Jude Samulski, one of the fathers of gene therapies, argues that rare diseases should be treated for free. “With what we learn from them we will treat the rest of the world from more complex diseases,” he said in an interview with EL PAÍS. Rare diseases affect very few people and are often due to a single genetic mutation. That makes them an ideal target for gene therapies. These types of treatments take advantage of the ability of viruses to hijack the cellular machinery of living beings, modify them and use them as a means of transport to introduce the protein that is missing due to a mutation. During the pandemic, another technique capable of inciting the body to produce molecules with therapeutic capacity was applied on an unprecedented scale. Messenger RNA technology makes it possible to design an RNA in the laboratory with instructions to make a piece of virus, as in Covid vaccines, or a protein that is missing due to a genetic disease.
This Wednesday, an article published in the magazine Nature reports the results of a preliminary trial to treat a rare disease with messenger RNA injections. The disease is propionic acidemia, a condition that affects one in every 100,000 babies, and is caused by mutations in the PCCA and PCBB genes. These defects prevent the body from producing the enzymes necessary to break down food properly and facilitate the accumulation of substances with toxic effects. The first symptoms appear, in many cases, from birth, in the form of vomiting, dehydration or difficulties eating. Gradually, damage to the brain and nervous system, growth retardation, arrhythmias or recurrent pancreatitis appear. At the moment, apart from liver transplantation, there are only palliative treatments and many babies die in the first year of life.
The experimental treatment, named mRNA-3927 and produced by the biotechnology company Moderna, one of the manufacturers of Covid vaccines, is designed to restore the production of missing enzymes by introducing the instructions for their manufacture into the patients' liver. . This study, which is in an early phase, tested the effectiveness and safety of the therapy in 16 people between 1 and 28 years of age. In eight of the patients, the metabolic decompensations caused by the disease were reduced by 70%. Although side effects such as vomiting or diarrhea were observed, the safety of the therapy is not considered to be an issue. However, the authors recognize that the small number of patients treated makes it difficult to assess whether the results are significant.
Gloria González, Director of Innovation and Transfer del Cima at the University of Navarra and specialist in gene therapy for liver diseases, believes that there is “an undeniable medical need” for this type of treatment and that the work presented today in Nature “offers a very promising alternative.” However, the researcher believes that information is missing. “I am interested in knowing what effects this treatment has on parameters that go beyond metabolic decompensation, to see if they gain weight or if they have a better quality of life,” she says. There are other factors that make it difficult to know if the treatment can be useful against the disease. Some patients are past adolescence, which means they have milder versions of the disease and in whom the therapeutic effect may be better than in more severe patients. Furthermore, the authors are looking for a therapeutic dose, which they consider would be the highest. “If the criterion [de valoración clínica] are the decompensation events and in the last cohort [en la que se prueba la dosis más elevada] You do not have any event, it is difficult for you to conclude what the therapeutic dose is,” explains González.
From a practical point of view, the scientist points out that the application of these injections, which should be performed every two weeks throughout life in a hospital, suggests that it would be an expensive and complex treatment, a disadvantage with gene therapies, which They can maintain their effect for years. A treatment for propionic acidemia is of greatest interest in young children, when the effects of the disease that affect their lives can still be avoided. “I would like to see if the patient's symptoms can be reversed, if they have a better quality of life, much more than other parameters. The fact that they do not say anything in the article makes me think that the effects they have seen have not been so dramatic,” González concludes.
Ignacio Pérez de Castro, director of the Gene Therapy Unit of the Rare Disease Research Institute (IIER), in Madrid, values the safety of the therapy presented by the Moderna team, although “it has the drawback that it would be a lifelong treatment.” Although gene therapies with viruses are longer lasting, they have more risks and are not usually given at very early ages, unless there is no alternative. This would make it possible for messenger RNA therapies to be used in combination with longer-lasting ones, to avoid the appearance of damage before a gene therapy can be applied. Pérez de Castro also points out that a therapy like mRNA-3927 is useful for “liver diseases,” but “it is much more difficult than lipid particles.” [que transportan el ARN] reach the muscle or nervous tissue”, something that will make it difficult to expand its use against other rare diseases.
Dwight Koeberl, a pediatrician at Duke University Hospital and co-author of the study, acknowledges that mRNA therapy would have a potential disadvantage “if a gene therapy were available to treat propionic acidemia.” “For now, the only stable treatment available is liver transplant, which is not readily available.” “Giving RNA infusions seems reasonable in the current situation, if the therapy successfully treats propionic acidemia,” he adds. Studies will still be necessary to verify that this condition is met.
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