Genetics, science’s great hope in the fight against rare diseases

On the occasion of International Rare Disease Day and in light of the historic UN resolution urging member countries to develop comprehensive plans for the treatment of these diseases, LifeScientist talks to leading experts in the field to address the prospects for treatment that are opening up with the development of genetics and technologies such as CRISPR or messenger RNA, as well as the strengthening of research networks and new paradigms that promote a cross-cutting approach to tackling these diseases.

In the European Union, a disease can be officially classified as rare when it affects a maximum of five out of every 10,000 people, which is the only requirement to include diseases that are not necessarily related to each other under the same label. With this fact on the table, one could conclude that rare diseases are but a minor health problem. But in this case, “rare” is not synonymous with scarce. Although individually they affect small segments of the population, the larger list of all rare diseases discovered to date numbers in the order of 5,000 to 7,000, multiplying their rate of incidence to between 6% and 8% of the population in Europe, while at the same time having both extremely complicated and expensive research and treatments.

In addition to the usual difficulties posed by these chronic and incapacitating diseases, more complications have emerged with the outbreak of COVID-10 pandemic. The shock of COVID-19 has caused a huge disruption to healthcare systems worldwide, negatively affecting some 300 million rare disease patients who have seen their healthcare options limited or postponed due to the collapse of healthcare facilities, and the additional vulnerabilities that their conditions may confer on them in the face of SARS-CoV-2.

But the pandemic has also brought some much needed discussion topics to the forefront. In the wake of the viral scourge of the past two years, healthcare, in all its various guises, has once again become the focus of public debate. Moreover, rare diseases, which have been relatively neglected during these pandemic times, have once again come to the forefront of the political and institutional landscape, especially after the historic UN declaration of 16th December, 2021, which urges member countries to strengthen their health systems and to promote comprehensive strategies to improve the lives of people affected by these diseases.

God’s scissors: CRISPR and its opportunities for rare diseases

The fight against the pandemic has been accompanied by a strong push for research and science, which has resulted in an uncontested victory with the facilitated development of messenger RNA vaccines. This new technology, which would have been impossible without prior research and development work dating back long before the pandemic, has already proven useful in the treatment of rare diseases such as amyloidosis. On the other hand, CRISPR gene editing tools, which have played a key role in the development of messenger RNA-based therapies, constitutes one of science’s main hopes for the treatment of rare diseases. “It is God’s scissors, something incredible. What used to take months of work before can now be done in hours,” says Joaquín Paloma, coordinator of the Rare Diseases Plan in the Spanish region of Murcia, one of the communities at the forefront of rare disease treatment in the country.

The main common denominator of these rare diseases, in addition to their infrequency, is the involvement of a genetic component that is present in nearly two thirds of them. That is why doctors and researchers do not hide their enthusiasm at the possibility of using CRISPR to directly operate on the genes that cause them, although that clinical future is still a long ways off. “It seems that it will have an important impact in the near future in the clinic, but not at present, as there are still many parameters that are not fully controlled (…) that prevent the safe and effective use of CRISPR technology in in-vivo gene therapies,” says scientist Lluis Montoliu, a member of the National Centre for Biotechnology (CNB) of the CSIC.

But CRISPR tools are just the tip of the iceberg of the medical gene technology revolution that has been operating in recent years with promising applications for rare diseases. “The first gene therapies are showing promising results, mainly in monogenic diseases for now, with some drugs already approved and many others currently in clinical trials,” Beatriz Gómez, Scientific Activity Manager at the Centre for Biomedical Research Network on Rare Diseases (CIBERER), explains to LifeScientist.

While the clinical applications of genetics are promising, where genetics has undoubtedly demonstrated its usefulness has been in the realm of disease detection. In most cases, early diagnosis can ostensibly improve the prospects of rare disease patients’ quality of life and treatment. “Genetics has made it possible to identify many rare diseases by being able to associate them to a specific gene. Whenever there is suspicion, genetic sequencing is performed and that gene is tested. This greatly shortens the diagnostic time,” adds Paloma.

Therefore, although advances in genetic sequencing have already opened the door to a much faster and more efficient diagnosis, it is striking that today in Spain it takes an average of four years for a person with a rare disease to obtain a diagnosis. This “diagnostic odyssey” complicates the patients’ quality of life according to experts, who, in line with the International Rare Diseases Research Consortium (IRDiRC), aim to reduce the average diagnosis time down to one year.

