Progress, challenges and global approaches to rare diseases.

Rare diseases occur globally at every stage of life. Patients, families and caregivers have many unmet medical and social needs leading to extraordinary psychosocial and economic burdens. Efforts to improve diagnostic capabilities and to develop therapies for an estimated 7000 rare diseases have met with considerable success. In the United States, a rare disease or condition is one affecting fewer than 200,000 people. In the European Union (EU), a rare disease is any disease affecting fewer than 5 people in 10,000 (less than 1 in 2000 people). However, there are no effective treatments for 90 per cent of rare diseases. There is a need to expand awareness, advocacy and outreach to everyone including those with low incomes, poor literacy, minority ethnic status and living in underserved and marginalised populations in urban and rural areas as well as in developing nations throughout the world. The acceptance of patients as research partners complements the increased research emphasis and major regulatory initiatives leading to expedited review and approval programmes for products for serious or life-threatening conditions. The pipeline of new therapies provides hope to untreated patients. Advances in medical bioinformatics, artificial intelligence and machine learning with access to big data continue to identify novel therapeutics for screening and evaluation. Advanced analytics can identify the patterns of disease occurrence, predict disease progression, identify patient response to treatments, establish optimal care guidelines and generate research hypotheses with the narrowly identified research patient populations.

International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

Rare Diseases: Joining Mainstream Research and Treatment Based on Reliable Epidemiological Data.

Despite growing acceptance of patient registries and natural history studies to provide useful information, the rare disease community suffers from the absence of reliable epidemiological data on the prevalence and incidence of most rare diseases in national and global populations. Likewise, the patients and health care providers lack adequate information on the pathophysiology of rare diseases and expected outcomes of these disorders. The rare diseases community includes all of the stakeholders involved in the research and development and dissemination of products and information for the diagnosis, prevention or treatment of rare diseases or conditions. To replace many of the perceptions with realities, several global efforts have been implemented to sustain and increase the reported progress with the thousands of rare diseases. The first efforts is to develop a global research infrastructure of qualified investigators to stimulate and coordinate research efforts by seeking ways to provide access to clinical trials at multi-national research sites with common protocols and multi-disciplinary research teams. Next, is the continued identification and expansion of worldwide partnerships and collaborations of Patient Advocacy Groups (PAGs), research investigators, the biopharmaceutical and medical devices industries, and the government research and regulatory agencies for a specific rare disease or group of related diseases. Gaining access to information about rare diseases, patient advocacy groups, ongoing and planned research studies and products in research protocols continue to improve the lives of patients and their families. Many basic, clinical and translational research investigators, public and private sector funding organizations, patient advocacy groups, foundations, and the pharmaceutical, biotechnology, and medical devices industries are committed to translating research discoveries that will be useful in the treatment and care of patients with rare diseases over their lifespan. Evidence from well-constructed epidemiological studies will provide the evidence that point to the value of additional clinical studies to increase the understanding of rare diseases.

A Global Approach to Rare Diseases Research and Orphan Products Development: The International Rare Diseases Research Consortium (IRDiRC).

Rare diseases present unique challenges to researchers due to the global distribution of patients, complexity and low prevalence of each disease, and limited availability of data. They are also overwhelming and costly for patients, their families, communities, and society. As such, global integration of rare diseases research is necessary to accelerate the understanding, diagnosis, and treatment of rare disorders. The International Rare Diseases Research Consortium (IRDiRC) was born out of that need for a coordinated international community. IRDiRC was launched in 2011 to facilitate cooperation and collaboration on a global scale among the many stakeholders active in rare diseases research to stimulate better coordination, and thereby maximize output of rare diseases research efforts around the world. Members include funders, academic researchers, companies, and patient advocacy organizations all of whom share the common goals and principles of IRDiRC. The overarching objectives of the Consortium are to contribute to the development of 200 new therapies and a means to diagnose most rare diseases, by 2020. As IRDiRC approaches the end of its fifth year, these initial objectives have been largely achieved and new partners from across the globe are joining. This presents the Consortium with the exciting opportunity to set new and even more ambitious goals for the next phase with the ultimate goal of improved health through faster and better diagnostic capabilities and novel therapies for people living with rare diseases and conditions throughout the world.

