PXD037529

PXD037529 is an original dataset announced via ProteomeXchange.

Title	Lipid nanoparticles improves ex vivo gene editing of human hematopoietic cells
Description	Ex-vivo gene editing in T cells and hematopoietic stem/progenitor cells (HSPCs) holds promise for treating diseases by non-homologous end joining (NHEJ) gene disruption or homology-driven repair (HDR) gene correction. Gene editing encompasses delivery of nucleases by electroporation and, when aiming to HDR, of a DNA template often provided by viral vectors. Whereas HSPCs activate robust p53-dependent DNA damage response (DDR) upon editing, the responses triggered in T cells remain poorly characterized. Here, we performed comprehensive multi-omics analyses and found that electroporation is the culprit of cytotoxicity in T cells, causing death and cell cycle delay, perturbing metabolism and inducing inflammatory response. Nuclease delivery by lipid nanoparticles (LNPs) nearly abolished cell death and ameliorated cell growth, improving tolerance to the procedure and yielding higher number of edited cells compared to electroporation. Transient transcriptomic changes upon LNP treatment were mostly caused by cellular loading with exogenous cholesterol, whose potentially detrimental impact could be overcome by limiting exposure. Notably, LNP-based HSPC editing dampened p53 pathway induction and supported higher reconstitution by long-term repopulating HSPCs compared to electroporation, reaching similar editing efficiencies. Overall, LNPs may allow efficient and stealthier ex-vivo gene editing in hematopoietic cells for treatment of human diseases.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:25:48.089.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	alessandro cuomo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-10-18 08:02:51	ID requested
1	2024-01-26 07:09:45	announced
⏵ 2	2024-10-22 06:25:52	announced	2024-10-22: Updated project metadata.

10.1182/blood.2022019333;

Vavassori V, Ferrari S, Beretta S, Asperti C, Albano L, Annoni A, Gaddoni C, Varesi A, Soldi M, Cuomo A, Bonaldi T, Radrizzani M, Merelli I, Naldini L, vivo gene editing of human hematopoietic cells. Blood, 142(9):812-826(2023) [pubmed]

submitter keyword: Hunan, nanoparticles, hematopoietic cells

Luigi Naldini
contact affiliation	San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
contact email	naldini.luigi@hsr.it
lab head
alessandro cuomo
contact affiliation	IEO
contact email	alessandro.cuomo@ieo.it
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/01/PXD037529

PRIDE project URI

• PRIDE
  1. PXD037529
     1. Label: PRIDE project
     2. Name: Lipid nanoparticles improves ex vivo gene editing of human hematopoietic cells