di Alessia Argirò

Dr. Alessia Argirò works with a research grant from the University of Florence at the UNIT Cardiomyopathies of the AOU Careggi directed by Prof. Iacopo Olivotto

In 2023, with the support of the University of Florence and the AICARM APS association, I spent a period of study focused on new therapies for the treatment of cardiomyopathies at the University of California in San Diego (UCSD), where the first Cardiac gene therapy. But let's take a step back to better understand the topic.

Gene therapy is an innovative approach for the treatment of genetic diseases, and is already used for the treatment of neuromuscular diseases, ophthalmological and hematological diseases caused by a rare genetic mutation (also called "variant") in a single gene.

The objective of gene therapy is to treat the genetic pathology at the root, thus interacting with the genetic code of the cell. The genetic code (DNA) contains all the information necessary for the production of the proteins necessary for the functioning of our organism and its integrity is fundamental for the synthesis of proteins of adequate quality and quantity. Just as in a book an error in the writing of words can alter the meaning of a sentence, so a "variant" in the genetic code can determine the lack of a protein or the production of a malfunctioning protein. Gene therapy therefore consists in providing the cell with the "correct word", therefore a portion of functioning genetic code, so that the cell itself can produce the functioning protein. In order to carry the correct portion of genetic code a specific transporter is needed and the most common method is to use a modified virus. Gene therapy therefore consists of a portion of genetic code enclosed within a virus (adenovirus) harmless to our body, and is administered once in a lifetime with an intravenous infusion.

The first gene therapy for a hereditary heart disease was developed at the University of California San Diego (UCSD): Danon's disease, a disease characterized by the accumulation of glycogen.

La Danon's disease it is due to variants in the gene that codes for a protein necessary for the elimination of cellular waste. In fact, just as it is necessary to get rid of waste during household chores, the cell also needs to eliminate its worn-out components and carries out this process using small vesicles filled with "cellular detergents" called lysosomes. In Danon's disease the protein called LAMP2B, necessary for the maturation of lysosomes, and consequently "cellular waste", in this case the glycogen, accumulate, altering the functionality of the cell. At a cardiac level, the pathology manifests itself in males in different ways, often with a severe form of hypertrophic cardiomyopathy (CMI), which usually requires heart transplant by the age of 20, while in females the manifestations are later.

In the laboratory of Prof. Eric Adler, a type of gene therapy has been developed consisting of the LAMP2B gene contained in a virus capable of entering heart cells.

The product was initially tested in experimental animals: in mice with Danon's disease, in which the production of the missing protein and a prolongation of survival were observed. I would like to underline that the research activity that allowed this important discovery was financed by a patient, after whom the laboratory and the cardiomyopathy center are named (Strauss-Wilson Center for Cardiomyopathy). This approach was then tested in young patients with Danon's disease in a study in which the University of San Diego participated. The results of the study have not yet been published, but some preliminary results have been released which have shown the production of the protein functioning at the cardiac level and a regression of the CMI. The encouraging results of the study have allowed the trial to continue and a further study on male patients with will soon begin in Europe Danon's disease. The only center in Italy invited to participate will be the AOU Meyer and the main investigator will be Prof. Iacopo Olivotto.

In San Diego I had the opportunity to participate in clinical activities relating to gene therapy studies, getting to know the patients already treated in person and observing the drug administration techniques and subsequent monitoring. Furthermore, I was able to participate in the development activities of new gene therapy products for the treatment of other cardiomyopathies. Also in Prof. Adler's laboratory, a drug is being studied for patients with HCM, caused by a variant in the genes that code for the sarcomere, i.e. the "motor" that allows the heart to contract. In particular, the gene under study encodes the troponin I, a protein that acts as the “brake” of the heart muscle. In HCM caused by a variant in the troponin I gene, the protein does not sufficiently "brake" contraction and thus causes reduced relaxation of the heart. The drug, made up of the correct gene for the troponin I enclosed in a virus, will soon be tested on experimental animals.

There are numerous gene therapies in development and in clinical trials on humans suffering from Cardiomyopathy. In fact, gene therapy studies are underway for some types of HCM, in particular the form due to gene mutations MYBPC3, the most common, of  arrhythmogenic cardiomyopathy particularly the gene-dependent form PKP, di Fabry disease, of Friedreich's ataxia ed transthyretin cardiac amyloidosis.

In 'transthyretin cardiac amyloidosis the pathology is due to a progressive accumulation of altered protein (la transthyretin), not inside the heart cells (cardiomyocytes), but between cardiomyocytes, thus leading to an increase in wall thickness and the development of cardiomyopathy, usually in adulthood and advanced age. For this condition, a study is underway that uses a different technique, which consists of "cutting" the gene transthyretin so that the transthyretin is no longer produced. In this case, encouraging results have already been published on the use of this approach and a clinical study is underway at the Intercompany Center for Cardiomyopathies (AOU Meyer and Careggi).

We confidently await the results of clinical studies to evaluate the efficacy and safety of gene therapy, which could completely change the natural history of cardiomyopathies.

I sincerely thank AICARM for the financial support provided, as well as Prof. Cecchi and Olivotto who allowed me to have this exciting experience with the aim of starting to experiment with these new treatment techniques in Italy too.