Rare Disease Research Research Articles

Supporting rare and common disease research in mineralized tissues

Supporting rare and common disease research in mineralized tissues

Quantitative retrospective natural history modeling for orphan drug development.

The natural history of most rare diseases is incompletely understood and usually relies on studies with low level of evidence. Consistent with the goals for future research of rare disease research set by the International Rare Diseases Research Consortium in 2017, the purpose of this paper is to review the recently developed method of quantitative retrospective natural history modeling (QUARNAM) and to illustrate its usefulness through didactically selected analyses examples in an overall population of 849 patients worldwide with seven (ultra-) rare neurogenetic disorders. A quantitative understanding of the natural history of the disease is fundamental for the development of specific interventions and counseling afflicted families. QUARNAM has a similar relationship to a published case study as a meta-analysis has to an individual published study. QUARNAM relies on sophisticated statistical analyses of published case reports focusing on four research questions: How long does it take to make the diagnosis? How long do patients live? Which factors predict disease severity (eg, genotypes, signs/symptoms, biomarkers)? Where can patients be recruited for studies? Useful statistical techniques include Kaplan-Meier estimates, cluster analysis, regression techniques, binary decisions trees, word clouds, and geographic mapping. In comparison to other natural history study methods (prospective studies or retrospective studies such as chart reviews), QUARNAM can provide fast information on hard clinical endpoints (ie, survival, diagnostic delay) with a lower effort. The choice of method for a particular drug development program may be driven by the research question and may encompass combinatory approaches.

Identification of a Mosaic Activating Mutation in GNA11 in Atypical Sturge-Weber Syndrome

Identification of a Mosaic Activating Mutation in GNA11 in Atypical Sturge-Weber Syndrome

Grants for rare disease research

Grants for rare disease research

Profiling trial burden and patients\u2019 attitudes to improve clinical research in epidermolysis bullosa

BackgroundEpidermolysis bullosa (EB) comprises inherited mechanobullous dermatoses with considerable morbidity and mortality. While current treatments are symptomatic, a growing number of innovative therapeutic compounds are evaluated in clinical trials. Clinical research in rare diseases like EB, however, faces many challenges, including sample size requirements and recruitment failures. The objective of this study was to determine attitudes of EB patients towards clinical research and trial participation as well as the assessment of contextual motivating and discouraging factors in an effort to support patient-centered RD trial designing.MethodsA 53-items questionnaire was handed over to EB patients (of all types and ages) in contact with the EB House Austria, a designated national center of expertise for EB care. Main categories included level of interest in and personal knowledge about clinical studies, pros/cons for participation and extent of individual expenses considered acceptable for participation in a clinical study. Descriptive subgroup analysis was calculated with SPSS 20.0 and Microsoft Excel.ResultsThirty-six individuals (mean age 25.7 years), diagnosed for recessive dystrophic EB (36.1%), EB simplex (33.4%), junctional EB (8.3%), dominant dystrophic EB (2.8%) and acral peeling syndrome (2.8%) participated. Motivation for participation in and the desire to increase personal knowledge about clinical trials were (outmost) high in 57.2 and 66.7%, respectively. Altruism was the major motivating factor, followed by hope that alleviation of the own symptoms can be achieved. The greatest hurdle was travel distance, followed by concerns about possible adverse reactions. Patients diagnosed for severe subgroups (RDEB, JEB) were more impaired by the extent of scheduled invasive investigations and possible adverse reactions of the study medication. Patients with generally milder EB forms and older patients were accepting more frequent outpatient study visits, blood takes, skin biopsies and inpatient admissions in association with trial participation.ConclusionsThis study provides additional indications to better determine and address attitudes towards clinical research among EB patients as well as guidance to improve clinical trial protocols for patient centricity.

