A change to only one of the many thousands of genes that make up the human genome can result in serious health disorders in humans. Although cancer is probably the most well-known disease caused by a genetic mutation there are many others, most of which are relatively unknown as they affect only a small number of people.
These are the so-called rare diseases, conditions that are generally hereditary and for which genetic studies and gene therapy have often been shown to be the most effective diagnostic and treatment strategies. And all this has been explained by the experts participating in the scientific seminar organised by the Biomedical Research Institute (IBI) within the framework of the BIOCAPS programme.
The five speakers who presented important breakthroughs in the treatment of the most common rare diseases at the Colegio Médico de Vigo offered complementary views of the epidemiological, genetic, clinical and therapeutic aspects of such diseases.
Diana Valverde, an IBI researcher, explained the importance of genetic studies in the early diagnosis and identification of future therapeutic targets for ciliopathies. Several months ago, and as a result of the BIOCAPS project, Valverde was able to make progress in this line of research in collaboration with scientists from the Medical Research Council Laboratory of Molecular Biology in Cambridge.
Ciliopathies are disorders that arise due to anomalies in the cilia, organelles in cells responsible for emitting and receiving stimuli as a result of a signal-transport system, in other words they are responsible for vital communication with surrounding cells. Functional defects in cilia can result in a wide range of problems such as obesity, retinal dystrophy, diabetes or heart disease, which combine in syndromes such as Bardet–Biedl syndrome, polycystic kidney disease or nephronophthisis, amongst others.
As explained by the IBI researcher, the use of high-performance technologies now allows new genes that play a role in these syndromes to be identified. “Genetic studies allow us to establish the cause of the disease in the patient, which in turn allows us to identify the most prevalent mutations in our population and therefore to develop diagnostic logarithms to optimise studies in other families”, she notes. Moreover, analysis of the role of the proteins concerned helps us to understand the molecular mechanisms responsible for the appearance of characteristics such as obesity or diabetes. In addition, and as highlighted by Dr. Valverde, an understanding of the cell signalling pathways involved in these diseases will help us to understand the pathophysiological basis of the disease and to identify therapeutic targets for future treatments.
Martine Barkats, who works at another of the BIOCAPS advisory centres, namely the Institute of Myology in Paris, explained recent progress in gene therapy, which is helping in the design of treatments for spinal muscular atrophy (SMA), a condition that progressively destroys lower motor neurons, in other words the nerve cells in the brain stem and spinal cord that control essential voluntary muscle activity, such as speech, walking, breathing and swallowing.
SMA is caused by defects in the gene SMN1, which manufactures a protein that is important for the survival of motor neurons. Barkats and her group have identified a virus that acts as an efficient carrier for the gene that can reach the spinal cord via the bloodstream and modify the defective genetic material. Trials in mice and cats have demonstrated the efficacy of this gene therapy for correcting motor function and preventing neuronal death.
A clinical trial based on intravenous administration of the virus carrying “good” genes is currently being conducted at the Nationwide Children’s Hospital in Columbus (Ohio, USA). “Although the results of this trial are confidential and will not be released until August, I can confirm that they are highly promising”, noted Barkats.
The researcher Daniel Bachiller, from the Fundación Caubet-Cimera (Balearic Islands), dedicated his talk to the advantages provided by gene editing in the treatment of cystic fibrosis, a hereditary disease that attacks some of the regions of the body that produce secretions, especially the digestive system and lungs. This disease affects one out of every 3000 newborns, is the most common rare disease and in the European population, where its incidence is highest, a single mutation is responsible for more than 60% of all cases.
Gene editing allows the genetic defect that causes cystic fibrosis to be corrected and involves producing a type of stem cell known as an induced pluripotent stem cell, which can be “manufactured” at will from any person's skin. The genetic defect is repaired in these stem cells to obtain cells that no longer carry the disease and which, as they are from the patient, can be re-transplanted without causing rejection. This research is currently being tested in mice before commencing clinical trials in patients.
In order to be able to conduct such research it is essential to collect data and samples from patients affected by rare diseases, which are deposited in banks and registries. Manuel Posada, the Head of the Rare Diseases Research Institute at the Instituto de Salud Carlos III, explained to what extent this is relevant and called for more resources to be dedicated to such tasks. “Collecting information costs as much as investigating a drug, or even more”, he noted.
Such information allows the natural history of a disease to be understood and means that prevention protocols which use data that allow the risk of one person or another to be evaluated to be designed. Similarly, the recording of signs and symptoms helps with diagnosis and laboratory findings that indicate good or poor evolution help with prognosis. In addition, it is essential to record the variables that indicate whether a treatment is effective or not in order to continue with or change therapeutic strategies. “One good example of this is Duchenne muscular dystrophy, a very serious neuromuscular condition affecting children which has an international network known as TREAT-NMD. This network has recently published evidence for a treatment on the basis of a registry of 7000 cases worldwide and the study of their evolution over time”, explained Posada.