Genes (Basel). 2023 Nov 18;14(11):2100. doi: 10.3390/genes14112100.

ABSTRACT

Phenotypicheterogeneity is a phenomenon in which distinct phenotypes can develop in individuals bearing pathogenic variants in the same gene. Genetic factors, gene interactions, and environmental factors are usually considered the key mechanisms of this phenomenon. Phenotypic heterogeneity may impact the prognosis of the disease severity and symptoms. In our work, we used publicly available data on the association between genetic variants and Mendelian disease to investigate the genetic factors (such as the intragenic localization and type of a variant) driving the heterogeneity of gene-disease relationships. First, we showed that genes linked to multiple rare diseases (GMDs) are more constrained and tend to encode more transcripts with high levels of expression across tissues. Next, we assessed the role of variant localization and variant types in specifying the exact phenotype for GMD variants. We discovered that none of these factors is sufficient to explain the phenomenon of such heterogeneous gene-disease relationships. In total, we identified only 38 genes with a weak trend towards significant differences in variant localization and 30 genes with nominal significant differences in variant type for the two associated disorders. Remarkably, four of these genes showed significant differences in both tests. At the same time, our analysis suggests that variant localization and type are more important for genes linked to autosomal dominant disease. Taken together, our results emphasize the gene-level factors dissecting distinct Mendelian diseases linked to one common gene based on open-access genetic data and highlight the importance of exploring other factors that contributed to phenotypic heterogeneity.

PMID:38003043 | PMC:PMC10671084 | DOI:10.3390/genes14112100

Orphanet J Rare Dis. 2023 Nov 23;18(1):364. doi: 10.1186/s13023-023-02934-9.

ABSTRACT

BACKGROUND: Poorly coordinated care can have major impacts on patients and families affected by rare conditions, with negative physical health, psychosocial and financial consequences. This study aimed to understand how care is coordinated for rare diseases in the United Kingdom.

METHODS: We undertook a national survey in the UK involving 760 adults affected by rare diseases, 446 parents/carers of people affected by rare diseases, and 251 healthcare professionals who care for people affected by rare diseases.

RESULTS: Findings suggested that a wide range of patients, parents and carers do not have coordinated care. For example, few participants reported having a care coordinator (12% patients, 14% parents/carers), attending a specialist centre (32% patients, 33% parents/carers) or having a care plan (10% patients, 44% parents/carers). A very small number of patients (2%) and parents/carers (5%) had access to all three-a care coordinator, specialist centre and care plan. Fifty four percent of patients and 33% of parents/carers reported access to none of these. On the other hand, a higher proportion of healthcare professionals reported that families with rare conditions had access to care coordinators (35%), specialist centres (60%) and care plans (40%).

CONCLUSIONS: Care for families with rare conditions is generally not well coordinated in the UK, with findings indicating limited access to care coordinators, specialist centres and care plans. Better understanding of these issues can inform how care coordination might be improved and embrace the needs and preferences of patients and families affected by rare conditions.

PMID:37996938 | PMC:PMC10668407 | DOI:10.1186/s13023-023-02934-9

Orphanet J Rare Dis. 2023 Nov 23;18(1):363. doi: 10.1186/s13023-023-02892-2.

ABSTRACT

BACKGROUND: Although rare diseases (RD) are increasingly becoming a priority for healthcare activities and services around the world, developing research policy for investigating RD in public settings proves challenging due to the limited nature of existing evidence. Rare conditions require the involvement of a wide range of stakeholders in order to promote general awareness and garner political support. Consequently, it is critically important to identify trends in the various types of research focusing on rare disease stakeholders, including the specific topics or issues to be included in surveys and studies focused on RD stakeholders. This systematic review and thematic analysis analyses the existing literature based on RD surveys, including the stakeholders involved, and proposes potential research priorities and initiatives for policy-making related to RD.

METHODS: Articles were downloaded and analyzed from across five electronic databases (PubMed, EMBASE, Cochrane Central, Web of Science, and CINHAL) and 115 studies were included.

RESULTS: Across 115 studies, the main research participants were patients and/or caregivers (n = 77, 67.0%), health professionals (n = 18, 15.7%), and the public (n = 7, 6.1%). The studies discussed RDs in general (n = 46, 40.0%), endocrine, nutritional, and metabolic diseases (n = 20, 17.4%) and other RDs. Experiences with RD were examined by more than half of the selected studies (n = 74, 64.3%), followed by the opinions of stakeholders (n = 24, 20.9%). Most of the studies used surveys in order to collect relevant data (n = 114, 99.1%). Additionally, the majority of the studies were conducted in high-income countries (n = 92, 80.0%) and rarely in middle and low-income countries (n = 12, 13.8%).