Fatores de vulnerabilidades em itinerários terapêuticos de doenças raras: uma revisão integrativa

Objetivo: O artigo preocupa-se em ampliar a compreensão sobre conflitos éticos vivenciados por pacientes de doenças raras, identificandoos principais fatores de vulnerabilidades em itinerários terapêuticos de pessoas que vivem nessa condição.Método: Para tanto, realizou-se uma revisão integrativa da literatura desenvolvida nas bases de dados internacionais, publicada entre os anos de 2000 a 2016, compreendendo os idiomas português, inglês e espanhol. Resultados e discussão: Os resultados, a partir da análise qualitativa dos estudos selecionados, possibilitaram identificar os seguintes fatores de vulnerabilidades: falta de informações; despreparo profissional; dificuldade de se chegar a um diagnóstico; longos caminhos percorridos/ diversos serviços de saúde; faltam privacidade e autonomia na participação em pesquisas dedoenças raras; dificuldades de tratamentos e/ ou tratamentos de auto custo; dificuldades financeiras/empobrecimento; falta de organização e estrutura dos serviços de saúde; acolhimento diferenciado seja por discriminação, privações e/ou estigmatização, e sofrimento emocional.Conclusão: Ao discutir essas diferentes dimensões da vulnerabilidade a partir do campo da bioética, o artigo concluí pela necessidade de abordar os itinerários terapêuticos a partir de novas perspectivas interdisciplinares, buscando garantir o respeito ao direito à vida, à saúde e à proteção da dignidade das pessoas que vivem com doenças raras.

Prolactinoma as a Cause of Persistent Hyperprolactinemia in 6-Pyruvoyl-tetrahydropterin synthase Deficiency

© 2020 The Authors. Published by Journal of Rare Diseases Research & Treatment. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://www.rarediseasesjournal.com/articles/prolactinoma-as-a-cause-of-persistent-hyperprolactinemia-in-6-pyruvoyl-tetrahydropterin-synthase-deficiency.html

Patient engagement in research on rare gynecological tumors

Although patient engagement has become increasingly relevant, researchers find it difficult to involve patients, specifically in translational research. Particularly in rare disease research, patient engagement is crucial. First, since grant...

CRISPR/Cas9 Epigenome Editing Potential for Rare Imprinting Diseases: A Review.

Imprinting diseases (IDs) are rare congenital disorders caused by aberrant dosages of imprinted genes. Rare IDs are comprised by a group of several distinct disorders that share a great deal of homology in terms of genetic etiologies and symptoms. Disruption of genetic or epigenetic mechanisms can cause issues with regulating the expression of imprinted genes, thus leading to disease. Genetic mutations affect the imprinted genes, duplications, deletions, and uniparental disomy (UPD) are reoccurring phenomena causing imprinting diseases. Epigenetic alterations on methylation marks in imprinting control centers (ICRs) also alters the expression patterns and the majority of patients with rare IDs carries intact but either silenced or overexpressed imprinted genes. Canonical CRISPR/Cas9 editing relying on double-stranded DNA break repair has little to offer in terms of therapeutics for rare IDs. Instead CRISPR/Cas9 can be used in a more sophisticated way by targeting the epigenome. Catalytically dead Cas9 (dCas9) tethered with effector enzymes such as DNA de- and methyltransferases and histone code editors in addition to systems such as CRISPRa and CRISPRi have been shown to have high epigenome editing efficiency in eukaryotic cells. This new era of CRISPR epigenome editors could arguably be a game-changer for curing and treating rare IDs by refined activation and silencing of disturbed imprinted gene expression. This review describes major CRISPR-based epigenome editors and points out their potential use in research and therapy of rare imprinting diseases.

