Cas9 polypeptide.A heterologous polypeptide (e.g., adenine deaminase) can be inserted in place of a deleted region of a Cas9 polypeptide. The deleted region can correspond to an N-terminal or C-terminal portion of the Cas9 polypeptide. Exemplary internal fusions base editors are provided in Table 4A below: Table 4A: Insertion loci in Cas9 proteinsBE IDModificationOther IDIBE001Cas9 TadA ins 1015ISLAY01IBE002Cas9 TadA ins 1022ISLAY02IBE003Cas9 TadA ins 1029ISLAY03IBE004Cas9 TadA ins 1040ISLAY04IBE005Cas9 TadA ins 1068ISLAY05IBE006Cas9 TadA ins 1247ISLAY06IBE007Cas9 TadA ins 1054ISLAY07IBE008Cas9 TadA ins 1026ISLAY08IBE009Cas9 TadA ins 768ISLAY09IBE020delta HNH TadA 792ISLAY20IBE021N-term fusion single TadA helix truncated 165-endISLAY21IBE029TadA-Circular Permutant116 ins1067ISLAY29IBE031TadA- Circular Permutant 136 ins1248ISLAY31IBE032TadA- Circular Permutant 136ins 1052ISLAY32IBE035delta 792-872 TadA insISLAY35IBE036delta 792-906 TadA insISLAY36IBE043TadA-Circular Permutant 65 ins1246ISLAY43IBE044TadA ins C-term truncate2 791ISLAY44 A heterologous polypeptide (e.g., deaminase) can be inserted within a structural or functional domain of a Cas9 polypeptide. A heterologous polypeptide (e.g., deaminase) can be inserted between two structural or functional domains of a Cas9 polypeptide. A heterologous polypeptide (e.g., deaminase) can be inserted in place of a structural or functional domain of a Cas9 polypeptide, for example, after deleting the domain from the Cas9 polypeptide. The structural or functional domains of a Cas9 polypeptide can include, for example, RuvC I, RuvC II, RuvC III, Rec1, Rec2, PI, or HNH.A fusion protein can comprise a linker between the deaminase and the napDNAbp polypeptide. The linker can be a peptide or a non-peptide linker. For example, the linker can be an XTEN, (GGGS)n (SEQ ID NO: 246), SGGSSGGS (SEQ ID NO: 330), (GGGGS)n (SEQ ID NO: 247), (G)n, (EAAAK)n (SEQ ID NO: 248), (GGS)n, SGSETPGTSESATPES (SEQ ID NO: 249). In some embodiments, the fusion protein comprises a linker between the N-terminal Cas9 fragment and the deaminase. In some embodiments, the fusion protein comprises a linker between the C-terminal Cas9 fragment and the deaminase. In some embodiments, the N-terminal and C-terminal fragments of napDNAbp are connected to the deaminase with a linker. In some embodiments, the N-terminal and C-terminal fragments are joined to the deaminase domain without a linker. In some embodiments, the fusion protein comprises a linker between the N-terminal Cas9 fragment and the deaminase but does not comprise a linker between the C-terminal Cas9 fragment and the deaminase. In some embodiments, the fusion protein comprises a linker between the C-terminal Cas9 fragment and the deaminase but does not comprise a linker between the N-terminal Cas9 fragment and the deaminase.In some embodiments, the napDNAbp in the fusion protein or complex is a Cas12 polypeptide, e.g., Cas12b / C2c1, or a functional fragment thereof capable of associating with a nucleic acid (e.g., a gRNA) that guides the Cas12 to a specific nucleic acid sequence. The Cas12 polypeptide can be a variant Cas12 polypeptide. In other embodiments, the N- or C-terminal fragments of the Cas12 polypeptide comprise a nucleic acid programmable DNA binding domain or a RuvC domain. In other embodiments, the fusion protein contains a linker between the Cas12 polypeptide and the catalytic domain. In other embodiments, the amino acid sequence of the linker is GGSGGS (SEQ ID NO: 250) or GSSGSETPGTSESATPESSG (SEQ ID NO: 251). In other embodiments, the linker is a rigid linker. In other embodiments of the above aspects, the linker is encoded by GGAGGCTCTGGAGGAAGC (SEQ ID NO: 252) or GGCTCTTCTGGATCTGAAACACCTGGCACAAGCGAGAGCGCCACCCCTGAGAGCTCTGGC (SEQ ID NO: 253).In other embodiments, the fusion protein or complex contains a nuclear localization signal (e.g., a bipartite nuclear localization signal). In other embodiments, the amino acid sequence of the nuclear localization signal is MAPKKKRKVGIHGVPAA (SEQ ID NO: 261). In other embodiments of the above aspects, the nuclear localization signal is encoded by the following sequence:ATGGCCCCAAAGAAGAAGCGGAAGGTCGGTATCCACGGAGTCCCAGCAGCC (SEQ ID NO: 262). In other embodiments, the Cas12b polypeptide contains a mutation that silences the catalytic activity of a RuvC domain. In other embodiments, the Cas12b polypeptide contains D574A, D829A and / or D952A mutations.In some embodiments, the fusion protein or complex comprises a napDNAbp domain (e.g., Cas12-derived domain) with an internally fused nucleobase editing domain (e.g., all or a portion (e.g., a functional portion) of a deaminase domain, e.g., an adenosine deaminase domain). In some embodiments, the napDNAbp is a Cas12b. In some embodiments, the base editor comprises a BhCas12b domain with an internally fused TadA*8 domain inserted at the loci provided in Table 4B below. Table 4B:Insertion loci in Cas12b proteinsBhCas12bInsertion siteInserted between aaposition 1153PSposition 2255KEposition 3306DEposition 4980DGposition 51019KLposition 6534FPposition 7604KGposition 8344HF   BvCas12bInsertion siteInserted between aaposition 1147PDposition 2248GGposition 3299PEposition 4991GEposition 51031KM   AaCas12bInsertion siteInserted between aaposition 1157PGposition 2258VGposition 3310DPposition 41008GEposition 51044GK In some embodiments, the base editing system described herein is an ABE with TadA inserted into a Cas9. Polypeptide sequences of relevant ABEs with TadA inserted into a Cas9 are provided in the attached Sequence Listing as SEQ ID NOs: 263-308.Exemplary, yet nonlimiting, fusion proteins are described in International PCT Application Nos. PCT / US2020 / 016285 and U.S. Provisional Application Nos. 62 / 852,228 and 62 / 852,224, the contents of which are incorporated by reference herein in their entireties. A to G EditingIn some embodiments, a base editor described herein comprises an adenosine deaminase domain. Such an adenosine deaminase domain of a base editor can facilitate the editing of an adenine (A) nucleobase to a guanine (G) nucleobase by deaminating the A to form inosine (I), which exhibits base pairing properties of G. In some embodiments, an A-to-G base editor further comprises an inhibitor of inosine base excision repair, for example, a uracil glycosylase inhibitor (UGI) domain or a catalytically inactive inosine specific nuclease. Without wishing to be bound by any particular theory, the UGI domain or catalytically inactive inosine specific nuclease can inhibit or prevent base excision repair of a deaminated adenosine residue (e.g., inosine), which can improve the activity or efficiency of the base editor.A base editor comprising an adenosine deaminase can act on any polynucleotide, including DNA, RNA and DNA-RNA hybrids. In an embodiment an adenosine deaminase domain of a base editor comprises all or a portion (e.g., a functional portion) of an ADAT comprising one or more mutations which permit the ADAT to deaminate a target A in DNA. For example, the base editor can comprise all or a portion (e.g., a functional portion) of an ADAT from Escherichia coli (EcTadA) comprising one or more of the following mutations: D108N, A106V, D147Y, E155V, L84F, H123Y, I156F, or a corresponding mutation in another adenosine deaminase. Exemplary ADAT homolog polypeptide sequences are provided in the Sequence Listing as SEQ ID NOs: 1 and 309-315.The adenosine deaminase can be derived from any suitable organism (e.g., E. coli). In some embodiments, the adenosine deaminase is from Escherichia coli, Staphylococcus aureus, Salmonella typhi, Shewanella putrefaciens, Haemophilus influenzae, Caulobacter crescentus, or Bacillus subtilis. In some embodiments, the adenine deaminase is a naturally-occurring adenosine deaminase that includes one or more mutations corresponding to any of the mutations provided herein (e.g., mutations in ecTadA). The corresponding residue in any homologous protein can be identified by e.g., sequence alignment and determination of homologous residues. The mutations in any naturally-occurring adenosine deaminase (e.g., having homology to ecTadA) that correspond to any of the mutations described herein (e.g., any of the mutations identified in ecTadA) can be generated accordingly.In some embodiments, the adenosine deaminase comprises an amino acid sequence that is 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 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to any one of the amino acid sequences set forth in any of the adenosine deaminases provided herein. It should be appreciated that adenosine deaminases provided herein may include one or more mutations (e.g., any of the mutations provided herein). The disclosure provides any deaminase domains with a certain percent identify plus any of the mutations or combinations thereof described herein. In some embodiments, the adenosine deaminase comprises an amino acid sequence 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 more mutations compared to a reference sequence, or any of the adenosine deaminases provided herein.It should be appreciated that any of the mutations provided herein (e.g., based on a TadA reference sequence, such as TadA*7.10 (SEQ ID NO: 1)) can be introduced into other adenosine deaminases, such as E. coli TadA (ecTadA), S. aureus TadA (saTadA), or other adenosine deaminases (e.g., bacterial adenosine deaminases). In some embodiments, the TadA reference sequence is TadA*7.10 (SEQ ID NO: 1). It would be apparent to the skilled artisan that additional deaminases may similarly be aligned to identify homologous amino acid residues that can be mutated as provided herein. Thus, any of the mutations identified in a TadA reference sequence can be made in other adenosine deaminases (e.g., ecTada) that have homologous amino acid residues. It should also be appreciated that any of the mutations provided herein can be made individually or in any combination in a TadA reference sequence or another adenosine deaminase.In some embodiments, the adenosine deaminase comprises an alteration or set of alterations selected from those listed in Tables 5A-5E below: Table 5A. Adenosine Deaminase Variants. Residue positions in the E. coli TadA variant (TadA*) are indicated. 23263637484951728487106108123125142146147152155156157161TadA*0.1WRHNP RNLSADHGASDREIKKTadA*0.2WRHNP RNLSADHGASDREIKKTadA*1.1WRHNP RNLSANHGASDREIKKTadA*1.2WRHNP RNLSVNHGASDREIKKTadA*2.1WRHNP RNLSVNHGASYRVIKKTadA*2.2WRHNP RNLSVNHGASYRVIKKTadA*2.3WRHNP RNLSVNHGASYRVIKKTadA*2.4WRHNP RNLSVNHGASYRVIKKTadA*2.5WRHNP RNLSVNHGASYRVIKKTadA*2.6WRHNP RNLSVNHGASYRVIKKTadA*2.7WRHNP RNLSVNHGASYRVIKKTadA*2.8WRHNP RNLSVNHGASYRVIKKTadA*2.9WRHNP RNLSVNHGASYRVIKKTadA*2.10WRHNP RNLSVNHGASYRVIKKTadA*2.11WRHNP RNLSVNHGASYRVIKKTadA*2.12WRHNP RNLSVNHGASYRVIKKTadA*3.1WRHNP RNFSVNYGASYRVFKKTadA*3.2WRHNP RNFSVNYGASYRVFKKTadA*3.3WRHNP RNFSVNYGASYRVFKKTadA*3.4WRHNP RNFSVNYGASYRVFKKTadA*3.5WRHNP RNFSVNYGASYRVFKKTadA*3.6WRHNP RNFSVNYGASYRVFKKTadA*3.7WRHNP RNFSVNYGASYRVFKKTadA*3.8WRHNP RNFSVNYGASYRVFKKTadA*4.1WRHNP RNLSVNHGNSYRVIKKTadA*4.2WGHNP RNLSVNHGNSYRVIKKTadA*4.3WRHNP RNFSVNYGNSYRVFKKTadA*5.1WRLNP LNFSVNYGACYRVFNKTadA*5.2WRHSP RNFSVNYGASYRVFKTTadA*5.3WRLNP LNISVNYGACYRVFNKTadA*5.4WRHSP RNFSVNYGASYRVFKTTadA*5.5WRLNP LNFSVNYGACYRVFNKTadA*5.6WRLNP LNFSVNYGACYRVFNKTadA*5.7WRLNP LNFSVNYGACYRVFNKTadA*5.8WRLNP LNFSVNYGACYRVFNKTadA*5.9WRLNP LNFSVNYGACYRVFNKTadA*5.10WRLNP LNFSVNYGACYRVFNKTadA*5.11WRLNP LNFSVNYGACYRVFNKTadA*5.12WRLNP LNFSVNYGACYRVFNKTadA*5.13WRHNP LDFSVNYAASYRVFKKTadA*5.14WRHNS LNFCVNYGASYRVFKKTadA*6.1WRHNS LNFSVNYGNSYRVFKKTadA*6.2WRHNTVLNFSVNYGNSYRVFNKTadA*6.3WRLNS LNFSVNYGACYRVFNKTadA*6.4WRLNS LNFSVNYGNCYRVFNKTadA*6.5WRLNTVLNFSVNYGACYRVFNKTadA*6.6WRLNTVLNFSVNYGNCYRVFNKTadA*7.1WRLNA LNFSVNYGACYRVFNKTadA*7.2WRLNA LNFSVNYGNCYRVFNKTadA*7.3LRLNA LNFSVNYGACYRVFNKTadA*7.4RRLNA LNFSVNYGACYRVFNKTadA*7.5WRLNA LNFSVNYGACYHVFNKTadA*7.6WRLNA LNISVNYGACYPVFNKTadA*7.7LRLNA LNFSVNYGACYPVFNKTadA*7.8LRLNA LNFSVNYGNCYRVFNKTadA*7.9LRLNA LNFSVNYGNCYPVFNKTadA*7.10RRLNA LNFSVNYGACYPVFNK Table 5B.TadA*8 Adenosine Deaminase Variants. Residue positions in the E. coli TadA variant (TadA*) are indicated. Alterations are referenced to TadA*7.10 (first row).  23364851768284106108123146147152154155156157166TadA*7.10RLALIVFVNYCYPQVFNTTadA*8.1           T      TadA*8.2           R      TadA*8.3             S    TadA*8.4         H        TadA*8.5     S            TadA*8.6                 RTadA*8.7             R    TadA*8.8         H R R    TadA*8.9    Y      R R    TadA*8.10           R R   RTadA*8.11           T R    TadA*8.12           T S    TadA*8.13    Y    H R R    TadA*8.14    YS            TadA*8.15     S  &...