CONCLUSION: Stakeholder research on RD reveals that there are significant instances of unmet needs and various challenges faced by the medical system in dealing with RDs. Furthermore, public awareness and support is critical to ensuring political feasibility of increasing national-level investments for RDs and development of medical products and treatment.

PMID:37996931 | PMC:PMC10668415 | DOI:10.1186/s13023-023-02892-2

Anaesth Intensive Care. 2024 Jan;52(1):64-68. doi: 10.1177/0310057X231183981. Epub 2023 Nov 23.

ABSTRACT

A 19-year-old woman with known maple syrup urine disease presented to hospital with metabolic crisis in the setting of influenza type A infection and intractable vomiting, rapidly progressing to acute cerebral oedema manifesting as refractory seizures and decreased level of consciousness needing emergency intubation and mechanical ventilation, continuous veno-venous haemodiafiltration and thiopentone coma. A computed tomography scan and magnetic resonance imaging of the brain demonstrated classic signs of cerebral oedema secondary to a metabolic crisis from the metabolic disorder. Her management posed multiple challenges to all teams involved due to lack of familiarity and experience in managing this clinical scenario in the adult intensive care setting.

PMID:37994838 | DOI:10.1177/0310057X231183981

PLoS One. 2023 Nov 22;18(11):e0293503. doi: 10.1371/journal.pone.0293503. eCollection 2023.

ABSTRACT

Since 72% of rare diseases are genetic in origin and mostly paediatrics, genetic newborn screening represents a diagnostic "window of opportunity". Therefore, many gNBS initiatives started in different European countries. Screen4Care is a research project, which resulted of a joint effort between the European Union Commission and the European Federation of Pharmaceutical Industries and Associations. It focuses on genetic newborn screening and artificial intelligence-based tools which will be applied to a large European population of about 25.000 infants. The neonatal screening strategy will be based on targeted sequencing, while whole genome sequencing will be offered to all enrolled infants who may show early symptoms but have resulted negative at the targeted sequencing-based newborn screening. We will leverage artificial intelligence-based algorithms to identify patients using Electronic Health Records (EHR) and to build a repository "symptom checkers" for patients and healthcare providers. S4C will design an equitable, ethical, and sustainable framework for genetic newborn screening and new digital tools, corroborated by a large workout where legal, ethical, and social complexities will be addressed with the intent of making the framework highly and flexibly translatable into the diverse European health systems.

PMID:37992053 | PMC:PMC10664952 | DOI:10.1371/journal.pone.0293503

N Engl J Med. 2023 Nov 23;389(21):2010-2013. doi: 10.1056/NEJMe2310332.

NO ABSTRACT

PMID:37991861 | DOI:10.1056/NEJMe2310332

bioRxiv. 2023 Nov 6:2023.11.06.565899. doi: 10.1101/2023.11.06.565899. Preprint.

ABSTRACT

The mammalian cerebral cortex shows functional specialization into regions with distinct neuronal compositions, most strikingly in the human brain, but little is known in about how cellular lineages shape cortical regional variation and neuronal cell types during development. Here, we use somatic single nucleotide variants (sSNVs) to map lineages of neuronal sub-types and cortical regions. Early-occurring sSNVs rarely respect Brodmann area (BA) borders, while late-occurring sSNVs mark neuron-generating clones with modest regional restriction, though descendants often dispersed into neighboring BAs. Nevertheless, in visual cortex, BA17 contains 30-70% more sSNVs compared to the neighboring BA18, with clones across the BA17/18 border distributed asymmetrically and thus displaying different cortex-wide dispersion patterns. Moreover, we find that excitatory neuron-generating clones with modest regional restriction consistently share low-mosaic sSNVs with some inhibitory neurons, suggesting significant co-generation of excitatory and some inhibitory neurons in the dorsal cortex. Our analysis reveals human-specific cortical cell lineage patterns, with both regional inhomogeneities in progenitor proliferation and late divergence of excitatory/inhibitory lineages.

PMID:37986891 | PMC:PMC10659282 | DOI:10.1101/2023.11.06.565899

BMJ Open. 2023 Nov 21;13(11):e072001. doi: 10.1136/bmjopen-2023-072001.

