Beam Therapeutics Inc.

Harvard College

The Broad Institute, Inc.

Nicole Marie Gaudelli

Michael S Packer

Yi Yu

David R Liu

Bernd Zetsche

Ian Slaymaker

Seung-Joo Lee

David A Born

Jason Michael Gehrke

J Keith Joung

John Evans

Gregory Newby

David Bryson

Natalie Petrossian

Angelica Messana

Yanfang Fu

Yvonne Aratyn

Francine Gregoire

Genesis Lung

Shaunna Berkovitch

Provided herein are compositions and methods of using base editors comprising a polynucleotide programmable nucleotide binding domain and a nucleobase editing domain in conjunction with a guide polynucleotide. Also provided herein are base editor systems for editing nucleobases of target nucleotide sequences.

Methods of substituting pathogenic amino acids using programmable base editor systems

The present invention features compositions and methods for editing deleterious mutations associated with hemoglobinopathies, such as sickle cell disease (SCD). In particular embodiments, the invention provides methods for correcting mutations in a beta globin polynucleotide using modified adenosine base editors termed 'ABE8' having unprecedented levels (e.g., >60-70%) of efficiency.

Compositions and methods for treating hemoglobinopathies

The disclosure provides adenosine deaminases that are capable of deaminating adenosine in DNA. The disclosure also provides fusion proteins comprising a Cas9 (e.g., a Cas9 nickase) domain and adenosine deaminases that deaminate adenosine in DNA. In some embodiments, the fusion proteins further comprise a nuclear localization sequence (NLS), and/or an inhibitor of base repair, such as, a nuclease dead inosine specific nuclease (dISN).

Adenosine nucleobase editors and uses thereof

The disclosure provides methods and compositions for treating blood diseases/disorders, such as sickle cell disease, hemochromatosis, hemophilia, and beta-thalassemia. For example the disclosure provides therapeutic guide RNAs that target the promotor of HBG1/2 to generate point mutations that increase expression of fetal hemoglobin. As another example, the disclosure provides therapeutic guide RNAs that target mutations in HBB, Factor VIII, and HFE to treat sickle cell disease, beta-thalassemia, hemophilia and hemochromatosis. The disclosure also provides fusion proteins comprising a Cas9 (e.g., a Cas9 nickase) domain and adenosine deaminases that deaminate adenosine in DNA. In some embodiments, the fusion proteins are in complex with nucleic acids, such as guide RNAs (gRNAs), which target the fusion proteins to a DNA sequence (e.g., an HBG1 or HBG2 protmoter sequence, or an HFE, GBB, or F8 gene sequence). Such complexes may be useful for increasing expression of fetal hemoglobin or correcting a poing mutation (e.g., C282Y) in HFE.

Uses of adenosine base editors

The present invention features compositions and methods for editing deleterious mutations associated with hemoglobinopathies, such as sickle cell disease (SCD). In particular embodiments, the invention provides methods for correcting mutations in a beta globin polynucleotide using modified adenosine base editors termed 'ABE8' having unprecedented levels (e.g., &#x3e;60-70%) of efficiency.

The disclosure provides compositions comprising novel adenosine base editors (e.g., ABE8) that have increased efficiency and methods of using these adenosine deaminase variants for editing a target sequence.

Adenosine deaminase base editors and methods of using same to modify a nucleobase in a target sequence

Growing community of inventors

Cambridge, MA, United States of America

Nicole Marie Gaudelli