Field Of Rare Diseases Research Articles

A community-centric model for conference co-creation: the world conference on CDG for patients, families and professionals

BackgroundPatient and public co-creation and involvement in health initiatives have been witnessing great expansion in recent years. From healthcare to research settings, collaborative approaches are becoming increasingly prevalent and diverse, especially in the field of rare diseases which faces complex challenges. Conference development and implementation, however, have been primarily guided by passive, information-sharing models. There is a need for conferences to evolve towards more inclusive, interactive, collaborative, and problem-solving platforms. Here, we aimed to report on a pioneer model, emphasizing a community partnership approach to conference co-creation that takes the World Conference on Congenital Glycosylation Disorders (CDG) as an exemplary case.MethodsTo answer the need to overcome the lack of access to high-quality information which limits CDG diagnosis, research and treatment options, the World CDG Organization has been refining a community-centric model for conference co-creation. Focusing on the 5th edition of the conference, data on stakeholders’ preferences was collected using an online survey and a poll to define the conference agenda, guide its development and select optimal dates for an all-stakeholder inclusive, relevant and participatory event.ResultsWe describe the complexities of the community-centric conference co-creation model, detailing its refined methodology and the outcomes achieved. The model is grounded on a participative approach to promote people-centered research and care for CDG patients. The involvement of the public in the conference co-creation and in participatory methods allowed the generation of knowledge on community needs and preferences.ConclusionThis paper describes a reliable, highly adaptable conference co-creation model that fosters community-building, disseminates understandable information, and serves as a borderless platform to incentivize multiple stakeholder collaborations towards CDG research and drug development. We argue this is a reproducible model that can be endorsed and more widely adopted by other disease communities and events.

Zebrafish Models for Skeletal and Extraskeletal Osteogenesis Imperfecta Features: Unveiling Pathophysiology and Paving the Way for Drug Discovery.

In the last decades, the easy genetic manipulation, the external fertilization, the high percentage of homology with human genes and the reduced husbandry costs compared to rodents, made zebrafish a valid model for studying human diseases and for developing new therapeutical strategies. Since zebrafish shares with mammals the same bone cells and ossification types, it became widely used to dissect mechanisms and possible new therapeutic approaches in the field of common and rare bone diseases, such as osteoporosis and osteogenesis imperfecta (OI), respectively. OI is a heritable skeletal disorder caused by defects in gene encoding collagen I or proteins/enzymes necessary for collagen I synthesis and secretion. Nevertheless, OI patients can be also characterized by extraskeletal manifestations such as dentinogenesis imperfecta, muscle weakness, cardiac valve and pulmonary abnormalities and skin laxity. In this review, we provide an overview of the available zebrafish models for both dominant and recessive forms of OI. An updated description of all the main similarities and differences between zebrafish and mammal skeleton, muscle, heart and skin, will be also discussed. Finally, a list of high- and low-throughput techniques available to exploit both larvae and adult OI zebrafish models as unique tools for the discovery of new therapeutic approaches will be presented.

Framework for Multistakeholder Patient Registries in the Field of Rare Diseases: Focus on Neurogenetic Diseases.

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.

Framing the European Rare Diseases field through a structured movement of patient organisations

EURORDIS-Rare Diseases Europe is an alliance of patient organisations, working across countries, empowering patients with trainings, and generating evidence through surveys. It advocates for the needs of people living with rare diseases in Europe, influencing policy, legislation, research, healthcare services, social inclusion, medicines development and access. Since its creation, EURORDIS has maintained a global perspective. By nature of the rarity of these conditions, knowledge and expertise are scattered, so collaboration on a global level is required to have an understanding of disease progression. Thus, every rare disease patient group must be equipped to collaborate beyond its own borders. EURORDIS impacts global activities with a focus on raising awareness; empowering a global alliance; supporting international, national and regional initiatives; and recognising rare diseases within the international community while fostering collaboration among stakeholders. For these reasons, the organisation’s impact extends beyond Europe, as demonstrated by its international partnerships. This perspective paper explores EURORDIS’ achievements over two decades, examining its role in shaping policies and regulations, to demonstrate the vital importance of global collaboration in the rare disease field. Looking ahead, EURORDIS’ Strategic Goals, to be achieved by 2030, align with the United Nations Sustainable Development Goals Agenda 2030 and advocate for a European Action Plan for Rare Diseases. This illustrates EURORDIS’ continued commitment to transforming policies into tangible outcomes. With its ongoing dedication, collaborative efforts, and enduring impact on the rare disease community, EURORDIS remains a driving force for positive change in the lives of people living with rare diseases.