ABSTRACT

INTRODUCTION: Rare diseases are chronic conditions, generally incurable, progressive and disabling, which may result in early death. Access to therapeutic products, both medicines and appropriate medical devices, is essential to prevent the progression of the disease and maintain the patients' quality of life. Pharmacists can be part of health teams, in charge of guiding patients' journey, monitoring pharmacotherapy and identifying risks. This scoping review aims to identify and summarise evidence on the role of pharmacists and its impact in the field of rare diseases.

METHODS AND ANALYSIS: The searches will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline for protocols. Three electronic databases will be consulted. Studies reporting on qualitative and/or quantitative data from any world region will be considered. There will be no language or initial time limit for studies inclusion, until December 2022. To be eligible for inclusion, studies must focus on the role pharmacists in clinical services aimed at promote the access to medicines, prevention and resolution of problems related to pharmacotherapy. No assessments of items' quality will be made, as the purpose of this scoping review is to synthesise and describe the coverage of the evidence. Clinical, humanistic or economic outcomes from studies that meet the inclusion criteria will be included in the review. The analysis will synthesise the available evidence and may be able to push pharmaceutical practice forward, aiding professionals, educators and managers in the implementation of new approaches to better meet the needs of rare diseases and providing opportunities for future research.

ETHICS AND DISSEMINATION: Primary data will not be collected in this study and formal ethical approval is not required. The findings of this study will be disseminated through peer-reviewed publications and conference presentations.

PMID:37989368 | PMC:PMC10668274 | DOI:10.1136/bmjopen-2023-072001

J Patient Rep Outcomes. 2023 Nov 20;7(1):119. doi: 10.1186/s41687-023-00655-y.

ABSTRACT

BACKGROUND: Erythropoietic protoporphyria is a rare, inherited disorder presenting in early childhood with severe, painful phototoxicity. EPP has significant impacts on health-related quality of life, though there is variable disease severity. Accurately capturing how much time individuals with EPP can spend outdoors before they develop symptoms is critical to understanding HRQoL and measuring therapeutic response. Therefore, the goal of this study was to develop a comprehensive and content valid sun exposure diary to assess the efficacy of new therapies in individuals with EPP.

METHODS: Qualitative interviews were conducted with adult and adolescent EPP participants, as well as five clinical experts, to obtain their input on the content of an existing sun exposure diary. Revisions to the diary were made based on evidence generated in cognitive debriefing interviews analyzed in eight consecutive groups of EPP participant.

RESULTS: Interviews were conducted with 17 adults and 6 adolescents with EPP. The average age of adults was 40 years and of adolescents was 14 years. Clinical experts thought the original diary needed clarification on the description of symptoms, how time outdoors was captured, and the distinction between direct vs. indirect sunlight. Participants with EPP also noted these items needed revision, and that the distinction between prodromal symptoms and full reaction symptoms should be clarified. In the final diary version, participants with EPP found most items to be clear and easy to complete/think about. Seventy-six percent of participants (13/17) asked thought the diary was easy to complete. The remainder thought the majority of the diary was easy to complete with the exception of select questions.

CONCLUSIONS: Evaluating a new treatment for EPP requires accurately capturing time in sunlight and symptoms in this unique disorder. The newly developed sun exposure diary is content valid and can be used to assess important aspects of symptoms and daily life and therefore evaluate clinically meaningful therapeutic response.

PMID:37982964 | DOI:10.1186/s41687-023-00655-y

Med Sci Monit. 2023 Nov 20;29:e941536. doi: 10.12659/MSM.941536.

ABSTRACT

BACKGROUND A rare disease is a health condition that rarely occurs in the population. It is estimated that up to 400 million people around the world suffer from a rare disease. This retrospective study aimed to investigate factors associated with length of hospitalization in 78 626 patients with sarcoidosis, 3294 patients with adults-onset Still's disease, and 35 549 patients with systemic sclerosis between 2009 and 2018 using data from the National Institute of Public Health in Poland. MATERIAL AND METHODS In this population-based study, we analyzed hospital discharge records of first-time and subsequent hospitalizations. To perform the statistical analyses, R software was used. RESULTS The average length of hospitalization over the selected period in the diseases was 5.39 days for sarcoidosis, 6.22 days for scleroderma, and 7.44 days for Still's disease, and was shorter for each of the diseases analyzed compared with the length of hospitalization for second and subsequent stays. There were no substantial differences in length of hospitalization between males and females. The average length of hospitalization increased with each additional comorbidity. CONCLUSIONS The study showed that hospitalizations for selected rare diseases do not cause a significant burden on the healthcare system. The results also showed that advanced age and comorbidities are important factors determining the length of hospitalization. The average length of hospital stay for selected rare diseases in Poland is not longer than the European Union (EU) average, so it can be assumed that the process of inpatient treatment in Poland is optimal.

