Treatment Of Rare Diseases Research Articles

Skeletal dysplasias-Multidisciplinary orthopedics

Skeletal dysplasias (SD) are a heterogeneous group of rare hereditary diseases with pronounced skeletal involvement and include over 750 phenotypes, which are associated with disease-triggering variants in more than 550 genes. In addition to orthopedic treatment, a network of various disciplines is necessary to ensure high-quality diagnostics and treatment for SD. This is ideally carried out at a center specialized in the treatment of rare bone diseases (European Reference Network on Rare Bone Diseases). The close networking of orthopedics with pediatrics and other disciplines is important to enable a state-of-the-art treatment and to monitor the influences of new forms of pharmacotherapy on the musculoskeletal apparatus.

EE61 Approaches to Model Patient And Carer Utilities and Disutilities of Adverse Events in Economic Models for Rare Disease Treatments in NICE Appraisals

EE61 Approaches to Model Patient And Carer Utilities and Disutilities of Adverse Events in Economic Models for Rare Disease Treatments in NICE Appraisals

Strengthening collaboration within Europe: biliary atresia and the rise of the European Reference Networks.

Biliary atresia (BA) is a rare and devastating cholangiopathy with an incidence of 1:15 000-20 000 in Europe. There is a consensus that BA and related rare diseases should be managed at centers of expertise. However, current BA care in Europe is heterogeneous, with decentralized treatment in the majority of European countries. The varying outcomes in Europe, referring to overall and native liver survival following Kasai procedure, have led to an ongoing discussion on international clinical and scientific collaborations. In 2017, the European Reference Networks (ERN) have been launched by the European Commission to improve the treatment of rare diseases. The ERNs bring together centers of expertise, which undergo qualification and monitoring processes. The European Reference Network on Rare Hepatological Diseases (ERN RARE-LIVER) represents a network of medical practitioners and patient representatives with the goal of improving care for rare liver diseases with BA as one key disorder. Exchange programs, digital case discussions and the endorsement of clinical studies are part of the RARE-LIVER agenda, including the prospective European Biliary Atresia Registry (EBAR), which has recently been launched. Such sustainable joint European efforts and strategies are crucial to improve BA outcomes in the short term and long term.

Fatal Familial Insomnia: A Puzzle of a Rare Disease in Need of More Research

Rare diseases are diseases that affect fewer than 1 in 2,000 people. Due to their rarity, it can be extremely challenging for doctors to diagnose these diseases in their patients—it often takes 6–8 years for some patients to get a diagnosis. Even though they are uncommon, rare diseases still have a significant impact on families and communities and need greater attention. Fatal familial insomnia (FFI) is a rare disease that affects the brain and gradually reduces a person’s ability to sleep. FFI gets worse over time and causes severe complications. There is currently no cure for FFI, so more research is crucial—not only for understanding FFI but also for unlocking potential treatments for other rare diseases. Rare disease research brings hope for a better future to those living with FFI and other rare conditions.

Challenges and Progress of Orphan Drug Development for Rare Diseases.

Rare diseases, defined as conditions affecting fewer than 200,000 people in the United States or less than 1 in 2,000 people in Europe, pose significant challenges for healthcare systems and pharmaceutical research. This comprehensive review examines the evolving landscape of orphan drug development, analyzing scientific, economic, and regulatory challenges while highlighting recent technological breakthroughs and innovative approaches. We explore how artificial intelligence, next-generation sequencing, and personalized medicine are revolutionizing rare disease research and treatment development. The review details key advances in therapeutic approaches, including gene therapy, cell-based treatments, and drug repurposing strategies, which have led to breakthrough treatments for previously untreatable conditions. We analyze the impact of international collaborations, such as the International Rare Diseases Research Consortium, and discuss how regulatory frameworks worldwide have evolved to accelerate orphan drug development. The paper highlights the growing market for orphan drugs, projected to reach $242 billion by 2024 while examining the complex challenges of ensuring treatment accessibility and economic sustainability. We assess innovative clinical trial designs, patient registry development, and emerging strategies in personalized medicine that are transforming the field. Despite notable advancements, significant gaps remain in diagnosis, treatment accessibility, and sustainable funding for rare disease research. The review concludes by proposing specific actions for enhancing international collaboration, improving patient registries, and aligning incentives to address the unmet medical needs of rare disease patients, emphasizing the critical role of continued public-private partnerships and technological innovation in advancing orphan drug development.