Preparing for the Future of Rare Diseases.

Members of the rare disease community have devoted significant financial and personnel resources to address the numerous issues surrounding rare diseases. The past has been devoted to developing an emphasis on rare diseases including an emphasis on research studies or locating information on rare diseases and the requirements and limitations of conducting clinical trials with small patient populations. The expanded role of patient advocacy organizations and patient engagement in all aspects of clinical research continues to gain acceptance within the research community. The future will require a greater understanding and interpretation of available information from multiple sources including electronic health records and big data sources. The pipeline of potential orphan products continues to grow significantly and holds great promise for novel interventions due to advances in clinical trial design and data analyses. Expanding diagnostic procedures with improved sequencing methods will speed up the diagnosis or rare diseases. Accepting agreed upon nomenclature and codification of rare diseases will assist in differentiating diseases and identifying selected sub-populations of rare diseases. Improvements in patient recruitment and increased flexibility in the product review and approval procedures by regulatory agencies will facilitate product approvals. Children particularly will need help and assistance dealing with feelings of isolation from their peers due to their rare disease. During the transition from childhood to adolescence to adult, difficulties of fitting in with peers and not wanting to be different are a major concern. In response to increasing costs of treatments, Value-Based Care is gaining greater acceptance by the reimbursement and the payer community as a basis for payment for interventions. Mobile Health (M-health) Technologies have the potential to revolutionize how clinical research is conducted in the future. Wearable devices, remote sensors, and the development of mobile device applications (apps) will all assist in constant monitoring of patients for safety and efficacy of approved and investigational compounds. Tele Health and Tele Medicine may provide the necessary access to expert clinicians with a better understanding of individual rare diseases. The future promises great advances and even greater personalized treatments with the introduction of novel treatments and approaches to care.

Undiagnosed Diseases: Italy-US Collaboration and International Efforts to Tackle Rare and Common Diseases Lacking a Diagnosis.

Rare diseases (RD), according to European Union criteria, affect 5 per 10,000 persons, or 30 million people, in the EU; in the USA, RD are defined as conditions that affect fewer than 200,000 individuals in the population (320 million). Most known rare disorders are severe and chronic, with many being degenerative and life threatening. There are roughly 5000-8000 rare diseases (European Commission, DG Health and Food Safety, Public Health, Rare Diseases, Policy.http://ec.europa.eu/health/rare_diseases/policy/index_en.htm. Accessed 19 December 2016; NORD-The National Organization for Rare Diseases: https://rarediseases.org/). Patient populations for individual RD are small and scattered; international collaborations are crucial to pool resources fragmented across individual countries for better diagnosis and treatment. Undiagnosed RD (URD) are conditions that elude diagnosis; some patients wait years for a definitive diagnosis. URD may include groups of unnamed disorders with common characteristics, phenotypically well described diseases, diseases with an unknown molecular basis, or those due to unknown, non-genetic factors.The US NIH Undiagnosed Diseases Program arose in 2008 to provide a diagnosis for individuals who had long sought one without success; in 2013 a nationwide Undiagnosed Diseases Network was established in the United States. In 2015, the Undiagnosed Disease Network International (UDNI) was established and includes US, Australia, Canada, Japan, Italy and other European countries. Other national initiatives have also been undertaken and are in progress all over the world.

Undiagnosed Diseases Network International (UDNI): White paper for global actions to meet patient needs.

In 2008, the National Institutes of Health's (NIH) Undiagnosed Disease Program (UDP) was initiated to provide diagnoses for individuals who had long sought one without success. As a result of two international conferences (Rome 2014 and Budapest 2015), the Undiagnosed Diseases Network International (UDNI) was established, modeled in part after the NIH UDP. Undiagnosed diseases are a global health issue, calling for an international scientific and healthcare effort. To meet this demand, the UDNI has built a consensus framework of principles, best practices and governance; the Board of Directors reflects its international character, as it includes experts from Australia, Canada, Hungary, Italy, Japan and the USA. The UDNI involves centers with internationally recognized expertise, and its scientific resources and know-how aim to fill the knowledge gaps that impede diagnosis. Consequently, the UDNI fosters the translation of research into medical practice. Active patient involvement is critical; the Patient Advisory Group is expected to play an increasing role in UDNI activities. All information for physicians and patients will be available at the UDNI website.