PMID:37981760 | DOI:10.12659/MSM.941536

Metabolism. 2024 Jan;150:155738. doi: 10.1016/j.metabol.2023.155738. Epub 2023 Nov 18.

ABSTRACT

Inborn errors of metabolism (IEMs) are a group of more than 1000 inherited diseases that are individually rare but have a cumulative global prevalence of 50 per 100,000 births. Recently, it has been recognized that like common diseases, patients with rare diseases can greatly vary in the manifestation and severity of symptoms. Here, we review omics-driven approaches that enable an integrated, holistic view of metabolic phenotypes in IEM patients. We focus on applications of Constraint-based Reconstruction and Analysis (COBRA), a widely used mechanistic systems biology approach, to model the effects of inherited diseases. Moreover, we review evidence that the gut microbiome is also altered in rare diseases. Finally, we outline an approach using personalized metabolic models of IEM patients for the prediction of biomarkers and tailored therapeutic or dietary interventions. Such applications could pave the way towards personalized medicine not just for common, but also for rare diseases.

PMID:37981189 | DOI:10.1016/j.metabol.2023.155738

Orphanet J Rare Dis. 2023 Nov 17;18(1):362. doi: 10.1186/s13023-023-02944-7.

ABSTRACT

BACKGROUND: Rare diseases (RD) are a heterogeneous group of diseases, sharing aspects of complexity. Prognosis is variable, even in individuals with the same disease. Real-world data on RD as a whole are scarce. The aim of this study is to provide data on mortality and survival for a substantial group of RD deriving from a population-based registry, which covers the Veneto region in Italy (4.9 million inhabitants).

RESULTS: During the study period, 3367 deaths occurred, mainly in males (53.9%), elderly patients (63.5%) and patients with diseases having a reported prevalence of 1-9/100000 (65.6%). When standardizing by age, the mortality ratio was higher in RD patients than in the general population, SMR = 1.93 (95% CI 1.84-2.11), with an observed gender difference, 2.01 (95% CI 1.88-2.29) in females and 1.86 (95% CI 1.73-2.10) in males. The lowest survival rates are experienced by patients with rare neurologic diseases, rare skin diseases and rare systemic or rheumatologic diseases, 58%, 68% and 81%, respectively, after a 15-year observation period. It should be noted that only 18% of patients diagnosed with motor neuron diseases were alive after 15 years from diagnosis.

CONCLUSIONS: Despite progress in diagnosis, treatment and care in recent years, RD patients globally have higher mortality rates and reduced survival compared to the general population, with specific variations according to gender, age and disease group.

PMID:37978388 | PMC:PMC10655462 | DOI:10.1186/s13023-023-02944-7

Med Sci (Paris). 2023 Nov;39 Hors série n° 1:67-71. doi: 10.1051/medsci/2023138. Epub 2023 Nov 17.

NO ABSTRACT

PMID:37975776 | DOI:10.1051/medsci/2023138

Lancet Neurol. 2023 Dec;22(12):1125-1139. doi: 10.1016/S1474-4422(23)00313-7.

ABSTRACT

BACKGROUND: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1.

METHODS: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated.

FINDINGS: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure).

INTERPRETATION: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing.

FUNDING: Astellas Gene Therapies.

PMID:37977713 | DOI:10.1016/S1474-4422(23)00313-7

Indian J Otolaryngol Head Neck Surg. 2023 Dec;75(4):3798-3814. doi: 10.1007/s12070-023-03998-6. Epub 2023 Jul 10.

ABSTRACT

Tracheobronchopathia osteochondroplastica (TO) is an orphan disease of the tracheobronchial tree without any known etiological attributes. There are several case reports published on this condition, yet the available information about the TO is discrete and of little clinical value. This scoping review is the first large-scale review on TO that collates individual patient data from the published case reports and descriptively analyses the clinicopathological features of this unique condition along with its management approaches and therapeutic outcomes. The objective was to synthesize comprehensive literature review on TO that can aid clinical practice and further research. An electronic search conducted in five large databases, including PubMed, EMBASE, CINAHL, CENTRAL, and Web of Science, for the published articles of TO yielded 1072 items. After screening, the individual patient data of 371 TO cases from 228 eligible articles were included and analysed in this scoping review.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12070-023-03998-6.