Claims

CLAIMSWhat is claimed:

1. A lipid nanoparticle (LNP) comprising:A) a guide RNA, or a polynucleotide encoding the guide RNA, wherein the guide RNA comprises a spacer comprising a nucleotide sequence selected from GCCAUCCUGCCAAGAAUGAG (SEQ ID NO: 472) and those listed in any of Tables IB, 1C, ID, IE, 2A, 2B, 2D, or 2E;B) an mRNA molecule, or a polynucleotide encoding the mRNA molecule, wherein the mRNA molecule encodes a base editor polypeptide comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises: i) an amino acid sequence having at least 90% identity to the following TadA*7. 10 amino acid sequence, or a truncation thereof lacking only the first M: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAA GSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1), and ii) a combination of amino acid alterations relative to the TadA*7.10 amino acid sequence selected from the group consisting of: a) I76Y, V82T, Y123H, Y147R, and Q154R; b)V82T, Y123H, D147R, and Q154R; c) V82T, Y123H, D147T, and Q154S; d) V82T and Q154R; e) V82T, Y147T, and Q154S; f) I76Y, V82T, Y123H, Y147T, and Q154S; andC) an ionizable lipid according to any one of the following formulas, or a pharmaceutically acceptable salt thereof: i) a compound of Formula (Ih):wherein: each L1and L1is independently -C(0)- or -OC(O)-; each L2and L2is independently an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain;L3is a covalent bond, -O-, -C(O)O-, -OC(O)-, or -OC(O)O-;R1is optionally substituted C1-20 aliphatic,LCyAis a covalent bond or an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain;CyAis an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;LRais an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain; each Raand R1is independently optionally substituted C1-20 aliphatic;Y1is -C(O)- or -C(O)O-;Y2is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-6 hydrocarbon chain;Y3is optionally substituted C1-20 aliphatic;X1is a covalent bond, -O-, or -NR-;X2is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -O- or -NR-;X3is hydrogen or an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or optionally substituted C1-6 aliphatic; ii) a compound of Formula (la):wherein:R1is C9-C20 alkyl or C9-C20 alkenyl with 1-3 units of unsaturation;X1and X2are each independently absent or selected from -O-, -NR2- and wherein each R2is independently hydrogen or C1-C6alkyl;each a is independently an integer between 1 and 6;X3and X4are each independently absent or selected from the group consisting of: 4- to 8-membered heterocyclyl optionally substituted with 1 or 2 C1-C6alkyl groups, 5- to 6- membered heteroaryl optionally substituted with 1 or 2 C1-C6alkyl groups, 5- to 6-membered aryl optionally substituted with 1 or 2 C1-C6alkyl groups, 4- to 7-membered cycloalkyl optionally substituted with 1 or 2 C1-C6alkyl groups, -O- and -NR3-, wherein each R3is a independently a hydrogen atom or C1-C6alkyl and wherein X1-X2-X3-X4does not contain any oxygen-oxygen, oxygen-nitrogen or nitrogen-nitrogen bonds;X5is -(CH2)b-, wherein b is an integer between 0 and 6;X6is hydrogen, C1-C6alkyl, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C1-C6alkyl groups, or -NR4R5, wherein R4and R5are each independently hydrogen or C1-C6alkyl; or alternatively R4and R5join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C1-C6alkyl groups, wherein the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen; each X7is independently hydrogen, hydroxyl or -NR6R7, wherein R6and R7are each independently hydrogen or C1-C6alkyl; or alternatively R6and R7join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C1-C6alkyl groups, wherein the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen; at least one of X1, X2, X3, X4, and X5is present;A1and A2are each independently selected from the group consisting of: C5-C12 haloalkyl, C5-C12 alkenyl, C5-C12 alkynyl, (C5-C12 alkoxy)-(CH2)n2-, (C5-C10 aryl)-(CH2)n3-optionally ring substituted with one or two halo, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy groups, and (Ca-Cs cycloalkyl)-(CH2)n4- optionally ring substituted with 1 or 2 C1-C6alkyl groups; or alternatively A1and A2join together with the atoms to which they are bound to form a 5- to 6-membered cyclic acetal substituted with 1 or 2 C4-C10 alkyl groups; nl, n2 and n3 are each individually an integer between 1 and 4; and n4 is an integer between zero and 4; iii) A compound of Formula (lb):wherein:R1is C9-C20 alkyl or C9-C20 alkenyl with 1-3 units of unsaturation;X1and X2are each independently absent or selected from -O-, NR2, andwherein R2is C1-C6alkyl, and wherein X1and X2are not both -O- or NR2; a is an integer between 1 and 6;X3and X4are each independently absent or selected from the group consisting of: 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C1-C6alkyl groups, 5- to 6- membered heteroaryl optionally substituted with 1 or 2 C1-C6alkyl groups, and -NR3-, wherein each R3is a hydrogen atom or C1-C6alkyl;X5is — (CH jb— , wherein b is an integer between 0 and 6;X6is hydrogen, C1-C6alkyl, 5- to 6-membered heteroaryl optionally substituted with 1 or 2 C1-C6alkyl groups, or -NR4R5, wherein R4and R5are each independently hydrogen or C1-C6alkyl; or alternatively R4and R5join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C1-C6alkyl groups, wherein the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen;X7is hydrogen or -NR6R7, wherein R6and R7are each independently hydrogen or C1-C6alkyl; or alternatively R6and R7join together with the nitrogen to which they are bound to form a 4- to 7-membered heterocyclyl optionally substituted with 1 or 2 C1-C6alkylgroups, wherein the heterocyclyl optionally includes an additional heteroatom selected from oxygen, sulfur, and nitrogen; at least one of X1, X2, X3, X4, and X5is present; and provided that when either X1or X2is -O-, neither X3nor X4is, and when either X1or X2is -O-, R4and R5are not both ethyl; iv) A compound of Formula (Ic):or its N-oxide, or a salt thereof, whereinLI is Cl -6 