Materials and methods to enhance hematopoietic stem cells engraftment procedures

Abstract

This disclosure is directed to the methods of enhancing hematopoietic stem cells (HSPC) and progenitor cell (HSPC) engraftment procedure. Treatment in vivo of a HSPC donor with compounds that reduce PGE2 biosynthesis or PGE2 receptor antagonists alone, or in combination with other hematopoietic mobilization agents such as AMD3100 and G-CSF, increases the circulation of available HSPCs. Compounds that reduce the cellular synthesis of PGE2 include non−steroidal anti-inflammatory compounds such as indomethacin. Treatment ex vivo of HSPC with an effective amount of PGE2 or at least one of its derivatives such as 16,16-dimethyl prostaglandin E2 (dmPGE2), promotes HSPC engraftment. Similar methods may also be used to increase viral-mediated gene transduction efficacy into HSPC.

1 .- 27 . (canceled) 
     
     
         28 . A method for gene therapy comprising: administering to a subject in need thereof a hematopoietic stem or progenitor cell that has been contacted ex vivo with an effective amount of a prostaglandin E 2  or a derivative thereof; and transduced with a viral vector that contains at least one gene of interest. 
     
     
         29 . The method according to  claim 28 , wherein the prostaglandin E 2  or a derivative thereof is selected from the group consisting of PGE 2  and dmPGE 2 . 
     
     
         30 . The method according to  claim 28 , wherein the hematopoietic stem or progenitor cell is obtained from Umbilical Cord Blood (UCB) or mobilized Peripheral Blood (PB) drawn from a donor. 
     
     
         31 . The method according to  claim 28 , wherein the cell has been contacted with the prostaglandin E 2  or a derivative thereof for at least one hour. 
     
     
         32 . The method according to  claim 28 , wherein the cell has been contacted with the prostaglandin E 2  or a derivative thereof for about 2 hours. 
     
     
         33 . The method according to  claim 28 , wherein the cell has been washed after contact with the prostaglandin E 2  or a derivative thereof. 
     
     
         34 . The method according to  claim 28 , wherein the cell has been washed prior to being administered to the subject. 
     
     
         35 . A human hematopoietic stem or progenitor cell that has been contacted ex vivo with an effective amount of a prostaglandin E 2  or a derivative thereof and that comprises a viral vector that contains at least one gene of interest. 
     
     
         36 . The human hematopoietic stem or progenitor cell according to  claim 35 , wherein the prostaglandin E 2  or a derivative thereof is selected from the group consisting of PGE 2  and dmPGE 2 . 
     
     
         37 . The human hematopoietic stem or progenitor cell according to  claim 35 , wherein the cell has been contacted with the prostaglandin E 2  or a derivative thereof for about one to about  6  hours. 
     
     
         38 . The human hematopoietic stem or progenitor cell according to  claim 35 , wherein the cell has been contacted with the prostaglandin E 2  or a derivative thereof for about 2 hours. 
     
     
         39 . The human hematopoietic stem or progenitor cell according to  claim 35 , wherein the cell has been washed after contact with the prostaglandin E 2  or a derivative thereof. 
     
     
         40 . The human hematopoietic stem or progenitor cell according to  claim 35 , wherein the cell has been washed prior to being transplanted into a subject. 
     
     
         41 . The human hematopoietic stem or progenitor cell according to  claim 35 , wherein the human hematopoietic stem cell is CD34+. 
     
     
         42 . A composition for use in an ex vivo method of enhancing viral transduction efficacy, the composition comprising:
 (a) a human hematopoietic stem or progenitor cell;   (b) a prostaglandin E 2  or a derivative thereof in an amount sufficient to enhance ex vivo viral transduction efficacy of the human hematopoietic stem or progenitor cell; and   (c) a viral vector that contains at least one gene of interest.   
     
     
         43 . The composition of  claim 42 , wherein the prostaglandin E 2  or a derivative thereof is selected from the group consisting of PGE 2  and dmPGE 2 . 
     
     
         44 . The composition of  claim 42 , wherein the prostaglandin E 2  or a derivative thereof is present at a concentration of about 1 μM to about 10 μM. 
     
     
         45 . The composition of  claim 42 , wherein the prostaglandin E 2  or a derivative thereof is present at a concentration of about 1 μM.