Scientists at the San Raffaele Telethon Institute for Gene
Therapy in Milan have found a way to make genome editing safer for blood
disorders minus the side effects.
thus controlling the stem cells' natural damage response pathways.
Pietro Genovese, senior co-author said that despite the therapeutic potential of correcting blood disorders with
genome editing; the challenge has been to circumvent the serious side effects
development of cancers.
Gene Editing can be made 'Safer' for Blood Disordersp53 is a protein
often termed the 'guardian of the genome'
as it preserves the stability of DNA and
prevents against unwanted mutations. When CRISPR is used to cut genes, it cuts
the two strands of the DNA at a specific location. This action of cutting the
DNA strands can actually send out a wrong signal to p53 communicating that
there is something going wrong in the DNA.
p53 then starts its action and prevents the
cells from multiplying
while the desired effect is actual proliferation
cells as a therapeutic. The difficulty of p53 is that it cannot be silenced or
shut down as this can lead to cancers. p53 is the
body's main defense mechanism against cancers
The research team found a simple method to overcome this
obstacle with p53. Gene editing techniques use genetic scissors like nucleases
to induce DNA breaks and then uses a viral vector to insert the corrected
sequence. If the genetic scissors are not specific, more than the required DNA
breaks will be induced which gives out the wrong signal to p53.
Use of Specific Nucleases and
The team used specific nucleases and vectors to induce only
the intended DNA breaks in hematopoietic stem/progenitor cells (HSPCs).
Luigi Naldini, senior co-author and director of the
said that if the genetic scissors are not specific enough,
there will be more than the intended breaks and consequently off-target effects
prolonged p53 response. Using highly specific nucleases and
extra purified reagents can actually eliminate these unwanted side effects.
Rafaella di Mico, third author and head of a lab at the
institute said that HSPCs tolerate only a few DNA breaks with transient p53
activation. Inactivating p53 response temporarily during gene editing can
improve the yield of cells with greater proliferation
and desired effects
without disturbing the genome's stability or increasing the risk of unwanted
The research team is confident that this
specific technology of gene editing can be successfully translated into human
published their research in the journal Cell Stem
- Precise Gene Editing Preserves Hematopoietic Stem Cell Function following Transient p53-Mediated DNA Damage Response- (https://doi.org/10.1016/j.stem.2019.02.019)