alkylenyl, or C2-6 heteroalkylenyl; each L2is independently C2-10 alkylenyl, or C3-10 heteroalkylenyl;L is absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl;L3is absent, C1-10 alkylenyl, or C2-10 heteroalkylenyl;X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R is independently hydrogen,optionally substituted group selected from C6-20 aliphatic, C6-20 haloaliphatic, a 3 - to 7-membered cycloaliphatic ring, 1- adamantyl, 2-adamantyl, sterolyl, and phenyl;R1is hydrogen, a 3- to 7-membered cycloaliphatic ring, a 3- to 7-membered heterocyclic ring comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR2, -C(O)OR2, -C(O)SR2, -OC(O)R2, -OC(O)OR2, -CN, -N(R2)2, -C(O)N(R2)2, -NR2C(O)R2, -OC(O)N(R2)2, -N(R2)C(O)OR2, -NR2S(O)2R2, -NR2C(O)N(R2)2, -NR2C(S)N(R2)2, -NR2C(NR2)N(R2)2, -NR2C(CHR2)N(R2)2, -N(OR2)C(O)R2, -N(OR2)S(O)2R2, -N(OR2)C(O)OR2, -N(OR2)C(O)N(R2)2, -N(OR2)C(S)N(R2)2, -N(OR2)C(NR2)N(R2)2, -N(OR2)C(CHR2)N(R2)2, -C(NR2)N(R2)2, -C(NR2)R2,each R2is independently hydrogen, -CN, -NO2, -OR4, -S(O)2R4, -S(O)2N(R4)2, -(CH2)n-R4, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 7-membered cycloaliphatic ring, and a 3- to 7- membered heterocyclic ring comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two occurrences of R2, taken together with the atom(s) to which they are attached, form an optionally substituted 4- to 7-membered heterocyclic ring comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; each R3is independently -(CH2)n-R4, or two occurrences of R3, taken together with the atoms to which they are attached, form an optionally substituted 5- to 6-membered heterocyclic ring comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; each R4is independently hydrogen, -OR5, -N(R5)2, -OC(O)R5, -OC(O)OR5, -CN, -C(O)N(R5)2,-NR5C(O)R5, -OC(O)N(R5)2, -N(R5)C(O)OR5, -NR5S(O)2R5, -NR5C(O)N(R5)2,each R5is independently hydrogen, optionally substituted C1-6 aliphatic, or two occurrences of R5, taken together with the atom(s) to which they are attached, form an optionally substituted 4- to 7-membered heterocyclic ring comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; each R6is independently C4-12 aliphatic; and n is 0 to 4; v) A compound of Formula (Id):or its N-oxide, or a pharmaceutically acceptable salt thereof, whereinLI is absent, Cl -6 alkylenyl, or C2-6 heteroalkylenyl; each L2 is independently optionally substituted C2-15 alkylenyl, or optionally substituted C3-15 heteroalkylenyl;L3is absent, optionally substituted C1-10 alkylenyl, or optionally substituted C2-10 heteroalkylenyl;X is absent, -OC(O)-, -C(O)O-, or -OC(O)O-; each R’ is independently an optionally substituted group selected from C4-12 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2- adamantyl, sterolyl, and phenyl;R is hydrogen,optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;R1is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10-membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR2, -C(O)OR2, -C(O)SR2, -OC(O)R2, -OC(O)OR2, -CN, -N(R2)2, -C(O)N(R2)2, -S(O)2N(R2)2, -NR2C(O)R2, -OC(O)N(R2)2, -N(R2)C(O)OR2, -NR2S(O)2R2, -NR2C(O)N(R2)2, -NR2C(S)N(R2)2, -NR2C(NR2)N(R2)2, -NR2C(CHR2)N(R2)2, -N(OR2)C(O)R2, -N(OR2)S(O)2R2, -N(OR2)C(O)OR2, -N(OR2)C(O)N(R2)2, -N(OR2)C(S)N(R2)2, -N(OR2)C(NR2)N(R2)2, -N(OR2)C(CHR2)N(R2)2, -C(NR2)N(R2)2,-C(NR2)R2, -C(O)N(R2)OR2, -C(R2)N(R2)2C(O)OR2, -CR2(R3)2, -OP(O)(OR2)2, or -P(O)(OR2)2; orring selected from 3- to 7-membered cycloaliphatic and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloaliphatic or heterocyclyl ring is optionally substituted with 1-4 R2or R3groups; each R2is independently hydrogen, oxo, -CN, -NO2, -OR4, -S(O)2R4, -S(O)2N(R4)2, - (CH2)n-R4, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 3- to 7- membered cycloaliphatic, 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R2, taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; each R3is independently -(CH2)n-R4; or two occurrences of R3, taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; each R4is independently hydrogen, -OR5, -N(R5)2, -OC(O)R5, -OC(O)OR5, -CN, - C(O)N(R5)2,-NR5C(O)R5, -OC(O)N(R5)2, -N(R5)C(O)OR5, -NR5S(O)2R5, -NR5C(O)N(R5)2,each R5is independently hydrogen, or optionally substituted C1-6 aliphatic; or two occurrences of R5, taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; each R6is independently C4-12 aliphatic; andeach n is independently 0 to 4; vi) A compound of Formula (le):or a pharmaceutically acceptable salt thereof, wherein:L1is a covalent bond, -C(O)-, or -OC(O)-;L2is a covalent bond, an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain, oCyAis an optionally substituted ring selected from phenylene and 3- to 7-membered saturated or partially unsaturated carbocyclene; each m is independently 0, 1, or 2;L3is a covalent bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, or -OC(O)O-;, or an optionally substituted saturated or unsaturated, straight or branchedC1-C20 hydrocarbon chain wherein 1-3 methylene units are optionally and independently replaced with -O- or -NR-;CyBis an optionally substituted ring selected from 3- to 12-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2-adamantyl,, sterolyl, and phenyl; p is 0, 1, 2, or 3;X1is a covalent bond, -O-, or -NR-;X2is a covalent bond or an optionally substituted, bivalent saturated or unsaturated, straight or branched, C1-C12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -O-, -NR-, or -Cyc-;Cycis an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclene, phenylene, 3- to 7-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur, and 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;X3is hydrogen or an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted C1-C6aliphatic group;Z1is a covalent bond or -O-;Z2is an optionally substituted group selected from 4- to 12-membered saturated or partially unsaturated carbocyclyl, phenyl, 1-adamantyl, and 2-adamantyl;Z3is hydrogen, or an optionally substituted group selected from Ci-Cio aliphatic, and 4- to 12-membered