On June the 29th and 30th, a workshop was held at Vall d'Hebron on the use of gene therapies to treat rare neurological disorders. These treatments are promising to be disruptive and offer improvements and solutions that until recently were unthinkable for patients. More than 50 gene therapies are expected to be available in the next 10 years, but as with any new technology, there are uncertainties and challenges that must first be overcome. The aim of the organisers of this conference was to bring together the latest research and all the perspectives of the stakeholders involved to create a robust training programme for clinicians, researchers and other stakeholders.

The initiative has been a collaboration of the Vall d'Hebron Campus, the European Coordinated Programme on Rare Diseases (EJP-RD) and the European Reference Network on Neurological Minority Disorders (ERN-RND). Together, they have designed an exclusive programme with experts from all over the world, which both in-person and online trainees have been able to take advantage of. The training was divided into two days: the first focused on basic research and the second on the clinical implementation of new therapies.

The importance of vectors for safer and cheaper therapies

The first panel discussed vectors, or DNA molecules used as a vehicle to introduce genetic material into a cell. An overview was given on all those available and the most promising initiatives to discover or create new ones. Currently, most are virus-based (lentiviruses, adenoviruses and adeno-associated viruses), but there are also non-viral ones (nanoparticles, virus-like particles, etc.) The choice of the appropriate vector in each case is key to the success of the therapy.

Another point that was emphasised is the long-term effectiveness of these therapies. In ex-vivo strategies with integrative vectors such as lentiviruses, they are expected to last a lifetime. In contrast, in vivo cases with non-integrative vectors will depend on the type of organ treated (muscle, liver, central nervous system, etc.).

Finally, the main objectives of research in this area have been outlined: reducing the toxicity of viral vectors, improving non-viral systems and innovative technologies such as gene editing. The ultimate goal is, as Dr. Jordi Barquinero, head of the Gene and Cell Therapy group at Vall d'Hebron Institute of Research (VHIR) comments: "To make therapies more specific, safer and cheaper so that they can reach more patients, especially in less developed countries".

The second discussion panel presented complementary gene techniques that are used when gene replacement is not sufficient to achieve the required effect. A comprehensive review of all of them was given. Of particular note were 'gene editing' and 'antisense oligonucleotides', which can be used to treat many disorders, although the latter is still in search of an effective method to use. Other techniques are more specific to particular genetic problems, 'gene silencing' is intended for diseases caused by the accumulation of metabolites or proteins and 'artificial transcription factors' for cases where there is a haploinsufficiency of a gene. The latter techniques are designed for a specific pathology: 'gene addition' and 'gene expression regulation with specific promoters' to treat epilepsy, 'gene complementation' for deafness and 'miniproteins' for Duchenne muscular dystrophy and other similar pathologies.

A technique with a multidisciplinary use that requires a transversal effort to advance it.

The second day focused on the transfer of this technology to a clinical application. At the first panel, doctors who have used the therapy in a clinical context explained their experiences and difficulties, focusing mainly on improving the safety and efficacy of the treatments.

Key players in the therapy were then invited to share their perspective. Two members of the European Medicines Agency on behalf of the regulatory bodies, an official from CatSalut on behalf of the funding organisations, employees from Roche and Pfizer to express the point of view of the pharmaceutical industry, and finally, a patient, a member of the Duchenne Relative Project, intervened. All emphasised the need to take into account all perspectives for safe and reliable therapies.

Besides actors outside of research, gene therapy is a technique with a multidisciplinary application and therefore also involves a heterogeneity of researchers. After lunch, several scientists talked about how they can use it in their respective areas, be it neurology, hepatology or to treat a specific pathology such as haemolyticourèmica syndrome. As the training was specialised in rare neurological disorders, the importance of these disorders for the early detection and treatment of severe hereditary neurological diseases with no chance of cure was highlighted.

To explain a real case, the treatments for Spinal Muscular Atrophy (SMA) that are already being used clinically were explained, specifically gene therapy for SMA type I; and with antisense oligonucleotides and small molecules in all types of SMA with the possibility of response. On the other hand, there are clinical trials with gene therapy for Duchenne Muscular Dystrophy and other Limb-girdle Muscular Dystrophies that are expected to demonstrate efficacy and safety and move into real life.

Training for researchers, healthcare professionals and donors

The two days provided the trainees with a comprehensive overview of the latest innovations in gene therapy and their potential applications in the field of rare neurological disorders. In addition to researchers and healthcare professionals, several members of charitable associations that raise funds for research, such as the Aefat association on Ataxia Telangiectasia, participated in the training. Thanks to the knowledge gained in the training, they will be able to choose the research with the greatest potential to invest the money collected.