Pediatric Pulmonology 2023 year in review: Rare and diffuse lung disease.

The field of pediatric rare and diffuse lung disease continues its maturation as research advances the understanding of diagnosis and treatment of children's interstitial lung disease, noncystic fibrosis bronchiectasis, and primary ciliary dyskinesia. The rarity and breadth of these conditions make them challenging to study, yet we continue to make progress in our understanding of pathophysiology, genotype/phenotype relationships, and treatment. Papers published on these topics in Pediatric Pulmonology and other journals in 2023 describe the power of multicenter cooperation and patient registries, enhance our understanding of pathophysiology and genotype/phenotype relationships, and report progress in treatments. In this review, we hope to increase awareness and knowledge of these conditions and to inspire future research.

#1276 Clinical practice of complement inhibitor use in hemolytic uremic syndrome: findings from the European rare kidney disease registry

Abstract Background and Aims Over the last decade, significant advancements have emerged in the field of rare kidney diseases, notably the introduction of C5 inhibitor therapy. The C5 inhibition has transformed the prognosis for atypical Hemolytic Uremic Syndrome (aHUS), offering improved clinical outcomes. However, despite these advancements, the utilization of C5 inhibitor therapy varies significantly, with disparities in treatment duration, reasons for discontinuation, and consideration of extending treatment to patients with infectious HUS (iHUS). This variability is further compounded by the considerable cost associated with C5 inhibitor treatment. Method This retrospective cohort study utilized data from the ERKNet Registry. The study cohort comprised 608 HUS patients enrolled in the ERKNet Registry between November 2018 and September 2023. The dataset encompassed patient demographics, disease and diagnostic records, medication profiles, dialysis or transplantation requirements, kidney function monitoring at the last visit, and clinical outcomes. Results Among 230 aHUS patients, 23 underwent kidney transplantation. 11 received C5 inhibitor therapy before kidney failure. The majority of these patients had genetic aHUS with various mutations (3 CFH, 2 CFI, and 1 CD46). The only death in the study was from this group of patients, unresponsive to C5 Inhibition. Out of 175 aHUS patients treated with Eculizumab, 23 (13%) transitioned to Ravulizumab. Among 104 patients who discontinued C5 inhibitors, 14 (14%) had to resume treatment, half of them with genetic aHUS, with 3 cases of CD46 mutations, 2 cases CFHR5 mutations, and one each involving mutations in CFI and C3. Only two patients required dialysis.. Among 371 iHUS patients, 82 (22%) received C5 Inhibitor treatment. Conclusion In the context of aHUS, we found that discontinuing C5 inhibitors is generally safe, with a slightly higher relapse rate in patients with complement gene variants, though most relapses were mild, requiring dialysis in only a few cases. Long-term follow-up revealed a return to normal kidney function following TMA relapses. Transitioning from Eculizumab to Ravulizumab exhibited promising outcomes, with no relapses or kidney failures in 23 patients. Our analysis of C5 inhibitor use in iHUS emphasized its association with more severe disease progression. While some studies question C5 inhibitors' acute-phase efficacy, others report remarkable improvements in patients unresponsive to other treatments. Overall, our findings underscore the safety of discontinuation practices, the potential benefits of Ravulizumab, and the ongoing need for further research on C5 inhibitor treatment in iHUS.