saturated or partially unsaturated carbocyclyl; and d is 0, 1, 2, 3, 4, 5, or 6;, , provided that when L is a covalent bond, then R must bvii) A compound of Formula (If):or a pharmaceutically acceptable salt thereof, wherein: each L1and L1is independently -C(O)- or -C(O)O-; each L2and L2is independently a covalent bond, an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain, or; each CyAis independently an optionally substituted ring selected from phenylene or a 3- to 7-membered saturated or partially unsaturated carbocyclene; each m is independently 0, 1, or 2; each L3and L3is independently a covalent bond, -C(O)O-, -OC(O)-, -O-, or -OC(O)O-; each R1and R1is independently an optionally substituted group selected from a saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain, wherein 1-3methylene units are optionally and independently replaced with -O- or -NR-, a 3- to 12- membered saturated or partially unsaturated carbocyclic ring, 1-adamantyl, 2-adamantyl, sterolyl, phenyl,each L4is independently a bivalent saturated or unsaturated, straight or branched Ci- Ce hydrocarbon chain; each A1and A2is independently an optionally substituted C1-C20 aliphatic or -L5-R5; or A1and A2, together with their intervening atoms, may form an optionally substituted ring: wherex is selected from 1 or 2; and# represents the point of attachment to L4; each L5is independently a bivalent saturated or unsaturated, straight or branched Ci- C20 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -O- or -NR-; each R5is independently an optionally substituted group selected from a 5 - to 10- membered aryl ring and a 3- to 8-membered carbocyclic ring ;X1is a covalent bond, -O-, or -NR-;X2is a covalent bond or an optionally substituted, bivalent saturated or unsaturated, straight or branched, C1-C12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -O- or -NR-;X3is hydrogen or -CyB;CyBis an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or an optionally substituted C1-C6aliphatic group; provided that when X3is hydrogen, at least one of R1or R1isviii) a compound of Formula (Ig):or a pharmaceutically acceptable salt thereof, wherein: each of L1and L1is independently a covalent bond, -C(O)-, or -OC(O)-; each of L2and L2is independently a covalent bond, an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain,each CyAis independently an optionally substituted ring selected from phenylene or 3- to 7-membered saturated or partially unsaturated carbocyclene; each m is independently 0, 1, or 2; each of L3and L3is independently a covalent bond, -O-, -C(O)O-, -OC(O)-, or - OC(O)O-; each of R1and R1is independently an optionally substituted group selected from saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain wherein 1-3 methylene units are optionally and independently replaced with -O- or -NR-, a 3- to 7- membered saturated or partially unsaturated carbocyclic ring, 1-adamantyl, 2-adamantyl, sterolyl, phenyl,each L4is independently a bivalent saturated or unsaturated, straight or branched Ci- C20 hydrocarbon chain; each A1and A2is independently an optionally substituted C1-C20 aliphatic or -L5-R5, or A1and A2, together with their intervening atoms, may form an optionally substituted ring:wherein x is selected from 1 or 2; and# represents the point of attachment to L4;each L5is independently a bivalent saturated or unsaturated, straight or branched Ci- C20 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -O- or -NR-; each R5is independently an optionally substituted group selected from a 6- to 10- membered aryl ring or a 3- to 8-membered carbocyclic ring;Y1is a covalent bond, -C(O)-, or -C(O)O-;Y2is a bivalent saturated or unsaturated, straight or branched C1-C6hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced with cyclopropylene, -O-, or -NR-;Y3is an optionally substituted group selected from saturated or unsaturated, straight or branched C1-C14 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -O- or -NR-, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, 1-adamantyl, 2-adamantyl, or phenyl;X1is a covalent bond, -O-, or -NR-;X2is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -O-, -NR-, or -CyB-; each CyBis independently an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclene, phenylene, 3- to 7-membered heterocyclene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;X3is hydrogen or an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or an optionally substituted C1-C6aliphatic group; ix) a compound of formula A’:A’ or its N-oxide, or a pharmaceutically acceptable salt thereof, whereinL1is absent, C1-6 alkylenyl, or C2-6 heteroalkylenyl; each L2is independently optionally substituted C2-15 alkylenyl, or optionally substituted C3-15 heteroalkylenyl;L is Ci-10 alkylenyl, or C2-10 heteroalkylenyl;X2is -OC(O)-, -C(O)O-, or -OC(O)O-;X is absent, -0C(0)-, -C(0)0-, or -OC(O)O-;R” is hydrogen, or an optionally substituted group selected from C6-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl; each of R and Rais independently hydrogen, or an optionally substituted group selected from Ce-20 aliphatic, 3- to 12-membered cycloaliphatic, 7- to 12-membered bridged bicyclic comprising 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 1- adamantyl, 2-adamantyl, sterolyl, and phenyl each of L3and L3ais independently absent, optionally substituted Ci-io alkylenyl, or optionally substituted C2-10 heteroalkylenyl;R1is hydrogen, optionally substituted phenyl, optionally substituted 3- to 7-membered cycloaliphatic, optionally substituted 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 8- to 10- membered bicyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -OR2, -C(O)OR2, -C(O)SR2, -OC(O)R2, -OC(O)OR2, -CN,-N(R2)2, -C(O)N(R2)2, -S(O)2N(R2)2, -NR2C(O)R2, -OC(O)N(R2)2, -N(R2)C(O)OR2, -NR2S(O)2R2, -NR2C(O)N(R2)2, -NR2C(S)N(R2)2, -NR2C(NR2)N(R2)2, - NR2C(CHR2)N(R2)2, -N(OR2)C(O)R2, -N(OR2)S(O)2R2, -N(OR2)C(O)OR2, - N(OR2)C(O)N(R2)2,-N(OR2)C(S)N(R2)2, -N(OR2)C(NR2)N(R2)2, -N(OR2)C(CHR2)N(R2)2, -C(NR2)N(R2)2, -C(NR2)R2, -C(O)N(R2)OR2, -C(R2)N(R2)2C(O)OR2, -CR2(R3)2, -OP(O)(OR2)2, or -P(O)(OR2)2; orring selected from 3- to 7-membered cycloaliphatic and 3- to 7- membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloaliphatic or heterocyclyl ring is optionally substituted with 1-4 R2or R3groups; each R2is independently hydrogen, oxo, -CN, -NO2, -OR4, -S(O)2R4, -S(O)2N(R4)2, -(CH2)n- R4, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 3- to 7- membered cycloaliphatic, 5- to 6-membered monocyclic heteroaryl comprising 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7- membered heterocyclyl comprising 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two occurrences of R2, taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; each R3is independently -(CH2)n-R4; or two occurrences of R3, taken together with the atom(s) to which they are attached, form optionally substituted 5- to 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; each R4is independently hydrogen, -OR5, -N(R5)2, -OC(O)R5, -OC(O)OR5, -CN, - C(O)N(R5)2,-NR5C(O)R5, -OC(O)N(R5)2, -N(R5)C(O)OR5, -NR5S(O)2R5, -NR5C(O)N(R5)2,each R5is independently hydrogen, or optionally substituted Ci-6 aliphatic; or two occurrences of R5, taken together with the atom(s) to which they are attached, form optionally substituted 4- to 7-membered heterocyclyl comprising 0-1 additional heteroatom selected from nitrogen, oxygen, and sulfur; each R6is independently C4-12 aliphatic; and each n is independently 0 to 4; or x) a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:L1is a covalent bond, -C(O)-, or -OC(O)-;L2is a covalent bond, an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain, orCyAis an optionally substituted ring selected from phenylene and 3- to 7-membered saturated or partially unsaturated carbocyclene; each m is independently 0, 1, or 2;L3is a covalent bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, or -OC(O)O-; an optionally substituted saturated or unsaturated, straight or branchedC1-C20 hydrocarbon chain wherein 1-3 methylene units are optionally and independently replaced with -O- or -NR-, orCyBis an optionally substituted ring selected from 3- to 12-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2-adamantyl,, sterolyl, and phenyl; p is 0, 1, 2, or 3; each L4is independently a bivalent saturated or unsaturated, straight or branched C1-C6hydrocarbon chain; each A1and A2is independently an optionally substituted C1-C20 aliphatic or -L5-R5;or A1and A2, together with their intervening atoms, may form an optionally substituted ring:where x is selected from 1 or 2; and# represents the point of attachment to L4; each L5is independently a bivalent saturated or unsaturated, straight or branched C1-C20 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -O- or -NR-; each R5is independently an optionally substituted group selected from a 5 - to 10-membered aryl ring or a 3- to 8-membered carbocyclic ring ;X1is a covalent bond, -O-, or -NR-;X2is a covalent bond or an optionally substituted, bivalent saturated or unsaturated, straight or branched, C1-C12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -O-, -NR-, or -Cyc-;Cycis an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclene, phenylene, 3- to 7-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;X3is hydrogen or an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or an optionally substituted C1-C6aliphatic group; provided that when L 3 is a covalent bond, then R i must be2. A lipid nanoparticle (LNP) comprising:A) a guide RNA, or a polynucleotide encoding the guide RNA, wherein the guide RNA is capable of directing a base editor polypeptide to alter a nucleotide in a transthyretin (TTR) polynucleotide;B) an mRNA molecule, or a polynucleotide encoding the mRNA molecule, wherein the mRNA molecule encodes a base editor polypeptide comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises: i) an amino acid sequence having at least 90% identity to the followingTadA*7.10 amino acid sequence, or a truncation thereof lacking only the first M:MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD(SEQ ID NO: 1), and ii) a combination of amino acid alterations relative to the TadA*7.10 amino acid sequence selected from the group consisting of: a) I76Y, V82T, Y123H, Y147R, and Q154R; b) V82T, Y123H, D147R, and Q154R; c) V82T, Y123H, D147T, and Q154S; d) V82T and Q154R; e) V82T, Y147T, and Q154S; f) I76Y, V82T, Y123H, Y147T, and Q154S; g) Y123H, Y147R, Q154R; h) I76Y, Y147R, and Q154R; i) Y147R, Q154R, and T166R; j) Y147T and Q154R; k) Y147T and Q154S; l) I76Y, Y123H, Y147R, and Q145R; m) I76Y and V82S; n) V82S and Y147R; o) V82S, Y123H, and Y147R; p) V82S and Q154R; q) V82S, Y123H, and Q154R; r) V82S, Y123H, Y147R, and Q154R; s) I76Y, V82S, Y123H, Y147R, and Q154R; andC) an ionizable lipid according to Formula (I), or a pharmaceutically acceptable salt thereof:wherein: each L1and L1is independently -C(0)- or -OC(O)-; each L2and L2is independently an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain;L3is a covalent bond, -O-, -C(O)O-, -OC(O)-, or -OC(O)O-;R1is optionally substituted C1-20 aliphatic,LCyAis a covalent bond or an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain;CyAis an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, 1-adamantyl, 2-adamantyl, sterolyl, and phenyl;LRais an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain; each Raand R1is independently optionally substituted C1-20 aliphatic;Y1is -C(O)- or -C(O)O-;Y2is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-6 hydrocarbon chain;Y3is optionally substituted C1-20 aliphatic;X1is a covalent bond, -O-, or -NR-;X2is an optionally substituted bivalent saturated or unsaturated, straight or branched C1-12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with -O- or -NR-;X3is hydrogen or an optionally substituted ring selected from 3- to 7- membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen or optionally substituted C1-6 aliphatic.

