Orphanet J Rare Dis. 2021 Oct 30;16(1):457. doi: 10.1186/s13023-021-02064-0.

ABSTRACT

BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease, characterised by fluctuating muscle weakness which makes it challenging to assess symptom severity. Mixed methods psychometrics (MMP), which combines evidence from qualitative research and modern psychometrics, is a versatile approach to the development of patient-centred outcome measures (PCOM) in the context of rare disease. Our objective was to develop the MG Symptom patient-reported outcome (PRO) to assess key aspects of MG severity from the patient perspective.

METHODS: We used MMP to develop a novel PRO instrument in a multi-step process. An initial conceptual model for MG patient experience was developed and expanded based on preliminary literature review and two waves of concept elicitation interviews with people with MG (Step 1). Based on this, the novel PRO instrument, the MG Symptoms PRO, was drafted. The draft instrument was refined by combining qualitative and quantitative data collected in a Phase 2 clinical study (Step 2).

RESULTS: Findings from the literature review and concept elicitation interviews (n = 96) indicated that patient experience in MG includes proximal muscle weakness symptoms related to several body parts, along with muscle weakness fatigability and general fatigue. Then, a set of 42 items across five scales (ocular-, bulbar-, and respiratory muscle weakness, physical fatigue, and muscle weakness fatigability) was developed. Qualitative evidence endorsed its relevance, clarity, and ease of completion; quantitative analysis with Rasch measurement theory methods demonstrated strong measurement properties, including good targeting and high reliability. Classical test theory analyses showed adequate reliability of the instrument and mild to moderate correlations with other widely used MG-specific outcome measures.

CONCLUSIONS: The MG Symptoms PRO has potential to be used both to measure treatment benefit in clinical trials and monitor symptom severity in clinical practice. Its component scales were purposefully designed to stand alone, enhancing interpretability of scores given the heterogeneity of MG, and enabling modular use. Compared with existing MG PROs, it contains more detailed assessments of muscle weakness and muscle weakness fatigability symptoms, which are of key importance to people with MG. The MMP approach used may serve as a case study for developing PCOMs across rare disease indications.

PMID:34717694 | PMC:PMC8556940 | DOI:10.1186/s13023-021-02064-0

Orphanet J Rare Dis. 2021 Oct 30;16(1):456. doi: 10.1186/s13023-021-02052-4.

ABSTRACT

BACKGROUND: Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, life-limiting lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase can stabilize or improve many somatic manifestations, but there remains a need for further analysis of long-term treatment outcomes. Using data from patients with MPS II enrolled in the Hunter Outcome Survey (HOS), mixed modeling was performed to evaluate and predict the effects of IV idursulfase treatment on selected clinical parameters for up to 8 years following treatment start. The modeling population comprised male patients followed prospectively in HOS who had received IV idursulfase for at least 5 years and who had data available for two or more time points (at least one post-ERT). Age at ERT start and time since ERT start were included as covariates.

RESULTS: In total, 481 patients were eligible for inclusion in at least one model. At 8 years post-ERT start, improvement from baseline was predicted for each age group (< 18 months, 18 months to < 5 years and ≥ 5 years at treatment start) in the following parameters: mean urinary glycosaminoglycan levels (percentage changes of > -75% in each group), mean left ventricular mass index (decreases of ~ 1 g/m2) and mean palpable liver size (decreases of > 2 cm). Improvements in mean 6-min walk test distance (increase of > 50 m) and stabilization in percent predicted forced vital capacity and forced expiratory volume in 1 s (decreases of ~ 4 and ~ 9 percentage points, respectively) at 8 years post-ERT start were predicted for patients aged ≥ 5 years at ERT start (these assessments are unsuitable for patients aged < 5 years). Predicted changes over time were similar across the three age groups; however, overall outcomes were most favorable in children aged < 18 months at ERT start.

CONCLUSIONS: These findings suggest that the previously reported positive effects of IV idursulfase on the somatic manifestations of MPS II are predicted to be maintained for at least 8 years following ERT initiation and highlight the value of statistical modeling to predict long-term treatment outcomes in patients with rare diseases.

PMID:34717704 | PMC:PMC8557006 | DOI:10.1186/s13023-021-02052-4

Orphanet J Rare Dis. 2021 Oct 29;16(1):454. doi: 10.1186/s13023-021-02089-5.