Phenylketonuria Scientific Review Conference: state of the science and future research needs.

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 µmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 µmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

The Rare Diseases Clinical Research Network's organization and approach to observational research and health outcomes research.

Established in 2003 by the Office of Rare Diseases Research (ORDR), in collaboration with several National Institutes of Health (NIH) Institutes/Centers, the Rare Diseases Clinical Research Network (RDCRN) consists of multiple clinical consortia conducting research in more than 200 rare diseases. The RDCRN supports longitudinal or natural history, pilot, Phase I, II, and III, case-control, cross-sectional, chart review, physician survey, bio-repository, and RDCRN Contact Registry (CR) studies. To date, there have been 24,684 participants enrolled on 120 studies from 446 sites worldwide. An additional 11,533 individuals participate in the CR. Through a central data management and coordinating center (DMCC), the RDCRN's platform for the conduct of observational research encompasses electronic case report forms, federated databases, and an online CR for epidemiological and survey research. An ORDR-governed data repository (through dbGaP, a database for genotype and phenotype information from the National Library of Medicine) has been created. DMCC coordinates with ORDR to register and upload study data to dbGaP for data sharing with the scientific community. The platform provided by the RDCRN DMCC has supported 128 studies, six of which were successfully conducted through the online CR, with 2,352 individuals accrued and a median enrollment time of just 2 months. The RDCRN has built a powerful suite of web-based tools that provide for integration of federated and online database support that can accommodate a large number of rare diseases on a global scale. RDCRN studies have made important advances in the diagnosis and treatment of rare diseases.

Global health for rare diseases through primary care.

Rare diseases affect over 300 million people worldwide and are gaining recognition as a global health priority. Their inclusion in the UN Sustainable Development Goals, the UN Resolution on Addressing the Challenges of Persons Living with a Rare Disease, and the anticipated WHO Global Network for Rare Diseases and WHO Resolution on Rare Diseases, which is yet to be announced, emphasise their significance. People with rare diseases often face unmet health needs, including access to screening, diagnosis, therapy, and comprehensive health care. These challenges highlight the need for awareness and targeted interventions, including comprehensive education, especially in primary care. The majority of rare disease research, clinical services, and health systems are addressed with specialist care. WHO Member States have committed to focusing on primary health care in both universal health coverage and health-related Sustainable Development Goals. Recognising this opportunity, the International Rare Diseases Research Consortium (IRDiRC) assembled a global, multistakeholder task force to identify key barriers and opportunities for empowering primary health-care providers in addressing rare disease challenges.

Expanding research to provide an evidence base for nutritional interventions for the management of inborn errors of metabolism.

A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers.

Towards the international interoperability of clinical research networks for rare diseases: recommendations from the IRDiRC Task Force.

BACKGROUND: Many patients with rare diseases are still lacking a timely diagnosis and approved therapies for their condition despite the tremendous efforts of the research community, biopharmaceutical, medical device industries, and patient support groups. The development of clinical research networks for rare diseases offers a tremendous opportunity for patients and multi-disciplinary teams to collaborate, share expertise, gain better understanding on specific rare diseases, and accelerate clinical research and innovation. Clinical Research Networks have been developed at a national or continental level, but global collaborative efforts to connect them are still lacking. The International Rare Diseases Research Consortium set a Task Force on Clinical Research Networks for Rare Diseases with the objective to analyse the structure and attributes of these networks and to identify the barriers and needs preventing their international collaboration. The Task Force created a survey and sent it to pre-identified clinical research networks located worldwide. RESULTS: A total of 34 responses were received. The survey analysis demonstrated that clinical research networks are diverse in their membership composition and emphasize community partnerships including patient groups, health care providers and researchers. The sustainability of the networks is mostly supported by public funding. Activities and research carried out at the networks span the research continuum from basic to clinical to translational research studies. Key elements and infrastructures conducive to collaboration are well adopted by the networks, but barriers to international interoperability are clearly identified. These hurdles can be grouped into five categories: funding limitation; lack of harmonization in regulatory and contracting process; need for common tools and data standards; need for a governance framework and coordination structures; and lack of awareness and robust interactions between networks. CONCLUSIONS: Through this analysis, the Task Force identified key elements that should support both developing and established clinical research networks for rare diseases in implementing the appropriate structures to achieve international interoperability worldwide. A global roadmap of actions and a specific research agenda, as suggested by this group, provides a platform to identify common goals between these networks.