3. The LNP of claim 1 or claim 2, wherein the lipid nanoparticle comprises an ionizable lipid having the following structure, or a pharmaceutically acceptable salt thereof:

4. The LNP of claim 1 or claim 2, wherein the lipid nanoparticle comprises an ionizable lipid having the following structure, or a pharmaceutically acceptable salt thereof:

5. The LNP of claim 1 or claim 2, wherein the guide RNA comprises a scaffold with the following nucleotide sequence: gUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugG caccgagucggugcuususus (SEQ ID NO: 478), wherein A is adenosine; C is cytidine; G is guanosine; U is uridine; a is 2’-O-methyladenosine; c is 2’-O-methylcytidine; g is 2’-O- methylguanosine; u is 2’-O-methyluridine, and s is a phosphorothioate (PS) backbone linkage.

6. The LNP of claim 1, 2, or 5, wherein the guide RNA comprises a spacer comprising the following nucleotide sequence: GCCAUCCUGCCAAGAAUGAG (SEQ ID NO: 472).

7. The LNP of claim 6, wherein the guide RNA comprises the following nucleotide sequence:A is adenosine; C is cytidine; G is guanosine; U is uridine; mA is 2’-O-methyladenosine; mC is 2’-O-methylcytidine; mG is 2’-O-methylguanosine; mU is 2’-O-methyluridine, and s is a phosphorothioate (PS) backbone linkage.

8. The LNP of claim 2 or claim 5, wherein the guide RNA comprises a spacer selected from those listed in any of Tables IB, 1C, ID, IE, 2A, 2B, 2D, or 2E.

9. The LNP of claim 1 or claim 2, wherein the guide RNA comprises 2-5 contiguous 2’- O-methylated nucleobases at the 3’ end and at the 5’ end.

10. The LNP of claim 1 or claim 2, wherein the guide RNA comprises 2-5 contiguous nucleobases at the 3 ’ end and at the 5 ’ end that comprise phosphorothioate intemucleotide linkages.

11. The LNP of claim 1 or claim 2, wherein the napDNAbp domain comprises a Cas9 polypeptide.

12. The LNP of claim 1 or claim 2, wherein the napDNAbp is a nickase.

13. The LNP of claim 1 or claim 2, wherein the base editor polypeptide comprises an amino acid sequence with at least about 90% identity to the following amino acid sequence: ABE9.5114. A lipid nanoparticle (LNP) comprising:A) a guide RNA having the following nucleotide sequence: mGsmCsmCsAUCCUGCCAAGAAUGAGmGUUUUAGmAmGmCmUmAGmAmAmAmUmAmGmCmAmAGUUmAAmAAmUAmAmGmGmCmUmAGUmCmCGUUAmUmCAAmCmUmUGmAmAmAmAmAmGmU mGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmU smU smUsmU (SEQ ID NO: 477), wherein A is adenosine; C is cytidine; G is guanosine; U is uridine; mA is 2’-O-methyladenosine; mC is 2’-O-methylcytidine; mG is 2’-O-methylguanosine; mU is 2’-O-methyluridine, and s is a phosphorothioate (PS) backbone linkage;B) a base editor polypeptide, or a polynucleotide encoding the base editor polypeptide, wherein the base editor polypeptide comprises a nucleic acid programmable DNA binding protein (napDNAbp) domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid sequence with at least 90% identity to the following amino TadA*7.10 amino acid sequence, or a truncation thereof lacking only the first M:MSEVE FSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAE IMA LRQGGLVMQNYRLIDATLYVT FEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVE ITEGILADECAALLCY FFRMPRQVFNAQKKAQSSTD (SEQ ID NO: 1), and comprises the following combination of amino acid alterations relative to the TadA*7.10 amino acid sequence: I76Y, V82T, Y123H, Y147R, and Q154R; andC) an ionizable lipid having the following structure, or a pharmaceutically acceptable salt thereof:(IZ4).

15. The lipid nanoparticle of claim 14, wherein the base editor polypeptide comprises an amino acid sequence with at least about 90% identity to the following amino acid sequence: ABE9.51PSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKV LSAYNKHRDKPIREQAENI IHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSI TGLYETRIDLSQLGGDEGADKRTADGSEFESPKKKRKV (SEQ ID NO: 463).