Rare Disease Research Partnership (RAinDRoP): a collaborative approach to identify the top 15 research priorities for rare diseases

Background: The Rare Disease Research Partnership (RAinDRoP) was established in 2018 to bring together a wide variety of diverse voices in the rare disease community in Ireland and form a research partnership. This approach enabled clinicians, patients, carers and researchers to work together to identify top research priorities for rare diseases, which focused on a life-course perspective rather than a disease-specific need. Methods: A participatory multiple phase approach was used to identify research priorities for rare diseases. The research process involved three main phases: Phase I, Public Consultation Survey on Research in Rare Diseases in Ireland (PCSRRDI); Phase II, Research Prioritisation Workshop (RPW); Phase III, Follow-up Public Consultation and Prioritisation Survey (FWPCPS). Results: In total, 240 individuals completed the phase I PCSRRDI, which comprised of a cross-section of health care professionals, researchers and people living with rare diseases. One thousand and fifteen statements were collected, reflecting issues and shared challenges in rare diseases. A shortlisting step by step was used to identify any statements that had received a total score of above 50% into 10-12 researchable questions or statements per the theme for the phase II workshop. Phase II was focused on three main themes: (1) Route to Diagnosis, (2) Living with Rare Disease, (3) Integrated and Palliative Care. In total, 62 individuals attended the overall workshop; 42 participated in the prioritisation sessions. A cross-section of health care professionals, researchers and people living with rare diseases were engaged at each workshop. Seventy-five individuals completed the final phase III public ranking by priority responses, and they ranked the top 15 research priorities defined by the multi-stakeholders at the phase II consensus meeting. Conclusions: This study identified priorities for rare diseases research aimed at improving the health and wellbeing of people living with rare diseases.

The TEAMMATE Trial: Study Design and Rationale of the First Pediatric Heart Transplant Randomized Clinical Trial

Currently there are no-FDA approved immunosuppressants specific to pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as an alternative to tacrolimus (TAC) as a primary immunosuppressant to prevent rejection that may also prevent kidney and coronary disease. However, the two regimens have never been evaluated systematically. The TEAMMATE Trial (IND 127980) is designed to evaluate the safety and efficacy of EVL and low-dose (LD-TAC) compared to standard-therapy TAC and mycophenolate mofetil (MMF). The study design and rationale are reviewed in light of challenges inherent in rare disease research. The TEAMMATE trial is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the risk-benefit profile of the two regimens to prevent major adverse transplant events (MATE), and to support FDA approval of 1 or both regimens for pediatric HT. Children <21 years at HT will be randomized (1:1 ratio) at 6 mo. post-HT to either regimen for 30 months (Figure). Children with recurrent rejection or a GFR <60 ml/min/1.73m2 are excluded. The primary efficacy hypothesis is that compared to TAC/MMF, EVL/LD-TAC is more effective in preventing 3 MATEs: cellular rejection, CKD and CAV. The primary safety hypothesis is that EVL/LD-TAC does not have a higher cumulative burden of 6 MATE (AMR, infection, and PTLD + the 3 above). The primary endpoint is the MATE Score, a surrogate endpoint reflecting the frequency and severity of MATEs and validated against graft loss. The study will enroll 210 patients across 26 sites and is powered to demonstrate superior efficacy of EVL/LDTAC. The trial is projected to be completed in 2022. The TEAMMATE trial is the first RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and effectiveness of EVL and TAC and provide valuable lessons into the design and conduct of future trials in pediatric HT.

Establishing Patient Registries for Rare Diseases: Rationale and Challenges.

Globally, an estimated 350 million people are affected by a rare disease diagnosis. Knowledge limitations persist for the majority of rare conditions due to systemic and structural challenges in healthcare and research. Disease-specific patient populations are often small and geographically dispersed; funding support for research is restricted; and diagnostic delays are common due to disease complexities, limited medical training for practitioners, and evolving foundational knowledge related to disease characterization. Patient registries can be effective, convenient, and cost-efficient tools to support documentation of the natural history of a disease, centering patients as research partners in the process while uniting rare communities around a common initiative. Current global trends towards innovative and patient-centered healthcare are enabling patient registries to increasingly emerge as valuable tools for use within rare disease research and drug development. This article describes the value of and rationale for establishing rare disease patient registries and the considerations and challenges that stakeholders, such as researchers, industry, health care providers, and patient community organizations, may encounter.

