• James Marchant

Gene therapy – A cure for a broken heart?

Updated: Apr 14

Cardiovascular diseases caused by genetic mutations could be treated using gene therapy technologies that can prevent and even reverse genetic disorders.



Cardiovascular disease often results from the accumulation of factors associated with lifestyle, age, and family history. Many risk factors can be managed, avoided, and even modified, whereas others cannot be controlled and are an inherent and integrated part of the genome. In some cases, cardiovascular disease is encoded in the genome and is an unavoidable consequence of a genetic disorder, for most of which, there is currently no cure.


Gene therapy is an experimental technique that uses genome editing tools to target a defective gene and replace it with a functional copy. Alternatively, the gene can be knocked out, the equivalent of deleting the gene from the genome, or new genes can be introduced into the genome to fight diseases. Thus, the treatment of some diseases could be revolutionized by novel gene therapy-based approaches.


Barth syndrome is a metabolic and neuromuscular disorder that is caused by a mutation in the tafazzin (TAZ) gene, located on the X chromosome. Mutations in this gene result in dilated cardiomyopathy, hypotonia, and dysfunction in mitochondria – the “energy factories” of the cell. Due to the chromosomal position of the mutated gene, the disorder is almost exclusively seen in males and is often diagnosed in infancy or early childhood. The symptoms are managed with a multitude of treatments, but there is currently no cure for the cause of the disorder.


New research conducted at the Boston children’s hospital suggests that gene therapy could prevent or even reverse cardiac dysfunction in patients with Barth syndrome. Cardiac-specific TAZ knockout mice were generated, and all developed progressive cardiomyopathy similar to human patients. Gene therapy was then used to replace the dysfunctional TAZ with a functional copy in adult mice using engineered viruses.


The transfer of a functional TAZ gene in adult mice reversed already established cardiac dysfunction and prevented the development of cardiac dysfunction in newborn mice [1]. The study was led by Dr. William Pu and was published in March 2020 in the journal Circulation Research.


Despite the encouraging findings of the study, the application of this technology in humans is challenging due to the limited efficiency of the therapy. Although the functional TAZ gene was successfully introduced in 70% of heart cells of the mice, the success rate is likely to drop considerably in humans due to the size difference between the two species.


Getting enough of the muscle cells corrected in humans may be a challenge,says Dr. William Pu, lead researcher on the project. “The problem is that neutralizing antibodies to the virus develop after the first dose.”

A whole-body mouse TAZ deletion model was also used to assess the efficiency of the therapy in skeletal muscles. Researchers found that the number of cells carrying the corrected gene gradually declined in skeletal muscles. Despite this, Dr. Pu remains positive about the outcome of the study.


"The biggest takeaway was that the gene therapy was highly effective," says Dr. Pu and adds that there are still some improvements to be made. "We have some things to think about to maximize the percentage of muscle cell transduction, and to make sure the gene therapy is durable, particularly in skeletal muscle" [2].

Danon disease is another rare genetic disorder that affects the heart skeletal muscle, neurologic system, eyes, and liver. The disease results from mutations in the lysosomal-associated membrane protein 2 (LAMP2) gene, and patients with Danon disease often require a heart transplant.


“We are currently treating all heart failure the same, with a transplant, but this isn’t practical with more than 3,000 people in the United States currently on the wait list for a heart,” says Dr. Eric Adler, cardiologist at UC San Diego Health and associate professor of medicine at UC San Diego School of Medicine – one of the few researchers in the USA studying Danon. “We need to find new therapies to address and treat Danon disease.”

Researchers at the University of California San Diego used a murine Danon disease model and demonstrated that gene therapy could be used to treat Danon disease. For their experiments, the researchers used a recombinant adeno-associated virus carrying a functional copy of LAMP2B.


Intravenous injection of the recombinant virus in mice with established Danon disease reversed the disease phenotype by improving cardiac contractile function [3]. The study was led by Dr. Eric Adler and was published in March 2020 in the journal Science Translational Medicine.


Although several lines of evidence from preclinical studies in animal models support the potential use of gene therapy to treat cardiovascular diseases that have a genetic basis, future clinical trials are required to confirm their efficacy in humans.




#gene #therapy #heart #cardiovascular #diseases #cardiology #molecular #medicine

[1] https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.315956

[2] https://discoveries.childrenshospital.org/barth-syndrome-gene-therapy/

[3] https://stm.sciencemag.org/content/12/535/eaax1744?hwshib2=authn%3A1585436532%3A20200327%253A3679c25a-f2bc-4ee8-b51c-1df90ed8036b%3A0%3A0%3A0%3AiaKb%2B7qNqyQMASl36hCnWw%3D%3D


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