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US 2025/0144149 A1Published application
Adenosine deaminase base editors and methods for use thereof
AssigneeBeam Therapeutics Inc.
InventorsNicole Gaudelli, Tanggis Bohnuud, Scott Haihua Chu
Life of this patent
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Abstract
Adenosine deaminase base editors, compositions comprising the same, and methods for use thereof for altering a target nucleobase in a polynucleotide sequence. In embodiments of the disclosure, the base editors of the disclosure may be used to treat a disease or disorder, such as a hemoglobinopathy (e.g., sickle cell disease (SCD)).
Claims20
A method for treating a hemoglobinopathy in a subject in need thereof, the method comprising:
- a) contacting an isolated hematopoietic stem cell or progenitor thereof with two or more guide polynucleotides, or one or more polynucleotides encoding the guide polynucleotides, and a base editor comprising a nucleic acid programmable DNA binding protein (napDNAbp) and an adenosine deaminase, or one or more polynucleotides encoding the base editor, wherein the adenosine deaminase comprises a combination of alterations relative to the following sequence of TadA*7.10 and has at least 85% sequence identity to the following sequence of TadA*7.10:
- MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO:
- 1), wherein the combination of alterations comprises:
- i) F149Y and V82T;
- or
- ii) F149Y, T166I, and/or D167N, and the alteration V82T;
- and
- wherein the two or more guide polynucleotides target the base editor to effect an alteration to a beta globin polynucleotide (HBB) that results in expression of a beta globin polypeptide having an alanine at position 6 (Hb G-Makassar), and wherein the two or more guide polynucleotides target the base editor to effect an alteration in a cluster of differentiation (CD117) polynucleotide that results in expression of a CD117 polypeptide with reduced binding to an antibody that selectively binds a wild type CD117 polypeptide, thereby generating an edited cell;
- and
- (b) wherein the cell is in the subject or the method further comprises administering the edited cell to the subject.
7 more elements
The method of 1, wherein the two or more guide polynucleotides comprise a spacer nucleotide sequence selected from the group consisting of:
- (SEQ ID NO 660;
- CC128)
- AAAUAUAAUAGCUGGCAUCA;
- (SEQ ID NO:
- 722;
- CC200)
- AUAAUAGCUGGCAUCACGGU;
- (SEQ ID NO:
- 723;
- gRNA889)
- CCACUAGCUUUCCAAACGGU;
- (SEQ ID NO:
- 724;
- gRNA908)
- GCUGAACUGAUAGUCAACGU;
- (SEQ ID NO:
- 725;
- gRNA918)
- UUUGACAAAGCCCGGAUCAG;
- (SEQ ID NO:
- 726;
- gRNA923)
- UGAAAGUGAGGCCAGGUACU;
- (SEQ ID NO:
- 727;
- gRNA928)
- AAACAGUCAGGUGAGUGAAU;
- (SEQ ID NO:
- 728;
- gRNA929)
- AACUACAGGAGAAAUAUAAU;
- and
- (SEQ ID NO:
- 729;
- gRNA944)
- GAUUAAAAGGCACCGAAGGA.
33 more elements
An adenosine deaminase polypeptide comprising a combination of alterations relative to the following sequence of TadA*7.10:
- MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO:
- 1), wherein the combination of alterations comprises F149Y and V82T, and wherein the adenosine deaminase has at least 85% sequence identity to TadA*7.10.
An adenosine deaminase polypeptide comprising the following amino acid sequence:
- SEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMAL RQGGLVMQNYRLYDATLYTTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHHPG MNHRVEITEGILADECAALLCRFYRMPRRVFNAQKKAQSSTD (SEQ ID NO:
- 518);
- or
- comprising a combination of alterations to the following sequence of TadA*7.10:
- MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD (SEQ ID NO:
- 1), wherein the combination of alterations comprises F149Y, T166I, and/or D167N, and the alteration V82T, and wherein the adenosine deaminase has at least 85% sequence identity to TadA*7.10.
3 more elements
A base editor comprising:
- a nucleic acid programmable DNA binding protein (napDNAbp) and an adenosine deaminase, wherein the adenosine deaminase comprises a combination of alterations relative to TadA*7.10:
- (SEQ ID NO:
- 1)
- MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAI
- GLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSR
- IGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCY
- FFRMPRQVFNAQKKAQSSTD,
- wherein the combination of alterations comprises I76Y, V82T, Y123H, Y147R, F149Y, and Q154R, and wherein the adenosine deaminase has at least 85% sequence identity to TadA*7.10;
- or
- the adenosine deaminase comprises a combination of alterations relative to TadA*7.10:
- (SEQ ID NO:
- 1)
- MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAI
- GLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSR
- IGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCY
- FFRMPRQVFNAQKKAQSSTD,
- wherein the combination of alterations comprises I76Y, V82T, Y123H, Y147D, F149Y, Q154R, T166I, and D167N, and wherein the adenosine deaminase has at least 85% sequence identity to TadA*7.10.
14 more elements
Dependencies are inferred from the claim text.