Characteristics of rare diseases in Zhejiang province, 2007-2017

Objective: To understand the characteristics of 24 388 inpatients with rare diseases in Zhejiang province during 2007-2017 and provide evidence for rare disease prevention and control. Methods: Inpatient data of rare diseases and the number of hospitalization in each year were collected in 10 hospitals of class Ⅲ (A) in Zhejiang province from 2007 to 2017, and descriptive statistical analysis was used. Results: A total of 24 388 cases of rare diseases were found, accounting for 2.69‰ (24 388/9 054 201) of total hospitalized cases. The top 3 types of rare diseases were "diseases of blood and blood-forming organs and certain disorders involving immune mechanism" (32.81%, 8 001/24 388), "congenital malformations, deformations and chromosomal abnormalities" (24.87%, 6 065/24 388) and "diseases of the nervous system" (19.01%, 4 635/24 388). The number of rare disease cases increased year by year from 2007 to 2017 with an average annual growth of 19.69%, however, the proportion of rare disease cases in the annual number of hospitalized cases only showed upward trend during 2016-2017, the time distribution of different types of rare diseases had different characteristics. The male to female ratio of rare diseases cases was 1.35∶1(13 990/10 398), "diseases of the digestive system" (4.45∶1, 1 180/265), "consequences of injury, poisoning and other external causes" (3.51∶1, 281/80) and "diseases of the nervous system" (2.26∶1, 3 213/1 422) had the highest male to female ratio. The distributions of rare disease types and diseases of different types in different age groups varied. The top 10 rare diseases accounted for 53.55% (13 060/24 388) of the total cases, and the top 3 diseases were adult idiopathic neutropenia (14.41%, 3 515/24 388), corticobasal degeneration (7.60%, 1 854/24 388) and henock-schoenlein purpura (6.01%, 1 466/24 388). Conclusion: The analysis on the characteristics of 24 388 rare disease cases in Zhejiang during 2007-2017 provided reference evidence for the promotion of rare disease research, monitoring, building registration database, and development of the prevention and control strategy for rare diseases in China.

The challenges of pharmacoepidemiology of orphan drugs in rare diseases

Large electronic health records database available at a national level offer great opportunity for research in rare diseases and orphan drugs. Methods and data used in pharmacoepidemiology present a great potential for epidemiology, drug utilization studies, drug safety, drug effectiveness and pharmacoeconomics. This review presents the different sources of data in Europe, with a special focus on the French situation, with the recent implementation of SNDS (système national des données de santé [French national health data wharehouse]). Some examples are given. Development of rigorous and innovative methods must be encouraged in the future.

Orphan drug designation in Europe: A booster for the research and development of drugs in rare diseases

The research and drug development process in rare diseases is challenging in addition to those for common diseases. To stimulate its development, the orphan drug designation (ODD) was introduced in in European Union in 2000. In the present paper, we describe the main characteristics of ODD in European Union in particular the requested criteria for ODD, the overview of the general procedure and the main incentives for Sponsors and finally the predicted factors related to successful development and marketing approval of orphan drugs after designation. In accordance with regulation, an application for ODD must be submitted to European Agency including a scientific part based on relevant scientific literature related to the condition and results on experimental studies with the specific product (and clinical studies if available). Three following criteria are a central position in this application: medical plausibility, rarity and medical significant benefit. The Committee for Orphan Medicinal Products (COMP) is the European Medicines Agency's (EMA) committee responsible for recommending orphan designation of medicines for rare diseases. Even if pre-submission meetings are not mandatory, EMA strongly encourages sponsors to request a pre-submission meeting with the Agency prior to filing an application. Experience has shown that they have a positive impact on the success rate of the applications. The full application should be submitted in English via secure online portal. ODD makes the sponsor eligible for a number of orphan incentives including the 10-year market exclusivity and the protocol assistance by COMP. Based on literature and on the experience accumulated by our team ORPHANDEV F-CRIN-labelled platform the successful translation of rare disease research into orphan drug discovery is dependent of a clearly justified medical significant benefit, the disease class, its prevalence and the disease-specific scientific output, previous experience of the sponsor with a previous successful orphan drug to the market increased.

A patient-researcher partnership for rare cancer research.

