open access: Future Medicine - Personalized medicine in rare diseases

Personalized medicine in rare diseases

Definition of personalized medicine is not an easy issue [1–3,101]. It is moving from personalized medical practice to the modern concept of personalizing the science of medicine to improve individual healthcare. 

In many aspects personalized medicine refers to the translation of the interaction between the biological individuality of the patient and the environment into clinical medicine and healthcare. By the term personalized medicine we envision a complete integration of clinical (phenotype), genetic, genomic, transcriptomic, proteomic and metabolomic profiles with environmental (including nutritional) information that is provided for a particular person. The major expected consequence is to optimize preventive healthcare strategies and response to drug therapies while people are either healthy or in an early stage of the disease. Personalized medicine tries to move the population-based evidence of medical interventions towards individual evidence of how to treat the specific person based on the biological profile, clinical history and environment. The aim is to offer tailored healthcare to every person. The personalized medicine based on the integration of individual information, from the genome variation, physiology and cellular phenotype to the interaction with the personal environment, may represent a proactive, preventive and prospective model of healthcare [4–6] that is opposite to the more traditional, disease-based, reactive approach to the health status of individuals.

The fundamentals of genomic and personalized medicine and application of new technologies that may define personal biological profiles apply to every type of pathological process, disease or condition, whatever the main organ or tissue is involved in the disorder affecting the person.

Personalized medicine today is addressing a number of elements that are relevant to any kind of disease. Such elements have to be considered when we are thinking in a prospective model of healthcare and generation of predictive markers. They include basic research and technology development (most of them based on ’omic approaches), translational research and characterization of biomarkers, further clinical application of new translational tools, and the social and ethical impact. However, the impact of personalized medicine has not been identical in all clinical areas. Traditionally, personalized medicine has been in practice in oncology and across other disease specialisms involving common diseases (CDs), such as cardiovascular disorders, diabetes and metabolic syndrome, and neurodegenerative diseases. In addition, in recent years rare diseases (RDs) have become an important field of interest for both translational research and the application of personalized medicine approach to individual patients. How personalized medicine may be incorporated in the healthcare of RDs? Are the personalized medicine premises and fundamentals for both RDs and CDs identical? Which are the main differences among RDs and CDs for the individual application of personalized medicine? To address these questions we need to answer some elements of medical thinking by responses that characterize RDs.

Elements for a conceptual framework of RD

By RDs we refer to nonfrequent disorders or conditions with a low prevalence that, in the EU, has been estimated to occur in less than five patients per 10,000 inhabitants. According to that definition, RDs affect 6–8% of Europe’s population, that is, approximately 30 million people in the EU (including all its 27 members) are affected. Despite their low frequency, these diseases show some common characteristics, which allow integrating individuals affected by a RD as a social group that share common health and social problems [7,102,103]. There are important factors to take into account when thinking of a RD: they used to be severe, chronic and progressive disorders with a high degree of incapacity; in spite of the fact that they are not common disorders, RDs are complex pathological conditions; and in most cases, RDs are genetic disorders that express first symptoms at the young age.
The individual patient and also patients as a whole are increasing the responsibility on their own life and their ability to make decisions, with appropriate information and autonomy; in some ways it can be stated that they are personalized decisions. The empowerment that patients have on their own illness, based on their experience and knowledge of life, makes them fundamental for the management of disease and lifestyle according to their needs. No matter how we define the RDs, patients have much to say about them. Some important issues that affect patients and for which they and the lay organizations are demanding attention may be summarized as follows [103]: lack of scientific knowledge regarding their illness, difficulty of access to correct diagnosis, delayed diagnosis, lack of care and multidisciplinary care, lack of quality information and support at the time of diagnosis, adverse social consequences, difficulty and lack of equity in access to treatment, rehabilitation and care, loss of confidence in medical and social services, and a lack of interest from health professionals.
As mentioned above, RDs are a broad and heterogeneous group of severe and disabling disorders, involving a small number of individuals in specific populations. The disease course used to be chronic with high morbidity and mortality, and therapies are still scarce. However, there are CDs showing a chronic and disabling natural history, with high morbidity and mortality rate, and limited therapeutic arsenal. Thus, what does make the difference among RDs and common chronic diseases? In the following paragraphs, I propose several elements that could help to create a single framework of the aspects that characterize RDs [8,104]. These elements are important when applying personalized medicine concepts and technologies to a person affected by a RD.

▪ Public health component

Each RD has a low prevalence; however, the involvement of roughly 30 million people with shared health problems in a population such as the EU, requires a scientific approach based on public health criteria and premises. This is what has been called the paradox of rarity.

▪ Natural history: diversity & heterogeneity

RDs represent a wide number of disorders so that clinical and biological diversity can be considered as an intrinsic feature of such conditions. The nature of diseases ranges from diseases that affect a single organ system up to illnesses that are multisystemic. The heterogeneity of these diseases is manifested in different profiles of natural history, including the age at onset, which determines the clinical intervention and preventive health services.

▪ Multidisciplinary & comprehensive healthcare

A RD is often chronic and disabling. In many cases, patients with these diseases need care that goes beyond the specific clinical care offered by a unique specialized service. This care should be considered in the context of overall management, with comprehensive medical and psychological care.

▪ Social & health integrative care

Many RDs involve a high degree of dependency and social, health and economic burden. This is not something particular to RDs, but there are other aspects that are specific to them and give them a certain degree of particularity. As previously mentioned, one of these specificities is the age at onset of the disease. Most RDs express first symptoms early in the life of patients varying from birth to young adult. Thus, in many cases patients require health and social care for a very long period of their lives.

▪ Genetic inheritance

A total of 80% of RDs are estimated to be due to genetic factors, mostly monogenic, and follow the laws of Mendelian inheritance (also mitochondrial inheritance). Knowledge regarding the genetic causes – mutations – and the underlying pathomechanisms are very important to address further research and translation into clinical medicine of these diseases.

▪ Risk of recurrence

Risk of recurrence of a genetic disease in families makes genetic counseling a support and therapeutic tool for these patients and their families, which is fundamental for planning reproductive decisions, prenatal diagnosis or preimplantational genetic diagnosis.

▪ Geographic dispersion

Except in cases of adverse toxicological, infectious agents or other environmental causative factors that may affect a specific population, disease used to be present in any population. This is especially true for chronic disorders either common or rare. However, the association of both random distribution and low prevalence observed for RDs is a phenomenon intrinsic to these disorders. This circumstance induces the isolation of the patient and the family with no contact with other affected people. Initially, after diagnosis, patients or parents may feel that they are alone as they never have heard of that disease. Even when they know about other patients, it is very frequent that no other patients are living close to them.

▪ Treatment opportunities & development of therapies

Therapeutic options in RDs are generally scarce and ineffective. However, the development of new therapies and drugs for these diseases aimed at specific molecular targets of RDs may be useful for not only themselves, but also for CDs that may share such biological targets or pathophysiogical pathways.............cont'd