A New Analytical LC-MS/MS Method for Determination of Eight Standard Nitrosamines (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, NDBA) in a Commercial Small Molecule Drug Product Capsules and its Active Pharmaeceutical Ingredient for Treatment of Fabry: A Rare Disease.

This study aims to develop and validate a highly sensitive LC-MS/MS method for quantifying eight nitrosamine (NA) impurities NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, and NDBA in a small molecule commercial Active Pharmaceutical Ingredients (API) and Drug Product (DP) capsules used for the treatment of Fabry rare disease in global patients. The method utilized gradient separation on a C18 column, ensuring optimum resolution between NAs and internal standards. Elution was monitored at precursor and product ions. The method was validated according to ICH Q2 (R1) guidelines, assessing specificity, linearity, recovery, and repeatability in both API and capsule matrices. Quantification of NAs ranged from 0.0215 to 0.780ppm in relation to a 20.5mg/mL sample concentration. Linearity coefficients ranged from 0.99 to 1.00. The Detection Limit (DL) was 0.154-0.560ng/mL, and the Quantitation Limit (QL) was 0.438-1.590ng/mL. Mean recoveries for all NAs were between 90 and 107%, and repeatability was under 15%. An Analytical Target Profile (ATP) concept was successfully employed to monitor Analytical Method Performance Characteristics (AMPC). The validated LC-MS/MS method proved effective for quantifying NAs (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, and NDBA) in both API and capsule matrices, with results consistently below the Quantitation Limit (QL) in confirmatory testing. This approach supports the elimination of routine NA testing, adhering to FDA and EMA's conservative Acceptable Intake (AI) limits, ensuring safety and regulatory compliance for global patients.

Public preferences for allocating health system resources in Canada: a systematic review

BackgroundConventional economic evaluations are based on the principle of health maximization. However, this approach does not consider societal preferences to prioritize health care for certain social groups and health conditions, and the public concern over health disparities. In recent years, equity-informative economic evaluation methods have been developed to incorporate societal concerns over for health inequities. These methods use quantitative evidence based on preference elicitation exercises to inform allocation of health system resources.ObjectiveTo systematically review Canadian studies that quantify public preferences for allocating health care resource across social groups and health conditions.MethodsThree electronic databases were searched on January 1st, 2024: Ovid Embase, Ovid MEDLINE, and EBSCO EconLit. In addition, the reference lists of relevant papers were also scanned to detect any other suitable studies. The systematic review included studies that met the following criteria: they were survey-based, sampled Canadian residents and involved preference elicitation, where participants made decisions about resource allocation or responded to hypothetical scenarios about redistributing lifetime health. Qualitative studies and non-preference-based studies were excluded. Risk of Bias was assessed using the CLARITY Group’s tool for evaluating cross-sectional surveys of attitudes and practices. Two reviewers conducted screening, full-text review, and data extraction. Studies were narratively synthesized.ResultsEight studies, with 8,969 participants, were identified that investigated public preferences for prioritizing health care in relation to age, income, disease rarity, and baseline health. Age-related preferences tended to favor children and younger patients over older patients. Aversion to socioeconomic-related health inequality was heterogeneous and was associated with respondent characteristics. No clear preference was found for treatments for rare diseases over common conditions, or for baseline quality of life and life expectancy. Two studies exposed participants to moral reasoning exercises that led to slightly lower levels of preference for prioritization of specific conditions or groups.ConclusionWhile the identified studies in the review were heterogenous, they provide some evidence supporting the prioritization of healthcare resources for children and younger patients over older patients. There is limited Canadian evidence on societal values related to health inequity associated with socioeconomic status, sex/gender, race/ethnicity, and other social determinants of health. Future research can help bridge this gap.

Traditional Chinese medicine for intractable and rare diseases: Research progress and future strategies.