Unmet needs in countries participating in the undiagnosed diseases network international: an international survey considering national health care and economic indicators.

Background: Patients, families, the healthcare system, and society as a whole are all significantly impacted by rare diseases (RDs). According to various classifications, there are currently up to 9,000 different rare diseases that have been recognized, and new diseases are discovered every month. Although very few people are affected by each uncommon disease individually, millions of people are thought to be impacted globally when all these conditions are considered. Therefore, RDs represent an important public health concern. Although crucial for clinical care, early and correct diagnosis is still difficult to achieve in many nations, especially those with low and middle incomes. Consequently, a sizeable amount of the overall burden of RD is attributable to undiagnosed RD (URD). Existing barriers and policy aspects impacting the care of patients with RD and URD remain to be investigated. Methods: To identify unmet needs and opportunities for patients with URD, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) conducted a survey among its members, who were from 20 different nations. The survey used a mix of multiple choice and dedicated open questions covering a variety of topics. To explore reported needs and analyze them in relation to national healthcare economical aspects, publicly available data on (a) World Bank ranking; (b) Current health expenditure per capita; (c) GDP per capita; (d) Domestic general government health expenditure (% of GDP); and (e) Life expectancy at birth, total (years) were incorporated in our study. Results: This study provides an in-depth evaluation of the unmet needs for 20 countries: low-income (3), middle-income (10), and high-income (7). When analyzing reported unmet needs, almost all countries (N = 19) indicated that major barriers still exist when attempting to improve the care of patients with UR and/or URD; most countries report unmet needs related to the availability of specialized care and dedicated facilities. However, while the countries ranked as low income by the World Bank showed the highest prevalence of referred unmet needs across the different domains, no specific trend appeared when comparing the high, upper, and low-middle income nations. No overt trend was observed when separating countries by current health expenditure per capita, GDP per capita, domestic general government health expenditure (% of GDP) and life expectancy at birth, total (years). Conversely, both the GDP and domestic general government health expenditure for each country impacted the presence of ongoing research. Conclusion: We found that policy characteristics varied greatly with the type of health system and country. No overall pattern in terms of referral for unmet needs when separating countries by main economic or health indicators were observed. Our findings highlight the importance of identifying actionable points (e.g., implemented orphan drug acts or registries where not available) in order to improve the care and diagnosis of RDs and URDs on a global scale.

Undiagnosed diseases: Needs and opportunities in 20 countries participating in the Undiagnosed Diseases Network International.

Introduction: Rare diseases (RD) are a health priority worldwide, overall affecting hundreds of millions of people globally. Early and accurate diagnosis is essential to support clinical care but remains challenging in many countries, especially the low- and medium-income ones. Hence, undiagnosed RD (URD) account for a significant portion of the overall RD burden. Methods: In October 2020, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) launched a survey among its members, belonging to 20 countries across all continents, to map unmet needs and opportunities for patients with URD. The survey was based on questions with open answers and included eight different domains. Conflicting interpretations were resolved in contact with the partners involved. Results: All members responded to the survey. The results indicated that the scientific and medical centers make substantial efforts to respond to the unmet needs of patients. In most countries, there is a high awareness of RD issues. Scarcity of resources was highlighted as a major problem, leading to reduced availability of diagnostic expertise and research. Serious equity in accessibility to services were highlighted both within and between participating countries. Regulatory problems, including securing informed consent, difficulties in sending DNA to foreign laboratories, protection of intellectual property, and conflicts of interest on the part of service providers, remain issues of concern. Finally, most respondents stressed the need to strengthen international cooperation in terms of data sharing, clinical research, and diagnostic expertise for URD patients in low and medium income countries. Discussion: The survey highlighted that many countries experienced a discrepancy between the growing expertise and scientific value, the level of awareness and commitment on the part of relevant parties, and funding bodies. Country-tailored public health actions, including general syllabus of medical schools and of the education of other health professionals, are needed to reduce such gaps.