ABSTRACT

BACKGROUND: Rare diseases (RDs) affect nearly 3 million people in France and at least 26-30 million people in Europe. These diseases, which represent a major medical concern, are mainly of genetic origin, often chronic, progressive, degenerative, life threatening and disabling, accounting for more than one third of all deaths occurring during infancy. In this context, there are needs for coordinated information on RDs at national/international levels, based on high quality, interoperable and sharable data. The main objective of the RaDiCo (Rare Disease Cohorts) program, coordinated by Inserm, was the development of RD e-cohorts via a national platform. The cohort projects were selected through a national call in 2014. The e-cohorts are supported by an interoperable platform, equivalent to an infrastructure, constructed on the "cloud computing" principle and in compliance with the European General Data Protection Regulation. It is dedicated to allow a continuous monitoring of data quality and consistency, in line with the French Health Data Hub.

RESULTS: Depending on cohorts, the objectives are to describe the natural history of the studied RD(s), identify the underlying disease genes, establish phenotype-genotype correlations, decipher their pathophysiology, assess their societal and medico-economic impact, and/or identify patients eligible for new therapeutic approaches. Inclusion of prevalent and incident cases started at the end of 2016. As of April 2021, 5558 patients have been included within 13 RD e-cohorts covering 67 diseases integrated in 10 European Reference Networks and contributing to the European Joint Program on RDs. Several original results have been obtained in relation with the secondary objectives of the RaDiCo cohorts. They deal with discovery of new disease genes, assessment of treatment management, deciphering the underlying pathophysiological mechanisms, diagnostic approaches, genotype-phenotype relationships, development and validation of questionnaires relative to disease burden, or methodological aspects.

CONCLUSION: RaDiCo currently hosts 13 RD e-cohorts on a sharable and interoperable platform constructed on the "cloud computing" principle. New RD e-cohorts at the European and international levels are targeted.

PMID:34715889 | PMC:PMC8555205 | DOI:10.1186/s13023-021-02089-5

Front Public Health. 2021 Oct 6;9:729162. doi: 10.3389/fpubh.2021.729162. eCollection 2021.

ABSTRACT

Background: Through collection and sorting of rare disease projects funded by the National Natural Science Foundation of China, an understanding was gained of the categories of projects funded by the foundation in the field of rare diseases, types of diseases, categories of disease systems, regional distribution, distribution of supporting institutions, and their dynamic changes, followed by an analysis of focuses and influences of relevant state policies. This will help improve the rare disease-relating policies of the state in supporting the key fields, thus promoting healthy and sustainable development in the field of rare diseases. Method: Through the website of inquiry of projects funded by the National Natural Science Foundation of China, a retrieval was made concerning the projects funded by the foundation in the field of rare diseases during the period from 1986 to 2019, followed by descriptive analysis of fund input of rare disease projects, number of projects, temporal and regional distribution, and the analysis of the law of their dynamic changes. Result: As of the end of 2019, there were 57 rare diseases and 678 related projects funded by the National Natural Science Foundation of China, with accumulated total funding of ¥ 253,525,000. Among the categories of projects, the most-funded projects were general (¥ 150,145,000, 59.22%), followed by Youth Foundation projects (¥ 53,719,000, 21.19%) and key projects (¥ 15,870,000, 6.26%); among the categories of disease systems, the most funded disease system was the nervous system (¥ 93,186,000, 37.76%), followed by the respiratory system (¥ 35,444,000, 13.98%); the most funded diseases were multiple sclerosis (¥ 34,870,000, 13.75%), idiopathic pulmonary fibrosis (¥ 29,854,000, 11.78%), and retinitis pigmentosa (¥ 27,005,000, 10.65%); the most funded regions were East China (¥ 106,987,000, 42.20%) and North China (¥ 71,844,000, 28.34%), while the least funded region was Northwest China (¥ 7,295,000, 2.88%); among the supporting institutions, the most funded institutions were Peking University (¥ 24,720,000, 9.75%), and Sun Yat-sen University (¥ 14,505,000, 5.72%). Conclusion: With the promulgation of more policies on encouragement of innovation and accelerated approval procedures, etc., the National Natural Science Foundation of China has been increasing its funding to rare diseases, covering increasingly more categories of funded projects, more types of diseases, and wider regions. Nonetheless, the support for scientific research in China is still relatively weak. Therefore, it is proposed that the healthy and sustainable development in the course of rare diseases should be promoted through the improvement of relevant rare disease policies, encouragement of R&D of medicine for rare diseases, the establishment of special funds for rare diseases, acceleration of fund circulation, and combination of balanced development and preferential funding to key regions and major diseases.

