Gene therapy can correct mutations in common heart diseases

Research
using the CRISPR-Cas9 gene-editing system to correct mutations that cause dilated cardiomyopathy.

Using the CRISPR-Cas9 gene-editing system, researchers at the University of Texas Southwestern corrected mutations in human cells and in mouse models of the disease that lead to a common inherited heart condition called dilated cardiomyopathy (DCM
).
Their findings, published in the journal Science Translational Medicine, could one day offer hope
that one in every 250 people worldwide suffer from the disease.

These are representative hearts from 12-week-old mice: normal heart (left) and enlarged heart, characteristic of
dilated cardiomyopathy.

"As a result of these mutations, all the disease features we saw were reversed by CRISPR-Cas9 therapy
.
To be fair, the success of this approach completely exceeded our expectations," said Eric Olson, Ph.
D.
, professor and chair of molecular biology at UTSW, who co-led the study
with colleagues Rhonda Bassel-Duby, Ph.
D.
, professor of molecular biology, and Takahiko Nishiyama, Ph.
D.
, a postdoc in Olson's lab.

DCM is caused by mutations in a gene called RNA-binding motif protein 20 (RBM20), which affects the production
of hundreds of proteins in cardiomyocytes responsible for heart pumping.
The disease causes extensive damage throughout the heart, gradually destroying the heart's ability to contract, causing it to become vastly enlarged and fail
over time.
Treatment is limited to drugs that improve systolic function but do not provide permanent repair, or heart transplants, which are usually not an option
due to a shortage of donor organs.

To eradicate the root causes of the disease, the authors studied CRISPR-Cas9, a popular genetic research tool that won the Nobel Prize
in Chemistry in 2020.
Using this system, researchers can potentially correct disease-causing mutations in important genes
.

So far, the U.
S.
Food and Drug Administration has approved a clinical trial
using this technique to treat sickle cell disease.
However, Dr.
Olson said CRISPR-Cas9 has great potential
in treating a number of other unspecified genetic diseases.
Using CRISPR gene-editing technology, Dr.
Olson and colleagues developed a technique that could halt the progression
of Duchenne muscular dystrophy in animal models.

To determine the feasibility of this approach for DCM, the research team used a virus to deliver CRISPR-Cas9 components to cardiomyocytes derived from human cells
that carry mutations caused by two different types of DCM.
Scientists use this gene-editing technique to exchange individual nucleotides (the basic basis of DNA) to correct one type of mutation.

In another group of cells, the researchers replaced a piece of DNA in the mutated RBM20 gene with a healthy fragment
of that gene.

After CRISPR-Cas9 treatment, the mutant cells gradually lost the inherent characteristics of DCM: the protein produced by RBM20 moved to its normal position in the nucleus, and the cell began to make healthy proteins
.

When the researchers treated 1-week-old mice with one of the mutations with CRISPR-Cas9, the animals never showed heart enlargement and lived normally
.
Untreated mice developed the same symptoms
as human DCM patients.

The scientists say there are several challenges
before this therapy can be applied to DCM patients.
Work is needed to ensure that the effects of CRISPR-Cas9 are permanent and precise, and that the smallest dose
possible is used.
It is also uncertain whether this treatment can be used in patients
with more severe conditions.
However, Dr.
Olson said he is optimistic that such a system could be used to treat a variety of other familial diseases
.

"The speed at which this space is evolving is really amazing," he said
.
"I expect that if this technology is applied to patients, we are not talking about decades, but within
years.
"