Rare diseases have become a global public health challenge due to their low prevalence, difficult diagnosis, and limited treatment options. Intractable diseases are more common but often involve complex mechanisms, treatment with limited efficacy, and high medical costs, placing a heavy burden on patients and healthcare systems. In recent years, traditional Chinese medicine (TCM) has demonstrated unique advantages in the treatment of intractable and rare diseases and has gradually become an important complementary treatment. The current work is a systematic review of the progress of clinical and experimental research on TCM in typical rare diseases such as amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus (SLE), mitochondrial encephalomyopathy, aplastic anemia (AA), and Wilson's disease (WD). It focuses on the multi-target therapeutic mechanisms of key Chinese herbal compound formulas, including immune regulation, antioxidative stress, and neuroprotection. The core TCM theories of "syndrome differentiation", "different treatments for the same disease" and the "same treatment for different diseases" are also discussed in the context of personalized medicine. In recent years, China has continuously promoted the development of TCM through a series of national plans and supportive policies, such as the 14th Five-Year Plan for TCM development, funding for key special projects, expedited approval pathways, and expanded coverage by medical insurance. These efforts have provided strong support for the clinical translation of TCM and technological innovation in the field of intractable and rare diseases. Notwithstanding the encouraging advances, the field of Chinese medicine continues to grapple with numerous challenges. In the future, the enhancement of mechanistic studies and quality multicenter clinical trials needs to be promoted while further enhancing policy support and international collaboration to substantiate the scientific basis and clinical value of TCM in the prevention and treatment of intractable and rare diseases.

Neutralizing Antibodies: Role in Immune Response and Viral Vector Based Gene Therapy.

Neutralizing antibodies (nAbs) are an important component of the immune system, which plays a dual role in modern medicine. On the one hand, they significantly limit the effectiveness of gene therapy based on viral vectors, reducing the effectiveness of treatment of diseases such as spinal muscular atrophy, which is especially evident with repeated administration of therapeutic vectors. On the other hand, nAbs is a promising tool for combating viral infections. This review systematizes current data on the mechanisms of nAbs formation against AAV vectors, analyzes the factors influencing their production, and discusses strategies to overcome this limitation, including modification of vectors and the development of methods to suppress the immune response. Special attention is paid to the prospects of using nAbs as therapeutic agents against viral infections. The key problems and possible directions of research development in this area are considered, which is important for improving approaches to the treatment of both rare genetic and infectious diseases.

Single-cell data combined with phenotypes improves variant interpretation

BackgroundWhole genome sequencing offers significant potential to improve the diagnosis and treatment of rare diseases by enabling the identification of thousands of rare, potentially pathogenic variants. Existing variant prioritisation tools can be complemented by approaches that incorporate phenotype specificity and provide contextual biological information, such as tissue or cell-type specificity. We hypothesised that integrating single-cell gene expression data into phenotype-specific models would improve the accuracy and interpretability of pathogenic variant prioritisation.MethodsTo test this hypothesis, we developed IMPPROVE, a new tool that constructs phenotype-specific ensemble models integrating CADD scores with bulk and single-cell gene expression data. We constructed a total of 1,866 Random Forest models for individual HPO terms, incorporating both bulk and single cell expression data.ResultsOur phenotype-specific models utilising expression data can better predict pathogenic variants in 90% of the phenotypes (HPO terms) considered. Using single-cell expression data instead of bulk benefited the models, significantly shifting the proportion of pathogenic variants that were correctly identified at a fixed false positive rate (p<10-30, using an approximate Wilcoxon signed rank test). We found 57 phenotypes’ models exhibited a large performance difference, depending on the dataset used. Further analysis revealed biological links between the pathology and the tissues or cell-types used by these 57 models.ConclusionsPhenotype-specific models that integrate gene expression data with CADD scores show great promise in improving variant prioritisation. In addition to improving diagnostic accuracy, these models offer insights into the underlying biological mechanisms of rare diseases. Enriching existing pathogenicity-related scores with gene expression datasets has the potential to advance personalised medicine through more accurate and interpretable variant prioritisation.

Risk of Pneumoconiosis in Workers Exposed to Crystalline Silica from Lava Rock Dust from Mount Etna.