PMID:34712637 | PMC:PMC8547256 | DOI:10.3389/fpubh.2021.729162

Lancet Haematol. 2021 Nov;8(11):e790-e791. doi: 10.1016/S2352-3026(21)00315-X.

NO ABSTRACT

PMID:34715047 | DOI:10.1016/S2352-3026(21)00315-X

J Postgrad Med. 2021 Oct-Dec;67(4):232-234. doi: 10.4103/jpgm.JPGM_1231_20.

ABSTRACT

Duodenal inversum is a rare disease not frequently encountered in clinical practice. The diagnosis is usually made late due to its rarity. Many other causes of abdominal pain like ulcer disease, pancreatitis, malrotation are mostly thought of initially and the diagnosis is usually missed. Only a few cases of duodenal inversum present with outlet obstruction. Duodenojejunostomy is perhaps the ideal management for duodenal inversum if the patient presents with outlet obstruction. Our intention is to create awareness of such a rare disease with an available definitive treatment option in the form of minimally invasive surgery. One such case of a 31-year-old man is described that was successfully managed by laparoscopic duodenojejunostomy.

PMID:34708698 | DOI:10.4103/jpgm.JPGM_1231_20

ERJ Open Res. 2021 Oct 25;7(4):00507-2021. doi: 10.1183/23120541.00507-2021. eCollection 2021 Oct.

ABSTRACT

Bronchiectasis has received increasing attention in recent years. At the same time, studies have shown a high incidence of this disease, especially in older populations, associated with high health-related costs and economic burden. https://bit.ly/2WPfVZ7.

PMID:34708118 | PMC:PMC8542967 | DOI:10.1183/23120541.00507-2021

Eur J Hum Genet. 2021 Oct 28. doi: 10.1038/s41431-021-00985-9. Online ahead of print.

ABSTRACT

ITSN1 plays an important role in brain development. Recent studies in large cohorts of subjects with neurodevelopmental disorders have identified de novo variants in ITSN1 gene thereby suggesting that this gene is involved in the development of such disorders. The aim of this study is to provide further proof of such a link. We performed trio exome sequencing in a patient presenting autism, intellectual disability, and severe behavioral difficulties. Additional affected patients with a neurodevelopmental disorder harboring a heterozygous variant in ITSN1 (NM_003024.2) were collected through a worldwide collaboration. All patients underwent detailed phenotypic and genetic assessment and data was collected and shared by healthcare givers. We identified ten novel patients from eight families with heterozygous truncating or missense variants in ITSN1 gene. In addition, four previously published patients from large meta-analysis studies were included. In total, 7/14 patients presented a de novo variant in ITSN1. All patients showed neurodevelopmental disorders from autism spectrum disorders (90%), intellectual disability (86%), and epilepsy (30%). We demonstrated that truncating variants are in the first half of ITSN1 whereas missense variants are clustered in C-terminal region. We suggest ITSN1 gene is involved in development of an autism spectrum disorder with variable additional neurodevelopmental deficiency, thus confirming the hypothesis that ITSN1 is important for brain development.

PMID:34707297 | DOI:10.1038/s41431-021-00985-9

Nature. 2021 Oct 27. doi: 10.1038/s41586-021-04044-7. Online ahead of print.

ABSTRACT

Inflammation early in life can prime the local immune milieu of peripheral tissues, which can cause lasting changes in immunological tone that confer disease protection or susceptibility1. The cellular and molecular mechanisms that prompt changes in immune tone in many nonlymphoid tissues remain largely unknown. Here we find that time-limited neonatal inflammation induced by a transient reduction in neonatal regulatory T cells causes a dysregulation of subcutaneous tissue in mouse skin. This is accompanied by the selective accumulation of type 2 helper T (TH2) cells within a distinct microanatomical niche. TH2 cells are maintained into adulthood through interactions with a fibroblast population in skin fascia that we refer to as TH2-interacting fascial fibroblasts (TIFFs), which expand in response to TH2 cytokines to form subcutaneous fibrous bands. Activation of the TH2-TIFF niche due to neonatal inflammation primes the skin for altered reparative responses to wounding. Furthermore, we identify fibroblasts in healthy human skin that express the TIFF transcriptional signature and detect these cells at high levels in eosinophilic fasciitis, an orphan disease characterized by inflammation and fibrosis of the skin fascia. Taken together, these data define a previously unidentified TH2 cell niche in skin and functionally characterize a disease-associated fibroblast population. The results also suggest a mechanism of immunological priming whereby inflammation early in life creates networks between adaptive immune cells and stromal cells to establish an immunological set-point in tissues that is maintained throughout life.