The need for worldwide policy and action plans for rare diseases.

UNLABELLED: There are more than 6000 rare diseases (defined as affecting <5/10 000 individuals in Europe, <200 000 people in the United States). The rarity can create problems including: difficulties in obtaining timely, accurate diagnoses; lack of experienced healthcare providers; useful, reliable and timely information may be hard to find; research activities are less common; developing new medicines may not be economically feasible; treatments are sometimes very expensive; and in developing countries, the problems are compounded by other resource limitations. Emphasis is required to support appropriate research and development leading to better prevention, diagnosis and treatments of rare diseases. Notably, clinical trials using already existing drugs may result in new, affordable, treatment strategies. Moreover, rare diseases may teach us about common disorders. CONCLUSIONS: Countries are encouraged to implement specific research and development activities within their individual capabilities, so that patients worldwide have equal access to necessary interventions to maximize the potential of every individual.

Essential list of medicinal products for rare diseases: recommendations from the IRDiRC Rare Disease Treatment Access Working Group.

BACKGROUND: Treatments are often unavailable for rare disease patients, especially in low-and-middle-income countries. Reasons for this include lack of financial support for therapies and onerous regulatory requirements for approval of drugs. Other barriers include lack of reimbursement, administrative infrastructure, and knowledge about diagnosis and drug treatment options. The International Rare Diseases Research Consortium set up the Rare Disease Treatment Access Working Group with the first objective to develop an essential list of medicinal products for rare diseases. RESULTS: The Working Group extracted 204 drugs for rare diseases in the FDA, EMA databases and/or China's NMPA databases with approval and/or marketing authorization. The drugs were organized in seven disease categories: metabolic, neurologic, hematologic, anti-inflammatory, endocrine, pulmonary, and immunologic, plus a miscellaneous category. CONCLUSIONS: The proposed list of essential medicinal products for rare diseases is intended to initiate discussion and collaboration among patient advocacy groups, health care providers, industry and government agencies to enhance access to appropriate medicines for all rare disease patients throughout the world.

Rare diseases - avoiding misperceptions and establishing realities: the need for reliable epidemiological data.

The rare disease community suffers from the absence of reliable epidemiological data on the prevalence and incidence of rare diseases in the national and global populations. The rare diseases community includes all of the stakeholders involved in the research and development and dissemination of products and information for the diagnosis, prevention or treatment of rare diseases or conditions. To replace many of the perceived myths with realities, several global efforts are required if we are going to sustain and increase the reported progress with the thousands of rare diseases. One is the identification and expansion of worldwide partnerships and collaborations of Patient Advocacy Groups for individual rare diseases. Another requirement is to develop a global research infrastructure of qualified investigators to stimulate and coordinate research efforts by seeking ways to provide access to clinical trials at multi-national research sites with common protocols and multi-disciplinary research teams. Providing ready access to the information about rare diseases, patient advocacy groups, research studies and products in research protocols will continue to improve the lives of patients and their families. Many scientists, public and private sector organizations, patient advocacy groups, foundations, and the pharmaceutical, biotechnology, and medical devices industries are committed to translating research discoveries that will be useful in the care of patients with rare diseases over their lifespan. Evidence from well constructed epidemiological studies will provide the evidence that point to the value of additional clinical studies to increase the understanding of rare diseases.

Publisher Correction: Therapies for rare diseases: therapeutic modalities, progress and challenges ahead.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Therapies for rare diseases: therapeutic modalities, progress and challenges ahead.

Most rare diseases still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to catalyse the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. With this in mind, we discuss here the technological basis and rare disease applicability of the main therapeutic modalities, including small molecules, monoclonal antibodies, protein replacement therapies, oligonucleotides and gene and cell therapies, as well as drug repurposing. For each modality, we consider its strengths and limitations as a platform for rare disease therapy development and describe clinical progress so far in developing drugs based on it. We also discuss selected overarching topics in the development of therapies for rare diseases, such as approval statistics, engagement of patients in the process, regulatory pathways and digital tools.