PMID:37974722 | PMC:PMC10646011 | DOI:10.1007/s12070-023-03998-6

Semin Liver Dis. 2023 Nov;43(4):446-459. doi: 10.1055/s-0043-1776760. Epub 2023 Nov 16.

ABSTRACT

The porphyrias are a group of metabolic disorders that are caused by defects in heme biosynthesis pathway enzymes. The result is accumulation of heme precursors, which can cause neurovisceral and/or cutaneous photosensitivity. Liver is commonly either a source or target of excess porphyrins, and porphyria-associated hepatic dysfunction ranges from minor abnormalities to liver failure. In this review, the first of a three-part series, we describe the defects commonly found in each of the eight enzymes involved in heme biosynthesis. We also discuss the pathophysiology of the hepatic porphyrias in detail, covering epidemiology, histopathology, diagnosis, and complications. Cellular consequences of porphyrin accumulation are discussed, with an emphasis on oxidative stress, protein aggregation, hepatocellular cancer, and endothelial dysfunction. Finally, we review current therapies to treat and manage symptoms of hepatic porphyria.

PMID:37973028 | DOI:10.1055/s-0043-1776760

J Comp Eff Res. 2023 Nov 16:e230054. doi: 10.57264/cer-2023-0054. Online ahead of print.

ABSTRACT

Aim: Patients with Rett syndrome (RTT) experience gastrointestinal (GI) manifestations. This study aimed to describe the prevalence of GI manifestations and the associated medical costs in patients with RTT in the USA. Patients & Methods: The study combined an insurance claims database analysis with a survey of 100 physicians experienced in RTT management. Results: GI manifestations affected 43.0% of 5940 patients, with increased prevalence in pediatric patients (45.6%) relative to adult patients (40.2%). Annualized mean medical cost of managing GI manifestations was $4473. Only 5.9-8.2% of neurologists and pediatricians ranked GI symptom management among the five most important treatment goals. Conclusion: Patients with RTT experience a high burden of GI manifestations, which translate to considerable medical costs. Importantly, the prevalence of GI manifestations was likely underestimated in this study, as only those symptoms which resulted in a healthcare encounter were captured.

PMID:37971297 | DOI:10.57264/cer-2023-0054

Med. 2023 Dec 8;4(12):913-927.e3. doi: 10.1016/j.medj.2023.10.003. Epub 2023 Nov 13.

ABSTRACT

BACKGROUND: Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology specifically designed to organize medical procedures, therapies, and interventions.

METHODS: MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology.

FINDINGS: MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases.

CONCLUSIONS: MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO).

FUNDING: NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04.

PMID:37963467 | DOI:10.1016/j.medj.2023.10.003

BMC Med Res Methodol. 2023 Nov 13;23(1):269. doi: 10.1186/s12874-023-02080-7.

ABSTRACT

BACKGROUND: The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design.

METHODS: PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-‍1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies.

RESULTS: Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes.

CONCLUSIONS: A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development.

TRIAL REGISTRATION: NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).

PMID:37957586 | DOI:10.1186/s12874-023-02080-7

Int J Mol Sci. 2023 Nov 6;24(21):15999. doi: 10.3390/ijms242115999.

ABSTRACT

Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs is still elusive. Several metabolites, which accumulate in IEMs, were shown to self-assemble to form ordered structures. These structures display the same biophysical, biochemical, and biological characteristics as proteinaceous amyloid fibrils. Here, we have demonstrated, for the first time, the ability of each of the branched-chain amino acids (BCAAs) that accumulate in maple syrup urine disease (MSUD) to self-assemble into amyloid-like fibrils depicted by characteristic morphology, binding to indicative amyloid-specific dyes and dose-dependent cytotoxicity by a late apoptosis mechanism. We could also detect the presence of the assemblies in living cells. In addition, by employing several in vitro techniques, we demonstrated the ability of known polyphenols to inhibit the formation of the BCAA fibrils. Our study implies that BCAAs possess a pathological role in MSUD, extends the paradigm-shifting concept regarding the toxicity of metabolite amyloid-like structures, and suggests new pathological targets that may lead to highly needed novel therapeutic opportunities for this orphan disease.

PMID:37958982 | DOI:10.3390/ijms242115999