IP Library › Granted Patent US 12,558,435
Granted Patent B2
US 12,558,435 · App. 17/255,362 · Granted Feb 24, 2026

Transient inhibition of p53 in gene therapy

Inventors: Pietro Genovese (Milan, IT); Giulia Schiroli (Milan, IT); Luigi Naldini (Milan, IT); Aurelien Jacob (Milan, IT); Samuele Ferrari (Milan, IT)
Assignees: Ospedale San Raffaele S.R.L.; Fondazione Telethon ETS
A61K48/005C07K14/005C12N15/86C12N15/907C12N2310/20C12N2710/10022C12N2750/14143
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Quick Facts
Patent No.
US 12,558,435
App. No.
17/255,362
Granted
Feb 24, 2026
Kind
B2
Abstract

An agent which promotes homology directed DNA repair for use in haematopoietic stem and/or progenitor cell gene therapy, wherein said haematopoietic stem cells are gene edited. Use of an agent which promotes homology directed DNA repair, for increasing the survival and/or engraftment of gene edited haematopoietic stemand/or progenitorcells or for increasing the efficiency of gene editing of haematopoietic stem and/or progenitor cells.

Claims (20)

1 . A method of haematopoietic cell gene therapy, haematopoietic stem cell gene therapy, and/or haematopoietic progenitor cell gene therapy, wherein said gene therapy comprises gene editing, wherein said method comprises contacting a population of haematopoietic cells, haematopoietic stem cells and/or haematopoietic progenitor cells with an agent that comprises a p53 dominant negative peptide comprising a p53 homo-oligomerisation domain, or that comprises a nucleic acid comprising a nucleotide sequence encoding the p53 dominant negative peptide, wherein the method transiently inhibits p53 in the haematopoietic cells, haematopoietic stem cells and/or haematopoietic progenitor cells.

2 . The method of claim 1 , wherein the contacting the population of haematopoietic cells, haematopoietic stem cells and/or haematopoietic progenitor cells with the agent increases the survival and/or engraftment of gene edited haematopoietic cells, haematopoietic stem cells and/or haematopoietic progenitor cells, or increases the efficiency of gene editing of haematopoietic cells, haematopoietic stem cells, and/or haematopoietic progenitor cells.

3 . The method of claim 1 , wherein transient inhibition of p53 occurs during gene editing of the haematopoietic cells, haematopoietic stem cells and/or haematopoietic progenitor cells.

4 . The method of claim 1 , wherein the agent is added to the haematopoietic cell, haematopoietic stem cell and/or haematopoietic progenitor cells at a concentration of about 1-50 μM.

5 . The method of claim 1 , wherein the agent further comprises at least one adenoviral protein or a nucleic acid comprising a nucleic acid sequence encoding said at least one adenoviral protein.

6 . The method of claim 5 , wherein the at least one adenoviral protein is from an Adenovirus of serotype 4, Adenovirus of serotype 5, Adenovirus of serotype 7 and/or Adenovirus of serotype 9.

7 . The method of claim 5 , wherein the at least one adenoviral protein is: (a) E4ORF1 or (b) E4ORF6/7.

8 . The method of claim 5 , wherein the nucleic acid encoding the adenoviral protein is an mRNA.

9 . The method of claim 5 , wherein the adenoviral protein is expressed transiently in the haematopoietic cell, haematopoietic stem cell or haematopoietic progenitor cell.

10 . The method of claim 9 , wherein the transient expression occurs during gene editing of the haematopoietic cell, haematopoietic stem cell and/or haematopoietic progenitor cell.

11 . The method of claim 1 , wherein the agent further comprises: adenoviral protein E4ORF1, or a nucleic acid comprising a nucleic acid sequence encoding adenoviral protein E4ORF1; and adenoviral protein E4ORF6/7, or a nucleic acid comprising a nucleic acid sequence encoding adenoviral protein E4ORF6/7.

12 . The method of claim 1 , wherein the agent comprises:

(a) a p53 dominant negative peptide comprising a p53 homo-oligomerisation domain or a nucleic acid comprising a nucleic acid sequence encoding the p53 dominant negative peptide; and an adenoviral protein, or a nucleic acid comprising a nucleic acid sequence encoding the adenoviral protein;

(b) a p53 dominant negative peptide comprising a p53 homo-oligomerisation domain or a nucleic acid comprising a nucleic acid sequence encoding the p53 dominant negative peptide; and adenoviral protein E4ORF1, or a nucleic acid comprising a nucleic acid sequence encoding the adenoviral protein E4ORF1

(c) a p53 dominant negative peptide comprising a p53 homo-oligomerisation domain or a nucleic acid comprising a nucleic acid sequence encoding the p53 dominant negative peptide; and adenoviral protein E4ORF6/7, or a nucleic acid comprising a nucleic acid sequence encoding the adenoviral protein E4ORF6/7; or

(d) a p53 dominant negative peptide comprising a p53 homo-oligomerisation domain or a nucleic acid comprising a nucleic acid sequence encoding the p53 dominant negative peptide; adenoviral protein E4ORF1, or a nucleic acid comprising a nucleic acid sequence encoding the adenoviral protein E4ORF1; and adenoviral protein E4ORF6/7, or a nucleic acid comprising a nucleic acid sequence encoding the adenoviral protein E4ORF6/7.

13 . The method of claim 1 , wherein a target of the gene editing is selected from the group consisting of CD40L, RAG-1, IL-2RG, CYBA, CYBB, NCF1, NCF2, and NCF4.

14 . The method of claim 1 , wherein the agent comprises GSE56 or a variant thereof, or a nucleic acid comprising a nucleotide sequence encoding the GSE56.

15 . The method of claim 1 , wherein the agent comprises a p53 dominant negative peptide comprising an amino acid sequence having at least 80% identity to SEQ ID NO: 9, or a nucleic acid comprising a nucleotide sequence encoding the amino acid sequence.

16 . The method of claim 1 , wherein the agent is in the form of an mRNA.

Assignments (2)
CHANGE OF NAME Recorded Oct 14, 2025
From: FONDAZIONE TELETHON
To: FONDAZIONE TELETHON ETS
Reel/Frame 073069/0786 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 23, 2023
From: GENOVESE, PIETRO; SCHIROLI, GIULIA; NALDINI, LUIGI; JACOB, AURELIEN; FERRARI, SAMUELE
To: OSPEDALE SAN RAFFAELE S.R.L.; FONDAZIONE TELETHON
Reel/Frame 063075/0614 →
Priority Claims (1)
EP 18305807 · Jun 25, 2018 · regional
Continuity (1)
Related Publication 20210260216A1 · Aug 26, 2021
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