Needs and Experiences With Health Care Providers of Adult Rare Disease Patients and Caregivers of People With Rare Diseases: Protocol for a Qualitative Study.

Rare diseases in Europe are defined as diseases with a prevalence of less than 5 per 10,000 people. Despite their individual rarity, the total number of rare diseases is considerable. Rare diseases are often chronic and complex, affecting physical, mental, and neurological health. People with rare diseases face challenges such as delayed diagnosis, limited medical support, and financial burden. Caregivers, usually family members, bear significant physical and emotional burdens. Understanding the experiences of patients with rare disease and their caregivers is critical to effective care, but this is still underresearched. Better support and understanding of the challenges faced by both patients and caregivers is clearly needed. Our study will explore the experiences and needs of people with rare diseases and caregivers of people with rare diseases in relation to accessing health services. This study aims to explore the experiences of patients with rare disease and their caregivers with Slovenian health care providers and to create a theoretical model of needs and experiences. This is a qualitative thematic analysis study, using the codebook approach. The study will conduct semi-open-ended interviews to understand the experiences and needs of people with rare diseases and caregivers of people with rare diseases in relation to accessing health services. The interview questions will be based on an extensive literature review. Data from the interviews will be analyzed using thematic analysis to identify patterns and build a thematic map. Data will be analyzed by at least 2 coders. To ensure reliability, respondent validation will be conducted and negative cases investigated. Any discrepancies will be resolved by consulting the entire research team until a consensus is reached. This study was not specifically funded. However, author TČ is supported by grant number P3-0339 from the Slovenian Agency for Research and Innovation. This study was approved by the Medical Ethics Committee of the Republic of Slovenia (0120-47/2022/3), and recruitment is expected to begin in May 2024, with data analysis results anticipated by the end of 2025. This study will fill an important research gap in Slovenia by exploring the needs and experiences of people living with rare diseases and their caregivers. The results will contribute to the broader field of rare diseases and add knowledge that can inform future research processes and intervention strategies. It also aims to identify neglected areas that have a significant impact on the lives of people with rare diseases. This study is important not only because it addresses the immediate needs of the Slovenian rare disease community, but also because it contributes to a discussion on patient-centered care, health policy design, and the inclusion of psychosocial components in health care. PRR1-10.2196/53362.

Current genetic diagnostics in inborn errors of immunity.

New technologies in genetic diagnostics have revolutionized the understanding and management of rare diseases. This review highlights the significant advances and latest developments in genetic diagnostics in inborn errors of immunity (IEI), which encompass a diverse group of disorders characterized by defects in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and malignancies. Various diagnostic approaches, including targeted gene sequencing panels, whole exome sequencing, whole genome sequencing, RNA sequencing, or proteomics, have enabled the identification of causative genetic variants of rare diseases. These technologies not only facilitated the accurate diagnosis of IEI but also provided valuable insights into the underlying molecular mechanisms. Emerging technologies, currently mainly used in research, such as optical genome mapping, single cell sequencing or the application of artificial intelligence will allow even more insights in the aetiology of hereditary immune defects in the near future. The integration of genetic diagnostics into clinical practice significantly impacts patient care. Genetic testing enables early diagnosis, facilitating timely interventions and personalized treatment strategies. Additionally, establishing a genetic diagnosis is necessary for genetic counselling and prognostic assessments. Identifying specific genetic variants associated with inborn errors of immunity also paved the way for the development of targeted therapies and novel therapeutic approaches. This review emphasizes the challenges related with genetic diagnosis of rare diseases and provides future directions, specifically focusing on IEI. Despite the tremendous progress achieved over the last years, several obstacles remain or have become even more important due to the increasing amount of genetic data produced for each patient. This includes, first and foremost, the interpretation of variants of unknown significance (VUS) in known IEI genes and of variants in genes of unknown significance (GUS). Although genetic diagnostics have significantly contributed to the understanding and management of IEI and other rare diseases, further research, exchange between experts from different clinical disciplines, data integration and the establishment of comprehensive guidelines are crucial to tackle the remaining challenges and maximize the potential of genetic diagnostics in the field of rare diseases, such as IEI.