Background: Pneumoconiosis is a group of lung diseases characterized by the deposition and accumulation of dust or mineral fibers in the lung interstitium, primarily caused by occupational exposure. Methods: The aim of this study was to identify cases of pneumoconiosis induced by occupational exposure in patients living on the island of Sicily (South Italy), through the retrospective analysis of pneumoconiosis cases registered by the Reference Center for the Prevention, Diagnosis and Treatment of Interstitial Lung Diseases and Rare Lung Diseases (RCLD) of University of Catania, during the decade 2012-2022. Furthermore, the results of a screening conducted in the same 10-year period (2012-2022) on cohorts of workers potentially exposed to RCS generated by Etna's volcanic dust are reported. Results: From the consultation of the RCLD database, there does not appear to be any correlation between pulmonary fibrosis and exposure to dust of basaltic origin. Conclusions: These data seem to be confirmed by the data of the health monitoring conducted over 10 years on 200 workers involved in different processes of working with lava stone.

Unlocking access: a comprehensive analysis of medicines accessibility for rare diseases in Thailand

IntroductionIn Thailand, obtaining medicines for rare diseases presents significant challenges, with limited evidence highlighting these issues.ObjectivesTo evaluate the accessibility of medicines and the extent of health insurance coverage for treatments of rare diseases in Thailand.MethodThis study utilized a thorough review of current health policies, drug registration database, and insurance coverage conditions. Additionally, procurement data from the Ministry of Finance was analyzed to verify the acquisition of medicines intended for the treatment of rare diseases.ResultsA review of the availability and procurement of medicines for rare diseases in Thailand revealed considerable limitations in both registration and accessibility. According to the International Rare Diseases Research Consortium, only 46.80% of their recommended medicines were registered in Thailand, and of these, just 22.93% were included in the national essential medicines list. Additionally, a review of the state’s pharmaceutical procurement dataset over the past 5 years showed that merely 31.70% of these registered drugs had been purchased from suppliers for use in hospitals.ConclusionTo address these issues, the study recommended accelerating the approval process for rare disease medicines, expanding health insurance coverage, establishing financial support for patients, and creating a specific pricing policy for orphan drugs. Collaborative efforts among stakeholders were emphasized as crucial for improving access to essential medicines and enhancing treatment outcomes for patients with rare diseases in Thailand.

0188 Sleep Quality and Parental Stress in Mothers of Children with Complex Chronic Conditions

Abstract Introduction In recent years, there have been advancements in the diagnosis and treatment of acute and rare diseases. As a result, these diseases have become persistent throughout life, leading to long-term disability and the emergence of a subset of children with complex chronic conditions (CCC). The families of these children experience the burden of care transfer, which impacts their health and well-being, resulting in high levels of parental stress and sleep disturbances. Methods Cross-sectional observational quali-quantitative evaluation assessment involving primary caregivers of children and adolescents with CCC. Exclusion criteria encompassed CCC patients who deceased, were readmitted, or were unreachable by phone. Questionnaires covered main caregiver sociodemographic data. Pittsburgh Sleep Quality Index (PSQI) and Parental Stress Scale were employed. Analyses comprised descriptive statistics with mean, standard deviation, percentage, tests for normality, one-way ANOVA with post hoc analysis and ANCOVA. Results The sample comprised 31 caregivers of children and adolescents with CCC and 31 caregivers of healthy children. Among primary caregivers of children with CCC, 93% were female, a mean PSQI score of 7.6, an average total sleep time of 5 hours and 45 minutes, and sleep latency of 37 minutes. Among caregivers of healthy children, 90% were female, a mean PSQI score of 6.8, an average total sleep time of 6 hours and 27 minutes, and sleep latency of 16 minutes. Comparisons between the groups showed significant differences in daytime caregiving time (7.0 vs 2.8 hours), total parental stress scale scores (7.6 vs 6.8), parental stress domain scores (18.9 vs 13.8), and sleep latency (37.3 vs 16.6 minutes). The groups also differed in daytime caregiving time regardless of total sleep time (5 hours 45 minutes vs 6 hours and 27 minutes). Conclusion Families of children with CCC, compared to families of healthy children, spend more time on caregiving, experience higher parental stress, taking longer to fall asleep and have shorter total sleep durations. Support (if any) We would like to thank AFIP (Associação Fundo de Incentivo à Pesquisa) and CNPq for their collaboration with this study.

