PXD054579-1

PXD054579 is an original dataset announced via ProteomeXchange.

Title	Rational engineering of minimally immunogenic nucleases for gene therapy
Description	Genome editing using CRISPR-Cas systems is a promising avenue for the treatment of genetic diseases. However, cellular and humoral immunogenicity of genome editing tools, which originate from bacteria, complicates their clinical use. Here we report reduced immunogenicity (Red)(i)-variants of two clinically-relevant nucleases, SaCas9 and AsCas12a. Through MHC-associated peptide proteomics (MAPPs) analysis, we identified putative immunogenic epitopes on each nuclease. Then, we used computational modeling to rationally design these proteins to evade the immune response. SaCas9 and AsCas12a Redi variants were substantially less recognized by adaptive immune components, including reduced binding affinity to MHC molecules and attenuated generation of cytotoxic T cell responses, while maintaining wild-type levels of activity and specificity. In vivo editing of PCSK9 with SaCas9.Redi.1 was comparable in efficiency to wild-type SaCas9, but significantly reduced undesired immune responses. This demonstrates the utility of this approach in engineering proteins to evade immune detection.
HostingRepository	PRIDE
AnnounceDate	2024-11-07
AnnouncementXML	Submission_2024-11-07_02:40:57.286.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rumya Raghavan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	methionine oxidation with neutral loss of 80 Da; cysteinylation (disulfide with free L-cysteine); monohydroxylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-05 01:45:54	ID requested
⏵ 1	2024-11-07 02:40:57	announced

Dataset with its publication pending

submitter keyword: SaCas9, MAPPs, AsCas12a,Gene therapy

Feng Zhang
contact affiliation	Broad Institute
contact email	zhang@broadinstitute.org
lab head
Rumya Raghavan
contact affiliation	Broad Institute of MIT and Harvard
contact email	rumya@broadinstitute.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054579
     1. Label: PRIDE project
     2. Name: Rational engineering of minimally immunogenic nucleases for gene therapy