Abstract A034: A new international program to accelerate novel therapeutics for brain tumors: presenting the brain tumor research novel therapeutics accelerator

Abstract Each year, we see many journal manuscripts highlighting successful pre-clinical experiments for potential new brain tumor therapies. Only a few of these therapies move forward into successful clinical trials. Indeed, developing a comprehensive translational program covers many aspects, including but not limited to, medicinal chemistry, blood brain barrier penetration, tumor heterogeneity, delivery, commercialization, and navigating the regulatory environment. Because of this, bringing a successful translational project from bench to bedside requires access to a diverse set of cutting-edge expertise to give promising therapies the best chance of succeeding. Recognizing that this journey is not easy to navigate, the Tessa Jowell Brain Cancer Mission has launched an international Brain Tumor Research Novel Therapeutics Accelerator (BTR-NTA). This program is led by an international group of drug development and brain tumor experts who provide independent guidance to researchers to position their therapeutic along a realistic pathway to clinical trials. The BTR-NTA is open to any international academic and industry researchers developing a medicinal product, delivery technology or device for brain tumors. The BTR-NTA welcomes groups at any stage of pre-clinical or clinical work. Academics and smaller biotech’s could benefit from feedback on their pre-clinical studies and plans for commercialization, while larger pharmaceutical companies could benefit from access to brain tumor specific expertise and patient input into clinical trial design. Researchers can apply to BTR-NTA twice a year, and if accepted will go through the following process: 1. Complete an application form covering work to date and future plans under strict confidentiality agreements; 2. Attend an in-person meeting with a tailored group of experts to further discuss their work; and 3. Receive a comprehensive written report from the BTR-NTA committee with feedback on strengths and weaknesses and guidance on next steps. The expert committee dedicates half a day to reviewing the applicants’ work in-person, and extensive time pre- and post-meeting. Throughout the process, applicants receive up to 150 hours of expert input. The multidisciplinary nature of the review committee spans the entirety of the drug development pathway to support longitudinal collaboration and avoid a siloed approach to research. The BTR-NTA was designed after a similar program in another rare disease field yielded impressive results. Thanks to charitable funding, the BTR-NTA is free to academics and at low cost for industry. The BTR-NTA aims to help address barriers for researchers by highlighting potential pitfalls or risks, providing multi-disciplinary feedback on work to date, giving constructive guidance on next steps and strengthening international collaboration in the brain tumor field. The ultimate goal of the BTR-NTA is to enable researchers with therapy for brain tumors to navigate the drug development journey and make it to the clinic in a low-cost and timely way. Citation Format: Nicky Huskens, Charlotte Aitken, Katie Bushby. A new international program to accelerate novel therapeutics for brain tumors: presenting the brain tumor research novel therapeutics accelerator [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A034.

Are the European reference networks for rare diseases ready to embrace machine learning? A mixed-methods study

BackgroundThe delay in diagnosis for rare disease (RD) patients is often longer than for patients with common diseases. Machine learning (ML) technologies have the potential to speed up and increase the precision of diagnosis in this population group. We aim to explore the expectations and experiences of the members of the European Reference Networks (ERNs) for RDs with those technologies and their potential for application.MethodsWe used a mixed-methods approach with an online survey followed by a focus group discussion. Our study targeted primarily medical professionals but also other individuals affiliated with any of the 24 ERNs.ResultsThe online survey yielded 423 responses from ERN members. Participants reported a limited degree of knowledge of and experience with ML technologies. They considered improved diagnostic accuracy the most important potential benefit, closely followed by the synthesis of clinical information, and indicated the lack of training in these new technologies, which hinders adoption and implementation in routine care. Most respondents supported the option that ML should be an optional but recommended part of the diagnostic process for RDs. Most ERN members saw the use of ML limited to specialised units only in the next 5 years, where those technologies should be funded by public sources. Focus group discussions concluded that the potential of ML technologies is substantial and confirmed that the technologies will have an important impact on healthcare and RDs in particular. As ML technologies are not the core competency of health care professionals, participants deemed a close collaboration with developers necessary to ensure that results are valid and reliable. However, based on our results, we call for more research to understand other stakeholders’ opinions and expectations, including the views of patient organisations.ConclusionsWe found enthusiasm to implement and apply ML technologies, especially diagnostic tools in the field of RDs, despite the perceived lack of experience. Early dialogue and collaboration between health care professionals, developers, industry, policymakers, and patient associations seem to be crucial to building trust, improving performance, and ultimately increasing the willingness to accept diagnostics based on ML technologies.