Plant molecular farming: a promising frontier for orphan drug production.

Orphan diseases comprise a range of disorders that individually affect a small percentage of people, but collectively impact millions of people worldwide. Patients with this disorder often face significant challenges in diagnosis, treatment, and access to care due to their rare nature and limited understanding and treatment options. In recent years, significant advancements have been made in the global healthcare in addressing the accessibility of essential treatments and medicines, but still challenges persist particularly related to orphan drugs (to treat rare diseases) in the developing world. The accessibility of orphan drugs remains a major challenge, where patients face barriers such as high costs, limited availability, and inadequate healthcare infrastructure. The high cost associated with orphan drugs presents a barrier to affordability for both patients and healthcare systems, causing disparities in access to life-saving treatments. The molecular farming approach utilizing plant-based production systems for recombinant protein production offers a hope for overcoming barriers to orphan drug access in resource-constrained settings. Molecular farming has the potential to produce a wide range of therapeutic proteins and biologics for the treatment of various rare diseases. The FDA approval of plant-derived proteins for the treatment of Gaucher disease (Elelyso) and Fabry disease (Elfabrio) highlights the potential of plant-based expression systems for the development of suitable drugs targeting niche and orphan diseases. This review examines the potential of the plant system in producing orphan drugs and also highlights the opportunities and challenges related to orphan drug manufacturing.

GPI-anchorless prion disease is sensitive to oxidative stress and shows potential for treatment with edaravone, based on iPS-derived neuron study

Only a few reports have generated induced pluripotent stem cells from patients with prion diseases, making it important to conduct translational studies using cells derived from individuals with prion protein (PRNP) mutations. In this study, we established induced pluripotent stem cells from a patient with a glycosylphosphatidylinositol-anchorless PRNP mutation (Y162X), which leads to abnormal deposits of prion protein in various organs. While no abnormal intracellular prion protein deposits were observed in the neurons differentiated from PRNP Y162X induced pluripotent stem cells, extracellular PrP aggregates secretions were significantly increased, and these cells were significantly more sensitive to oxidative stress compared to control cells. Utilizing this PRNP Y162X iPSC-derived neuron model, we discovered that edaravone reduced the sensitivity of PRNP Y162X cells to oxidative stress. Following this finding, we treated a PRNP Y162X patient with edaravone for two years, which successfully suppressed indicators of disease progression. Our study demonstrates that the pathology of the glycosylphosphatidylinositol-anchorless PRNP mutation is associated with oxidative stress and highlights the potential of induced pluripotent stem cell technology in identifying novel treatments for rare prion diseases.

Aptamer-ODN Chimeras: Enabling Cell-Specific ODN Targeting Therapy.

Oligonucleotides (ODNs) such as siRNA, saRNA, and miRNA regulate gene expression through a variety of molecular mechanisms and show unique potential in the treatment of genetic diseases and rare diseases, but their clinical application is still limited by the efficiency of the delivery system, especially the problem of the insufficient targeting of extrahepatic tissues. As homologous nucleic acid molecules, aptamers have become a key tool to improve the targeted delivery of ODNs. Aptamer-ODN chimeras can not only bind to multiple proteins on the cell surface with high specificity and selectivity, but they can also internalize into cells. Furthermore, they outperform traditional delivery systems in terms of cost-effectiveness and chemical modification flexibility. This review systematically summarizes the origin and progress of aptamer-ODN chimera therapy, discusses some innovative design strategies, and proposes views on the future direction of aptamer-ODN chimeras.

Regulatory aspects of optogenetic research and therapy for retinitis pigmentosa under EU law.