A genetic study of angiosarcoma designed through an online patient-partnership model overcomes key barriers in rare-disease research and provides indicators of clinical approaches.

A call for global action for rare diseases in Africa.

The 11th International Conference on Rare Diseases and Orphan Drugs (ICORD), South Africa, included the Africa-Rare initiative launch and facilitated multi-stakeholder engagement in the challenges facing, and opportunities for, Africans living with rare diseases. The following ICORD Global Call to Action, developed in collaboration with the International Rare Diseases Research Consortium, synthesizes the outcomes of the deliberations and emphasizes the international collaborative efforts required to address the global effects of rare diseases on public health.

Objectivity in rare disease research: A philosophical approach.

Individuals living with rare conditions are faced with important challenges derived from the rarity of their conditions and aggravated by the low priority given to rare disease research. However, current realities of rare disease research require consideration of the relationship between subjectivity and 'traditional' objectivity. Objectivity in research has traditionally been associated with processes and descriptions that are independent of the investigator. The need for researchers to provide unbiased knowledge and achieve a balance between objectivity and the underlying values in nursing and scientific research requires an examination of how objectivity is conceptualized within the context of rare disease research. The aim of this paper is to examine scientific objectivity in rare disease research from a philosophical viewpoint and, in doing so, demonstrate the need to redefine it to reflect the current scientific environment. As such, healthcare providers working on this field need to redefine objectivity around ethical and moral obligation to advance science in an equitable manner with the end goal to produce knowledge that is trustworthy and beneficial to our patients.

Analysis of 30 clinical trials on rare neurological diseases in children

Objective To explore the methods for generating evidence on health outcomes in children with rare diseases. Methods The data from 30 clinical trials on rare neurological diseases in children from January 2008 to December 2018 were collected and analyzed.Statistical analysis was conducted on the relationship between the study sponsor and the study center, the number of participants and the prevalence rate. Results Thirty studies involved 6 types of diseases, including 14 kinds of diseases.(1) All global multicenter studies (14 items) were initiated by pharmaceutical companies, whereas most of single-center studies (6/7 kinds, 86%) and multiple centers within one country(7/9 kinds, 78%) were initiated by investigators.There was a significant correlation between the research center and the research sponsor(P<0.001). (2) Most of the drugs studied were selected based on previous clinical trials (9/30 items) and animal experiments (9/30 items). (3) The median number of participants included 39 cases (10-215 cases), and 60%(18/30 items) of the studies was fewer than 50 cases.(4) Study design: 53%(16/30 items) of studies were randomized controlled studies, 33%(10/30 items) studies were open-label single-arm studies, and 14% (4/30 items) were randomized cross-over trials.Seventy-five percent(12/16 items)of randomized controlled studies were initiated by pharmaceutical companies, 50%(5/10 items) open-label single-arm studies and all randomized cross-over trials were initiated by investigators.There was a statistical correlation between the study sponsors and the study design method (χ2=7.602, P=0.022). (5) Outcome index: Scale score was used as the primary outcome in half of studies.Other studies used symptom improvement or pathological changes. Conclusions Clinical trials in rare diseases enrolled fewer participants than that in non-rare diseases, and the study design method was relatively simple.Therefore, it is necessary to further improve the level of evidence of clinical research of rare diseases through global and multi-center recruitment, initiation of pharmaceutical companies and improving the study design method. Key words: Child; Rare diseases; Drug intervention study; Research design method

Advancing patient care through the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR)

Recent advances in rare disease research are accelerated by the work of consortia that have been supported by the National Institutes of Health. Development of such consortia rely on multidisciplinary relationships and engagement with patient advocacy groups, as well as the National Institutes of Health and industry and academic partners. In this rostrum we present the development of such a process that focuses on eosinophilic gastrointestinal diseases. Principal investigators, patient advocacy groups, research assistants, and trainees work together to perform natural history studies that promote clinical trial readiness tools, conduct clinical trials, train a new generation of investigators, and perform innovative pilot studies.