German Porphyria Registry (PoReGer)-Background and Setup.

Porphyrias, as most rare diseases, are characterized by complexity and scarcity of knowledge. A national registry in one of the largest European populations that prospectively collects longitudinal clinical and laboratory data are an important and effective tool to close this gap. The German Porphyria Registry (PoReGer) was founded by four centers with longstanding expertise in the field of porphyrias and rare diseases (Charité-Universitätsmedizin Berlin, Porphyria Center Saxony Chemnitz, University Medical Center Hamburg-Eppendorf, University Medical Center Göttingen) and the German reference laboratory for porphyria, and is supported by the largest German porphyria patient organization. A specified data matrix for three subgroups (acute, chronic blistering cutaneous, acute non-blistering cutaneous) includes data on demographics, specific porphyria-related symptoms, clinical course, general medical history, necessary follow-up assessments (including laboratory and imaging results), symptomatic and disease-modifying therapies, and side-effects. Additionally, the registry includes patient-reported outcome measures on quality of life, depression, and fatigue. PoReGer aims to broaden and deepen the understanding on all porphyria-related subjects. We expect these data to significantly improve the management and care of porphyria patients. Additionally, the data can be used for educational purposes to increase awareness, for the planning of healthcare services, and for machine learning algorithms for early detection of porphyrias.

Challenges And Solutions in Rare Disease Treatment: Value-Based Healthcare

This study is based on the realities of challenges within the field of rare disease treatment, as well as the concept of value-based healthcare. By analyzing treatment plans, rehabilitative care, cost-sharing, prospects for drug development markets and investment returns, as well as policy support, the paper delves into the complexities and diversities of rare disease treatment. Within the research, the focus is on the challenges of rare disease treatment, leveraging the principles of value-based healthcare. It discusses how personalized treatment plans, interdisciplinary collaboration, and reasonable cost-sharing can enhance patient treatment outcomes and quality of life. The article employs methods such as literature reviews and case analyses to deeply explore and analyze rare disease treatment from various angles. The research findings indicate that personalized treatment plans and interdisciplinary collaboration can significantly enhance treatment outcomes and quality of life for rare disease patients. Reasonable cost-sharing models and trends in drug development markets present opportunities for the sustainable growth of the rare disease field. Additionally, policy support and international cooperation mechanisms play vital roles in advancing rare disease treatment. Based on these research findings, the article proposes future research prospects, including strengthening data collection and analysis, deepening international collaboration, and optimizing drug development strategies.

Training of community health agents - a strategy for earlier recognition of mucopolysaccharidoses.

Primary Health Care (PHC) is the gateway for patients in the Brazilian unified health system (Sistema Único de Saúde-SUS), playing an extremely important role in the identification of potential patients with genetic diseases, and referral to specialized and tertiary health services. The PHC is composed of a multidisciplinary team, including the Community Health Agent, who is in direct contact with the community. To implement an educational program aimed at community health agents working in several municipalities in the state of Rio Grande do Sul (RS), Brazil. The training was focused on genetic diseases in general, with a special focus on identifying patients with Mucopolysaccharidosis (MPS). Tests were applied before and after the educational intervention, in order to assess the participants' knowledge on the topic at these two moments. The study covered a total of ten training sessions carried out in eight municipalities in the RS state, training 374 community health agents. The number of correct answers in the pre-test (n = 339) was 8,4 (SD 1.2), while in the post-test (n = 361) it was 9,2 (SD 0.8). Statistical analysis showed that the educational intervention effectively provided information about genetic diseases to the participants. Considering that community health agents are of fundamental importance in the identification and prevention of diseases and in the better navigation of the patients on the SUS, these professionals play a key role in the field of rare genetic diseases, and continuous training strategies should be taken.

