Science: First use of CRISPR-Cas9 base editing to treat heart disease

A study in mice showed that a new CRISPR-Cas9 method could target harmful signaling pathways in the heart, preventing ischemia/reperfusion damage
.
The findings suggest that gene editing could provide a permanent and advanced strategy for treating heart disease, a major cause of morbidity and mortality worldwide, and studies have shown that this approach could be used as an intervention
to repair heart damage immediately after a heart attack.

CRISPR-Cas9 gene editing is emerging as a prospective therapy
for genomic mutations.
However, current editing methods are primarily aimed at a relatively small patient population
with specific mutations.

The latest study describes a heart protection strategy
that may be applicable to patients with a wide range of heart diseases.
The researchers used base editing to eliminate the oxidative-activating site of CaMKIIδ, a major driver of heart disease
.
Shown in cardiomyocytes derived from human induced pluripotent stem cells, editing the CaMKIIδ gene eliminates oxidation-sensitive methionine residues, protecting them from ischemia/reperfusion (IR) damage
.
In addition, CaMKIIδ gene editing in mice at the time of IR genesis allowed the heart to recover function
from other serious damage.
Therefore, CaMKIIδ gene editing may represent a permanent, advanced treatment strategy
for heart disease.

Base editing

Since officially entering the field of gene editing in 2012, CRISPR-Cas9 has been favored by researchers for its powerful editing efficiency and simple operation, and its effectiveness has been confirmed
in experiments on various species.
However, when people focus on the treatment direction of human genetic diseases, this powerful tool seems to be somewhat "inadequate"
.
Most of the genetic diseases in humans are caused by point mutations, and CRISPR-Cas9 often has problems such as low efficiency and low biosafety when repairing these point mutations, and this impasse was not broken until the emergence of Base Editor
.

Base editing is a single-base editing technology developed based on CRISPR, first developed by the team of Professor Liu Ruqian of Harvard University in 2016, to treat diseases caused by single-base mutations such as Progeria and sickle anemia
.
In 2017, Nicole Gaudelli from Liu Ruqian's lab developed the first adeninebase editors (ABEs), creatively realizing the chemical conversion
of A/T bases to G/C bases.

Heart disease treatment

This technique has shown promise
as a treatment for genetic diseases.

Ischemia-reperfusion injury (IR), tissue damage that occurs after hypoxia, can be observed after a variety of injuries, including common injuries such as heart attack or stroke
.
A key protein that plays a role in this damage is calmodulin-dependent protein kinase II δ (CaMKIIδ).

In the latest study, Simon Lebek, Eric Olson and others demonstrated a CRISPR-Cas9 gene-editing therapy that could treat a range of heart disease patients
.
IR injury is a type of tissue damage that occurs after various cardiovascular injuries, including strokes and heart attacks
.
Chronic overactivation of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is known to cause several heart diseases, including IR damage
, in humans and mice.
Methionine residue oxidation promotes CaMKIIδ overactivation
.

The researchers found that in mouse models, using CRISPR-Cas9 adenine base editing to eliminate the oxidative activation site of the CaMKIIδ gene in cardiomyocytes protected cardiomyocytes from IR damage
.
What's more, they found that injecting mice with gene-editing reagents shortly after infrared injury allowed the animals to restore heart function
after severe injury.