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SUMMARY:Base Editing and Prime Editing: Precise Gene Correction Without Do
 uble-Strand DNA Breaks - Professor David Liu\, from the Broad Institute of
  MIT and Harvard\, Cambridge MA
DTSTART:20221013T130000Z
DTEND:20221013T140000Z
UID:TALK177050@talks.cam.ac.uk
CONTACT:Caroline Newnham
DESCRIPTION:In this lecture I describe the development and therapeutic app
 lication of two precision gene editing technologies that install or correc
 t targeted mutations without requiring double-strand DNA breaks\, thereby 
 minimizing undesired consequences of chromosomal cleavage such as transloc
 ations\, p53 activation\, chromothripsis\, and uncontrolled mixtures of in
 dels. We developed base editors\, proteins that directly perform chemistry
  on individual DNA bases in living cells to install or correct mutations a
 t targeted positions in genomic DNA. We recently engineered CRISPR-free\, 
 all-protein base editors that enabled the first purposeful changes in the 
 sequence of mitochondrial DNA in living cells. By integrating base editors
  with ex vivo and in vivo delivery strategies that deliver therapeutic pro
 teins\, we rescued animal models of human genetic diseases including sickl
 e-cell disease and progeria. Single-AAV base editing systems enhance the s
 afety and practicality of in vivo base editing. Our development of enginee
 red virus-like particles (eVLPs) provide additional in vivo delivery metho
 ds for gene editing proteins that minimize off-target editing and the risk
  of oncogenic DNA integration. Base editing clinical trials in three count
 ries to treat high cholesterol\, leukemia\, and sickle-cell disease are un
 derway. I will also describe prime editors\, engineered proteins that dire
 ctly write new genetic information into a specified DNA site without requi
 ring double-strand DNA breaks or donor DNA templates. Prime editing can me
 diate any base substitutions\, small insertions\, and/or small deletions i
 n living cells in vitro and in vivo\, and has been applied to directly cor
 rect pathogenic alleles that previously could not be corrected in therapeu
 tically relevant cells. We recently illuminated the cellular determinants 
 of prime editing outcomes\, and used the resulting insights to develop nex
 t-generation prime editing systems with substantially higher editing effic
 iencies and product purities. The combination of prime editing and recombi
 nases enable targeted gene-sized integration and inversion at loci of our 
 choosing in human cells. Base editing and prime editing enable precise tar
 get gene correction\, in addition to target gene disruption\, in a wide ra
 nge of organisms with broad implications for the life sciences and therape
 utics.
LOCATION:Zoom meeting
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