Research on Rare Diseases in Germany - The GAIN Registry: a registry for individuals with congenital multi-organ autoimmune diseases.

Patient registries are an important tool for networking medical caregivers and research, especially in the field of rare diseases. Individuals afflicted by multi-organ autoimmune diseases typically suffer from inflammation of multiple organs. GAIN (German genetic multi-organ Auto-Immunity Network) is the German network for research and therapy optimisation for individuals with congenital multi-organ autoimmune diseases. As a sub-project of the network, the registry systematically collects data from this patient group and makes it available for research purposes. A data set was developed and made available for the GAIN Registry that can map the complex clinical status of persons with multi-organ autoimmune diseases. Data from 486 individuals have been documented to date. The GAIN register allows for a very comprehensive documentation that clearly goes beyond previous approaches, e.g. by linking it to biosamples collected in the consortium. The planned inclusion of patients in the documentation, e.g. of data on quality of life, opens up a new field.

Qualified placebo for trials of herbal medicine treatment in rare diseases? A cross-sectional analysis

BackgroundWhile substantial placebos have been used in herbal medicine (HM) clinical trials for rare diseases, the use and quality of reporting of HM-placebo remain unclear. We aim to describe the use of HM-placebo in clinical trials for rare diseases and determine the quality of reporting in these trials.MethodsThis is a cross-sectional study. We searched PubMed, Embase, Web of Science, SinoMed, China National Knowledge Infrastructure, WanFang database, China Science and Technology Journal Database, National Institute of Informatics Support Academic Information Services, ClinicalTrials.gov and Chinese Clinical Trials Registry from their inception date to 14 February 2023 to identify registered and published trials that use placebos as a comparator in rare diseases. We collected data on placebo use reporting and the efficacy and safety of placebo. Descriptive statistics, the Chi-square test, and Binary multivariable logistic regression analysis were used to determine the placebo characteristics of the HM trial and its effect on reporting.ResultsAmong the 55 studies, we included that with a median administration time of placebo of 84 days (IQR 42–180) and a median placebo sample size of 30 (IQR 24–54). About half of the trials (27, 49.1%) did not provide their ethical approvals, and one trial had details of informed consent. None of the studies were fully reported and more than half of the items reported less than 50%. A total of 10 trials (18.2%) of placebo has active ingredients even though none of them performed pharmacological inert tests. Of the 29 studies with available data on adverse events, 5 (17.2%) trials did not show a better safety profile in the placebo group. Under the context that a relatively high-quality report is defined as a report with more than 9 items, there was a statistically significant difference between the two groups in the rate of relatively high-quality reports of the administration time (p = 0.047, OR 0.10, 95% CI 0.01 to 0.90), but the results are not representative.ConclusionThe overall situation of HM-placebo in the field of rare diseases was poor. In particular, the placebo is tied to the quality of trials, and poor placebo hinders the generation of high-quality evidence for herbal clinical trials in the field of rare diseases. We summarize the current methods of assessment involved in the use of placebos and propose various considerations for placebos in different contexts. Our study can greatly promote rare disease researchers to review the quality of their placebo and clinical trials. It is imperative to guarantee that meticulously conducted research generates clinical evidence of the highest caliber. We also expect that in the future, more rigorous relevant standards about the reporting and design of HM-placebo will be developed. High-quality clinical trials are the prerequisite for the wide clinical application of herbal medicines for rare diseases.

