For the first time ever, researchers at the SJD Barcelona Children's Hospital use gene therapy on a child under the age of four with a neuromuscular disease

Researchers from the Neuromuscular Diseases Department at the SJD Barcelona Children's Hospital have, for the first time ever, used gene therapy on a child under the age of four with Duchenne muscular dystrophy, as part of an international clinical trial. The trial is currently active and open to these patients, with six different hospitals from around the world already involved.

The team in the Clinical Research Unit at the SJD Barcelona Children's Hospital, led by Andrés Nascimento, has been the first in the world to include a patient under the age of four in the trial for this type of genetic treatment. The hope is that—thanks to the Hospital's status as a leading reference centre and the first facility to activate the study—more children under the age of four will have the opportunity to access this type of treatment.

Duchenne muscular dystrophy is an uncommon genetic condition within the category known as rare diseases. It is linked to the X chromosome and causes progressive muscle weakness. Children are diagnosed with this disease in their first years of life, with their muscles progressively weakening over time. Around three or four years old is when this disease begins to have a more obvious impact, with children eventually losing their ability to walk at around 12 or 14 years old. At present, there is no existing treatment that offers a cure or a way to improve symptoms of the disease. As such, it is very difficult to fight. The only therapies that exist are those which seek to delay the disease's progression, though they are still unable to completely stabilise symptoms.

Gene therapy, when it is applied as early as possible, is the most promising therapeutic option to combat this genetic muscular deterioration disease. Until now, only patients over the age of four had been treated, with very positive results. This led to the U.S. Food and Drug Administration approving this treatment for use on four- or five-year-old patients. An important aspect of this disease is that it is progressive. The more time that passes, the more muscle tissue is lost and replaced with fat and fibrosis. That is why it is important to provide treatment before muscle damage becomes irreversible.

‘Our team has been the first to include a child this young in this new clinical trial—known as Envol—in the hope that other hospital facilities follow suit. We are already studying other families to continue treating children using this gene therapy’, explains Andrés Nascimento, Head of the Neuromuscular Diseases Unit at the SJD Barcelona Children's Hospital, and member of the Applied Research Group in Neuromuscular Diseases at the SJD Research Institute (IRSJD).

Nascimento adds that ‘the treatment was given several weeks ago and the patient has remained stable, with no side-effects. We hope to be able to confirm positive results as time goes on. We have high hopes, as this gene therapy is being applied to healthier muscle tissue that has not started to significantly deteriorate yet’.

The first gene therapy application against Duchenne muscular dystrophy

The application of gene therapy is a significant step forward for pediatric patients with Duchenne muscular dystrophy. One of the challenges of this therapy is the size of the dystrophin gene, which is very large and cannot be introduced through normal adeno-associated viral vectors (modified adenovirus), which would carry the new gene to existing cells to incorporate it into them.

A few years ago, a group of patients were identified who had reached an advanced adult age, experienced muscle pain, had higher muscle enzymes, certain mobility issues and motor difficulties, but who were still able to walk. These individuals had alterations in their dystrophin gene, resulting in smaller but functional version of the protein, known as microdystrophins. This finding suggested that the presence of microdystrophin—albeit in a lesser quantity or size—could provide some level of protection against severe symptoms of Duchenne muscular dystrophy. Based on these findings, scientists began to explore the possibilities of using microdystrophin as a therapeutic option for patients with the disease.

From there, all the preclinical trials took off, with Sarepta—the laboratory behind this gene therapy—launching phases one and two, which showed that the therapy was safe and effective. This allowed for the development and eventual launch of phase three of the trial (Embark) for patients aged four to eight. In the clinical trial, the adeno-associated virus (vector), with the ability to inject new genetic material into muscle cells, does so with microdystrophin. The first children in this age group to be treated tolerated the treatment well, seeing significant improvements to their motor function.

Gene therapy is more effective when applied early

This same group of specialists took part in phase three of the Embark study, managing to recruit 12 patients aged four to eight. These data will be reviewed by the European Medicines Agency (EMA) in the hope that the therapy will be approved. A few weeks ago, the Envol clinical trial began for children under the age of four. The trial hopes to recruit an initial cohort of ten patients between age three and just under four, as per safety results for this group. Even younger patients will be allowed to take part at a later stage, such as those aged two to three, or even months’ old children—who, in fact, have not even been born yet—in order to determine the safety and efficacy of early treatment.

Six hospitals are taking part in this international trial, from the United Kingdom, Italy, the Netherlands, France, Belgium and Spain. The SJD Barcelona Children's Hospital has treated the first patient, and judging by the number of patients and families on the waiting list, we are confident that we will be able to recruit around four more participants. Once again, just like with the Embark study, our facility will offer the most patients to the study.

‘Our aim is to always try to offer every treatment option to our patients. However, not everyone is a candidate. There are several very specific clinical and genetic criteria that must be met. One of the most significant limiting factors in receiving this treatment is that patients must not have any antibodies against the vector (modified adenovirus) used to administer the dystrophin microgene’, highlights Andrés Nascimento.

A pioneering unit in neuromuscular disease

The Neuromuscular Diseases Unit at the SJD Barcelona Children's Hospital is made up of a multidisciplinary team with experience in the diagnosis of, treatment of and research into various diseases under the neuromuscular disorders group (NMD).

It is a pioneering unit in the treatment of patients with Duchenne muscular dystrophy and spinal muscular atrophy, among other disorders. It attends to 800 patients with NMD every year. The Unit works closely with healthcare entities and centres all over the world, and is developing an ambitious research and education programme focusing on patient and family healthcare provision. It has been working in close collaboration with the Clinical Research Unit for over 15 years.

Among the Unit's many accreditations, its membership of the European Reference Network for Neuromuscular Diseases (EURO NMD) stands out, not to mention its CSUR accreditation as a reference centre within the Neurology Department from the Spanish Ministry of Health. Within the context of Catalonia, the Unit is part of the Network of Units of Clinical Expertise (XUEC) for Care of Neuromuscular Diseases.

SJD and its commitment to pediatric clinical trials

The SJD Barcelona Children's Hospital is a reference centre in Spain for its work in the field of pediatric clinical research. Currently, the hospital provides support to 235 trials across 21 different therapeutic areas. Among these areas is the Neurology Department, in which several important investigations are being carried out to develop new treatments, such as advanced gene and cellular therapies. A significant portion of these trials—almost 70%—is focused on finding new, alternative treatments for rare diseases, many of which currently have no curative treatment method, such as Duchenne muscular dystrophy.

The high specialisation of the facility and its staff, as well as the possibility of offering new treatments that are currently in their research and investigation phase, means that the Hospital receives a high number of patient referrals—not just from within Spain, but from all over the world—to take part in these clinical trials.