Optogenetics has potentials for a treatment of retinitis pigmentosa and other rare degenerative retinal diseases. The technology allows controlling cell activity through combining genetic engineering and optical stimulation with light. First clinical studies are already being conducted, whereby the vision of participating patients who were blinded by retinitis pigmentosa was partially recovered. In view of the ongoing translational process, this paper examines regulatory aspects of preclinical and clinical research as well as a therapeutic application of optogenetics in ophthalmology. There is no prohibition or specific regulation of optogenetic methods in the European Union. Regarding preclinical research, legal issues related to animal research and stem cell research have importance. In clinical research and therapeutic applications, aspects of subjects' and patients' autonomy are relevant. Because at EU level, so far, no specific regulation exists for clinical studies in which a medicinal product and a medical device are evaluated simultaneously (combined studies) the requirements for clinical trials with medicinal products as well as those for clinical investigations on medical devices apply. This raises unresolved legal issues and is the case for optogenetic clinical studies, when for the gene transfer a viral vector classified as gene therapy medicinal product (GTMP) and for the light stimulation a device qualified as medical device are tested simultaneously. Medicinal products for optogenetic therapies of retinitis pigmentosa fulfill requirements for designation as orphan medicinal product, which goes along with regulatory and financial incentives. However, equivalent regulation does not exist for medical devices for rare diseases.

The PLN Foundation is striving for a cure, but who owns the disease?

The PLN Foundation, established in 2012, supports about 1700 individuals with a phospholamban (PLN) gene mutation causing severe cardiomyopathy. It aims to cure this rare disease by collaborating with universities, research institutions, and biotechnology companies. However, the foundation often faces challenges in being recognised as an equal research partner, with legal departments and technology transfer offices (TTOs) prioritising institutional interests over the public good, leading to delays and inefficiencies. The scientific culture’s ‘publish or perish’ mentality, patent ownership issues, and bureaucratic ethics review processes further complicate progress. To overcome these barriers, the foundation advocates IP co-ownership, patient leadership, streamlined agreements, provisional ethical approvals, improved research logistics, revised evaluation metrics for scientists, and a shift in TTO strategies towards co-creation. These measures aim to enhance collaboration, accelerate therapeutic development, and ensure the accessibility and affordability of new treatments for rare diseases.

Drug development for rare diseases: a case for patient-centricity, equity, and access to clinical trials

PurposeClinical trials often represent the only viable treatment option for many rare disease patients. However, these patients face significant barriers to participation, including cognitive and physical limitations, geographic disparities, misdiagnosis, and socioeconomic challenges, with minority groups being particularly affected. We chose to focus on clinical trials because they serve as a pivotal step in translating scientific advancements into tangible treatment options, making them a critical area for intervention. While the broader challenges in orphan drug development and commercialization are acknowledged, this study specifically targets the barriers to clinical trial access. Overcoming these obstacles is essential for improving patient outcomes and accelerating the availability of new treatments. By identifying these key challenges and proposing actionable solutions, this paper explores how regulatory frameworks can be adapted to incorporate patient-centric approaches and health equity principles, ultimately enhancing access to clinical trials and treatments for rare disease patients.MethodA two-pronged study was conducted. Group A involved a focus group discussion with 19 rare disease subject matter experts (SMEs) in regulation, policy, and healthcare. Group B consisted of 10 individuals directly connected to rare diseases. Semi-structured interviews were conducted to explore participants’ experiences and concerns regarding access to clinical trials, equity, and patient-centricity. The aim was to understand how these factors impact participation in clinical trials and the development of treatments.ResultsThree major impediments to accessing healthcare for the rare disease population were identified: inconsistent government regulations, inadequate support networks (financial and treatment gaps), and insufficient information on rare diseases. These regulatory inconsistencies, particularly between the USA and other countries, lead to delayed diagnoses and treatments. While emotional support is available, gaps remain in financial and treatment assistance. Additionally, significant information deficits exist for both patients and healthcare providers. Participants underscored the importance of incorporating patients and caregivers early in the drug development process to ensure treatments meet their needs and are inclusive.ConclusionThis study highlights the importance of adapting regulatory frameworks to integrate health equity and patient-centric approaches, improving clinical trial access and the overall treatment process for rare disease patients. By incorporating patient voices early in the drug development cycle, clinical trials can become more inclusive and effective, ensuring that treatments are both relevant and accessible to underserved populations.

Exemption System for Economic Evaluation Data Submission for Pharmaceuticals in South Korea: Achievements and Challenges.

Exemption System for Economic Evaluation Data Submission for Pharmaceuticals in South Korea: Achievements and Challenges.