Enhancing evidence-informed policymaking in medicine and healthcare: stakeholder involvement in the Commons Project for rare diseases in Japan

BackgroundAlthough stakeholder involvement in policymaking is attracting attention in the fields of medicine and healthcare, a practical methodology has not yet been established. Rare-disease policy, specifically research priority setting for the allocation of limited research resources, is an area where evidence generation through stakeholder involvement is expected to be effective. We generated evidence for rare-disease policymaking through stakeholder involvement and explored effective collaboration among stakeholders.MethodsWe constructed a space called ‘Evidence-generating Commons’, where patients, family members, researchers, and former policymakers can share their knowledge and experiences and engage in continual deliberations on evidence generation. Ten rare diseases were consequently represented. In the ‘Commons’, 25 consecutive workshops were held predominantly online, from 2019 to 2021. These workshops focused on (1) clarification of difficulties faced by rare-disease patients, (2) development and selection of criteria for priority setting, and (3) priority setting through the application of the criteria. For the first step, an on-site workshop using sticky notes was held. The data were analysed based on KJ method. For the second and third steps, workshops on specific themes were held to build consensus. The workshop agendas and methods were modified based on participants’ feedback.ResultsThe ‘Commons’ was established with 43 participants, resulting in positive effects such as capacity building, opportunities for interactions, mutual understanding, and empathy among the participants. The difficulties faced by patients with rare diseases were classified into 10 categories. Seven research topics were identified as priority issues to be addressed including ‘impediments to daily life’, ‘financial burden’, ‘anxiety’, and ‘burden of hospital visits’. This was performed by synthesising the results of the application of the two criteria that were particularly important to strengthen future research on rare diseases. We also clarified high-priority research topics by using criteria valued more by patients and family members than by researchers and former policymakers, and criteria with specific perspectives.ConclusionWe generated evidence for policymaking in the field of rare diseases. This study’s insights into stakeholder involvement can enhance evidence-informed policymaking. We engaged in comprehensive discussions with policymakers regarding policy implementation and planned analysis of the participants’ experiences in this project.

A novel in silico scaffold-hopping method for drug repositioning in rare and intractable diseases

In the field of rare and intractable diseases, new drug development is difficult and drug repositioning (DR) is a key method to improve this situation. In this study, we present a new method for finding DR candidates utilizing virtual screening, which integrates amino acid interaction mapping into scaffold-hopping (AI-AAM). At first, we used a spleen associated tyrosine kinase inhibitor as a reference to evaluate the technique, and succeeded in scaffold-hopping maintaining the pharmacological activity. Then we applied this method to five drugs and obtained 144 compounds with diverse structures. Among these, 31 compounds were known to target the same proteins as their reference compounds and 113 compounds were known to target different proteins. We found that AI-AAM dominantly selected functionally similar compounds; thus, these selected compounds may represent improved alternatives to their reference compounds. Moreover, the latter compounds were presumed to bind to the targets of their references as well. This new “compound-target” information provided DR candidates that could be utilized for future drug development.

The Tuscany Regional Network for rare diseases: from European Reference Networks’ experience to registry based organisation and management model for rare diseases

