Trial tests Covid vaccine technology against a rare disease that affects babies

R. Jude Samulski, one of the fathers of gene therapy, argues that rare diseases should be treated free of charge: “With what we learn from them, we can treat the rest of the world for more complex diseases,” he said in an interview with EL PAÍS. Rare diseases affect very few people and are often caused due to a single genetic mutation. This makes them an ideal target for gene therapies. This type of treatment takes advantage of the ability of viruses to hijack the cellular machinery of living beings, modifying them and using 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 organism 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 for making a piece of virus — as in Covid vaccines — or a protein that is missing because of a genetic disease.

On Wednesday, a paper published in the journal Nature laid out the results of a preliminary trial to treat a rare disease with injections of messenger RNA. The targeted disease is propionic acidaemia, an ailment that affects one in 100,000 babies, and which is caused by mutations in the PCCA and PCBB genes. These defects prevent the body from producing the enzymes needed 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 eating difficulties. Gradually, damage to the brain and the nervous system, growth retardation, arrhythmias or recurrent pancreatitis appear. For the time being, apart from liver transplantation, there are only palliative treatments and many affected babies die within their first year of life.

The experimental treatment, called mRNA-3927 and produced by the biotechnology company Moderna, one of the manufacturers of the Covid vaccines, is designed to restore the production of the absent enzymes by introducing the instructions for their manufacture into the liver of the patients. This early-stage study tested the efficacy and safety of the therapy in 16 people between the ages of one and 28. 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 a problem. However, the authors acknowledge that the small number of patients treated makes it difficult to assess whether the results are significant.

Gloria González, Director of Innovation and Transfer at the Center for Applied Medical Research at the University of Navarre and a specialist in gene therapy for liver diseases, considers that there is “an undeniable medical need” for this type of treatment and that the work presented in Nature “offers a very promising alternative.” However, the researcher believes that there is a lack of information. “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 assess if the treatment can be useful in combating the disease. Some patients are past adolescence, which means they have milder versions of the disease and the therapeutic effect may be pronounced in them than in patients with more severe symptoms. Additionally, the authors of the research are looking for a therapeutic dose, which they believe would be the highest. “If the [clinical endpoint] is decompensation events and in the last cohort [in which the highest dose is tested] you don’t have any events, it’s difficult for you to conclude what the therapeutic dose is,” explains Gonzalez.

From a practical point of view, González points out that the application of these injections — which would have to be performed every two weeks throughout a patient’s life in a hospital — suggests that it would be an expensive and complex treatment, a disadvantage compared to gene therapies, the effects of which can last for years. A treatment for propionic acidaemia is of most interest in young children, when the life-long effects of the disease can still be avoided. “I would like to see if the patient’s clinical condition can be reversed — if they have a better quality of life — much more than other parameters. The fact that they don’t mention anything in the article leads me to think that the effects they have seen have not been so dramatic,” Gonzalez concludes.

Ignacio Pérez de Castro, director of the Gene Therapy Unit at the Institute for Rare Diseases Research in Madrid, values the safety of the therapy presented by the Moderna team, although “it carries the disadvantage that it would be a lifelong treatment.” Although gene therapies with viruses are more durable, they present more risks and are not usually administered at very young ages unless there is no alternative. This would make it possible that messenger RNA therapies could be used in combination with other more durable therapies, to avoid the appearance of damage before a gene therapy can be applied. Pérez de Castro also points out that a therapy such as mRNA-3927 is useful for “liver diseases,” but “it is much more difficult for the lipid particles [that carry the RNA] to reach muscle or nerve tissue,” something that will make it difficult to extend its use to 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 downside “if there were a gene therapy available that treated propionic acidaemia. For now, the only stable treatment available is liver transplantation, which is not readily available. Giving RNA infusions seems reasonable in the current situation, if the therapy successfully treats propionic acidaemia,” he adds. Studies will still be necessary to verify that this condition is met.

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