To achieve this, most agree that one of the “unresolved issues” is the creation of a speciality in Human Genetics, which Spain lacks. “Spain is the only country in Europe and the developed world that does not have one, and this is a key issue. It is necessary for people to have easy access to diagnoses by fully qualified professionals in appropriate centres (…) that is why it is urgent for the speciality to be recognised and for patients to have access to genetic diagnosis; not only for the affected person but also for people at risk in their environment in order for family diagnoses to be made”, demands Dr. Encarga Guillén, president of the Spanish Association of Human Genetics.

Research networks, a model of success

In the fight against these elusive diseases, which can affect barely a dozen people across Spain, it is essential to have a structured research network at the national level that allows for information and projects to be pooled. This is the idea behind the Carlos III Institute’s Centre for Networked Biomedical Research on Rare Diseases (CIBERER), which for years has been coordinating research efforts and ensuring that it “reaches the patient and provides scientific answers to the questions arising from the interaction between doctors and patients”, in the words of Beatriz Gómez. One of the CIBERER‘s latest projects, IMPaCT-GENóMICA, seeks to respond to the shortcomings in diagnosis by promoting equal access throughout Spain to new generation genome sequencing techniques.

At the European level, a clear example of success in this regard is the European Reference Networks (ERNs): a total of 24 virtual networks connecting reference centres across Europe. “They aim to address complex or rare diseases and conditions, which require highly specialised treatment and concentrated knowledge and resources. The 24 ERNs, launched in 2017, enable a joint approach to healthcare for people with rare diseases that bring together healthcare providers from across Europe to address these complex or rare conditions that require highly specialised treatment,” explains Beatriz Gómez.

Another tool that experts consider indispensable for the identification of rare diseases is the generalisation of genetic newborn screening. A diagnosis immediately after birth can mean the difference between life and death for newborn patients with diseases such as cystic fibrosis, a condition that floods the airways with thick mucus that impedes breathing. Fibrosis, in its most virulent form, was once a death sentence for newborns if a lung transplant was not performed, but today, such a procedure is not necessary if the disease is detected early enough along.

In the opinion of many experts, all of the above demands should be gathered and structured through a Spanish National Plan for Genomic Medicine, which has been called for in the sector for some years now. “This plan, already implemented in other countries, would be fundamental to improve care, diagnosis and the search for therapies for rare diseases,” says Dr. Gómez.

In addition to the shortcomings of developing gene therapies for rare diseases, rare diseases also face other obstacles such as high difficulty in developing and approving both diseases-specific and relatively affordable drugs; these being the so-called ‘orphan drugs’. “Right now there are 126 authorised orphan drugs, of which there are 107 in Spain, but only 51 have received approval for funding. It is necessary to shorten the deadlines to have an effective treatment, we are talking about chronic and debilitating diseases, many of which occur in the paediatric age,” says Juan Paloma.

The President of the Spanish Federation for Rare Diseases, Juan Carrión, is of the same opinion and warns that the slow process of approval and marketing of medicines is pushing families to desperate resources such as “compassionate use”, which consists of early access to medicines in the research phase; or to try their luck with “off-label” medicines or medicines outside of authorised conditions. “We are concerned that these avenues of access either supplement or complement the 60% of orphan drugs that have not yet been authorised for use in our country,” he explains.

A cross-cutting strategy for rare diseases

Experts also agree on the need to approach these diseases from other fields beyond health, as their impact also has an economic and social dimension. For example, problems such as discrimination, child bullying, and the psychological impact that rare diseases have on both patients and their families of loved ones. “The emotional burden of a rare disease can be quite strong and involve the whole family. In the case of genetic diseases, several family members may be affected, so its impact extends beyond the nuclear family, not to mention its impact on education and work,” says Paloma.

The UN declaration of 16 December last year is precisely along these lines, that of a cross-cutting approach to the problem, not just a medical one. This new approach, in conjunction with technological innovations such as CRISPR, artificial intelligence, big data, and the strengthening of research and diagnostic networks, creates a window of opportunity that must be seized to achieve a better future for people suffering from a rare disease.

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