BackgroundIn the European Union, a disease is defined as rare when it affects fewer than 1 in 2000 people. Currently, there are up to 8000 described rare diseases (RDs), collectively affecting 30 million people in the European Union. In 2004 Tuscany region (Italy) established a Regional Network of hospital units to ensure highly specialised medical care in the field of RDs. Shortly after the Rare Diseases Registry of Tuscany (Registro Toscano Malattie Rare—RTMR) was implemented. Here we describe the analysis performed on RTMR data which has recently allowed to remap the Network based on European Reference Networks’ model.ResultsData analysis was performed on 60,367 cases registered in RTMR, regarding 628 RDs. Two-hundred and fifteen active presidia have been evaluated. The assignment of each RD to the suitable European Reference Network has been made considering not only the number of registered cases, certifications and treatment plans for each Regional Presidium but also the competence in multidisciplinary management of the patient, from diagnosis to treatment. This evaluation has led to the establishment of twenty-one Regional Coordination Centres. They aggregate and coordinate Hospital Units which diagnose and treat one or a group of related RDs. In case of wide groups of RDs, Clinical Subnets are instituted. Updated statistics regarding RDs in Tuscany, list of RDs and Coordination Centres, as well as information about single Presidia are published and freely available on a designated webpage. Regional Decrees are regularly updated according to the network evolution.ConclusionsThe Rare Diseases Regional Network in Tuscany, based on the ERN model, has played a pivotal role in enhancing RD management and research. The remapping has led to a dynamic system, following not only scientific research but also the development of Presidia’s expertise. By pooling resources and expertise, the network has improved the availability and accessibility of specialized care for patients with RDs. Collaborative efforts, data sharing, and standardized registries are crucial for advancing RD research, improving diagnosis and treatment, and ultimately enhancing the quality of life for individuals living with RDs.

Making Sense of New Disease Categories: Naming, Spatialising, and Serialising in Genomic Medicine

Intrigued by geneticists’ framing of new gene names as somehow devoid of meaning, I set out to explore how patients and families make sense of naming practices in the field of genomic medicine. The aim for ever-more precise disease categorisation has resulted in names for medical conditions that are more akin to car-licence plates, such as DPF2 and G246A. Conducting fieldwork in Denmark, I followed the introduction of personalised medicine—that is the aim to tailor prevention, diagnosis, and treatment to the individual based on genomic and other data—in the field of rare diseases and diabetes. Engaging with theories of naming, spatialisation and serialisation, I suggest that it is exactly because of their unsettled meaning and presupposed lack of history that new gene names provide patients extra room for creative identity work. I argue that some patients and families use the new genetic disease labels to escape unwanted moral regimes, relocating disease aetiology from a moralised landscape to a ‘molecularised’ genetic one. I discuss how practices of serialisation enable patients to feel recognised as unique persons. In conclusion, I suggest that while the new genetic names may not stigmatise, they do change the patients’ idea of who they are in surprising ways, some of which the geneticists had not anticipated.

The positive impact on translational research of Fondazione italiana di ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), a non-profit foundation focused on amyotrophic lateral sclerosis. Convergence of ex-ante evaluation and ex-post outcomes when goals are set upfront.

Charities investing on rare disease research greatly contribute to generate ground-breaking knowledge with the clear goal of finding a cure for their condition of interest. Although the amount of their investments may be relatively small compared to major funders, the advocacy groups' clear mission promotes innovative research and aggregates highly motivated and mission-oriented scientists. Here, we illustrate the case of Fondazione italiana di ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), the main Italian funding agency entirely dedicated to amyotrophic lateral sclerosis research. An international benchmark analysis of publications derived from AriSLA-funded projects indicated that their mean relative citation ratio values (iCite dashboard, National Institutes of Health, U.S.) were very high, suggesting a strong influence on the referring international scientific community. An interesting trend of research toward translation based on the "triangle of biomedicine" and paper citations (iCite) was also observed. Qualitative analysis on researchers' accomplishments was convergent with the bibliometric data, indicating a high level of performance of several working groups, lines of research that speak of progression toward clinical translation, and one study that has progressed from the investigation of cellular mechanisms to a Phase 2 international clinical trial. The key elements of the success of the AriSLA investment lie in: (i) the clear definition of the objectives (research with potential impact on patients, no matter how far), (ii) a rigorous peer-review process entrusted to an international panel of experts, (iii) diversification of the portfolio with ad hoc selection criteria, which also contributed to bringing new experts and younger scientists to the field, and (iv) a close interaction of AriSLA stakeholders with scientists, who developed a strong sense of belonging. Periodic review of the portfolio of investments is a vital practice for funding agencies. Sharing information between funding agencies about their own policies and research assessment methods and outcomes help guide the international debate on funding strategies and research directions to be undertaken, particularly in the field of rare diseases, where synergy is a relevant enabling factor.