16. A base editor system comprising:A) a guide RNA, or a polynucleotide encoding the guide RNA, wherein the guide RNA is capable of directing a base editor polypeptide to alter a nucleotide in a transthyretin (TTR) polynucleotide; andB) a base editor polypeptide, or one or more polynucleotide encoding the base editor polypeptide, wherein the base editor polypeptide comprises a nucleic acid programmable DNA binding protein (napDNAbp) domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises: i) an amino acid sequence with at least 90% identity to the following aminoTadA*7.10 amino acid sequence, or a truncation thereof lacking only the first M:MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAA GSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD(SEQ ID NO: 1), and ii) a combination of amino acid alterations relative to the TadA*7.10 amino acid sequence selected from the group consisting of: a) V82T, Y123H, D147R, and Q154R; b) V82T, Y123H, D147T, and Q154S; c) V82T and Q154R; d) V82T, Y147T, and Q154S; e) I76Y, V82T, Y123H, Y147R, and Q154R; and f) I76Y, V82T, Y123H, Y147T, and Q154S.

17. The base editor system of claim 16, wherein the guide RNA comprises a spacer selected from those listed in any of Tables IB, 1C, ID, IE, 2A, 2B, 2D, or 2E.

18. The base editor system of claim 16, wherein the guide RNA comprises a scaffold with the following nucleotide sequence: gUUUUAGagcuaGaaauagcaaGUUaAaAuAaggcuaGUccGUUAucAAcuuGaaaaagugG caccgagucggugcuususus (SEQ ID NO: 478), wherein A is adenosine; C is cytidine; Gis guanosine; U is uridine; a is 2’-O-methyladenosine; c is 2’-O-methylcytidine; g is 2’-O- methylguanosine; u is 2’-O-methyluridine, and s is a phosphorothioate (PS) backbone linkage.

19. The base editor system of claim 16 or claim 18, wherein the guide RNA comprises a spacer with the following nucleotide sequence: GCCAUCCUGCCAAGAAUGAG (SEQ ID NO: 472).

20. The base editor system of claim 16, wherein the guide RNA comprises 2-5 contiguous 2’-O-methylated nucleobases at the 3’ end and at the 5’ end.

21. The base editor system of claim 16, wherein the guide RNA comprises 2-5 contiguous nucleobases at the 3 ’ end and at the 5 ’ end that comprise phosphorothioate intemucleotide linkages.

22. The base editor system of claim 16, wherein the guide RNA comprises the following nucleotide sequence: mGsmCsmCsAUCCUGCCAAGAAUGAGmGUUUUAGmAmGmCmUmAGmAmAmAmUmAmGmCmAm AGUUmAAmAAmUAmAmGmGmCmUmAGUmCmCGUUAmUmCAAmCmUmUGmAmAmAmAmAmGmU mGGmCmAmCmCmGmAmGmUmCmGmGmUmGmCmU smU smUsmU (SEQ ID NO: 477), wherein A is adenosine; C is cytidine; G is guanosine; U is uridine; mA is 2’-O-methyladenosine; mC is 2’-O-methylcytidine; mG is 2’-O-methylguanosine; mU is 2’-O-methyluridine, and s is a phosphorothioate (PS) backbone linkage.

23. The base editor system of claim 16, wherein the napDNAbp domain comprises a Cas9 polypeptide.

24. The base editor system of claim 16, wherein the napDNAbp is a nickase.

25. The base editor system of claim 16, wherein the base editor polypeptide comprises an amino acid sequence with at least about 90% identity to the following amino acid sequence: ABE9.51MSEVE FSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAE IMA LRQGGLVMQNYRLYDATLYTT FEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHHP26. A polynucleotide or set of polynucleotides encoding the base editor system of any one of claims 16-25.

27. A cell comprising the base editor system of any one of claims 16-25 or the polynucleotide or set of polynucleotides of claim 26.

28. A pharmaceutical composition comprising the lipid nanoparticle of any one of claims 1-15, the base editor system of any one of claims 16-25, the polynucleotide or set ofpolynucleotides of claim 26, or the cell of claim 27, and a pharmaceutically acceptable carrier or excipient.

29. A kit containing the lipid nanoparticle of any one of claims 1-15, the base editor system of any one of claims 16-25, the polynucleotide or set of polynucleotides of claim 26, the cell of claim 27, or the pharmaceutical composition of claim 28, and a container.

30. A method for modifying a target nucleobase in a transthyretin (TTR) polynucleotide in a cell, the method comprising contacting the cell with the lipid nanoparticle of any one of claims 1-15 or the base editor system of any one of claims 16-25, thereby modifying the target nucleobase in the TTR polynucleotide.

31. The method of claim 30, wherein the cell is in a subject.

32. A method of treating a disease in a subject in need thereof, wherein the disease is associated with a pathogenic mutation in a transthyretin (TTR) polynucleotide in the subject, the method comprising administering to the subject the lipid nanoparticle of any one of claims 1-15 or the base editor system of any one of claims 16-25, thereby altering a target nucleobase in the TTR polynucleotide.

33. The method of claim 31 or claim 32, wherein an ionizable lipid of the lipid nanoparticle has a half-life in the liver of the subject that is less than 14 days.

34. The method of claim 31 or claim 32, wherein the target nucleobase is altered with an editing efficiency of at least about 50% or 60% in in the cell and / or in the liver of the subject.

35. The method of claim 31 or claim 32, wherein altering the target nucleobase results in a reduction in TTR polypeptide levels in the cell and / or in the subject.

36. The method of claim 35, wherein TTR polypeptide levels are reduced by at least about 80% or 90%.

37. The method of claim 32, wherein the method is associated with only a transient increase or no increase in alkaline phosphatase (ALP), alanine transaminase (ALT), and / or aspartate aminotransferase (AST) levels in the subject.

38. The method of claim 37, wherein the method is associated with no increase in ALP levels in the subject.

39. The method of claim 32, wherein the disease is selected from the group consisting of amyloidosis, cardiomyopathy, familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), familial transthyretin amyloidosis (FTA), senile systemic amyloidosis (SSA), and transthyretin amyloidosis.

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