PMID:34707292 | DOI:10.1038/s41586-021-04044-7

Arq Neuropsiquiatr. 2021 Oct;79(10):912-923. doi: 10.1590/0004-282X-ANP-2020-0429.

ABSTRACT

BACKGROUND: Adult-onset spinal muscular atrophy (SMA) represents an expanding group of inherited neurodegenerative disorders in clinical practice.

OBJECTIVE: This review aims to synthesize the main clinical, genetic, radiological, biochemical, and neurophysiological aspects related to the classical and recently described forms of proximal SMA.

METHODS: The authors performed a non-systematic critical review summarizing adult-onset proximal SMA presentations.

RESULTS: Previously limited to cases of SMN1-related SMA type 4 (adult form), this group has now more than 15 different clinical conditions that have in common the symmetrical and progressive compromise of lower motor neurons starting in adulthood or elderly stage. New clinical and genetic subtypes of adult-onset proximal SMA have been recognized and are currently target of wide neuroradiological, pathological, and genetic studies.

CONCLUSIONS: This new complex group of rare disorders typically present with lower motor neuron disease in association with other neurological or systemic signs of impairment, which are relatively specific and typical for each genetic subtype.

PMID:34706022 | DOI:10.1590/0004-282X-ANP-2020-0429

Curr Issues Mol Biol. 2021 Sep 25;43(3):1267-1281. doi: 10.3390/cimb43030090.

ABSTRACT

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by out-of-frame or nonsense mutation in the dystrophin gene. It begins with a loss of ambulation between 9 and 14 years of age, followed by various other symptoms including cardiac dysfunction. Exon skipping of patients' DMD pre-mRNA induced by antisense oligonucleotides (AOs) is expected to produce shorter but partly functional dystrophin proteins, such as those possessed by patients with the less severe Becker muscular dystrophy. We are working on developing modified nucleotides, such as 2'-O,4'-C-ethylene-bridged nucleic acids (ENAs), possessing high nuclease resistance and high affinity for complementary RNA strands. Here, we demonstrate the preclinical characteristics (exon-skipping activity in vivo, stability in blood, pharmacokinetics, and tissue distribution) of renadirsen, a novel AO modified with 2'-O-methyl RNA/ENA chimera phosphorothioate designed for dystrophin exon 45 skipping and currently under clinical trials. Notably, systemic delivery of renadirsen sodium promoted dystrophin exon skipping in cardiac muscle, skeletal muscle, and diaphragm, compared with AOs with the same sequence as renadirsen but conventionally modified by PMO and 2'OMePS. These findings suggest the promise of renadirsen sodium as a therapeutic agent that improves not only skeletal muscle symptoms but also other symptoms in DMD patients, such as cardiac dysfunction.

PMID:34698059 | DOI:10.3390/cimb43030090

Pharmacoeconomics. 2021 Oct 26. doi: 10.1007/s40273-021-01096-5. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Orphan drugs' high prices raise questions about whether their costs are worth their benefits. We examined the association between an orphan drug's cost-effectiveness and health plan coverage restrictiveness.

METHODS: We analyzed a dataset of US commercial health plan coverage decisions (information current as of 2019) for orphan drugs (n = 3298). We used multi-level random-effect logistic regression to examine the association between orphan drug cost-effectiveness and coverage restrictiveness. We identified cost-effectiveness estimates from the Tufts Medical Center Cost-Effectiveness Analysis Registry, and from the Institute for Clinical and Economic Review's value assessments. We included only cost-effectiveness studies not funded by product manufacturers. We included the following independent variables: cancer indication, availability of alternatives, pediatric population, number of years since US Food and Drug Administration (FDA) approval, disease prevalence, annual cost, additional non-orphan indication, safety, and inclusion in a FDA expedited review program.

RESULTS: Plans restricted drug coverage in 29.7% (n = 981) of decisions. Plans were more likely to restrict drugs with incremental cost-effectiveness ratios of $50,000-$175,000 per quality-adjusted life-year [QALY] (odds ratio = 1.855, p < 0.05), $175,000-$500,000 per QALY (odds ratio = 1.859, p < 0.05), and >$500,000 per QALY/dominated (odds ratio = 2.032, p < 0.01), compared to drugs with incremental cost-effectiveness ratios <$50,000 per QALY. Plans more often restricted drugs with non-cancer indications, having available alternatives, with more recent approval, in an FDA expedited review program, and for which the FDA additionally issued approval for a non-orphan disease. Plans more often restricted drugs with higher annual costs, and drugs indicated for higher prevalence diseases. All findings p < 0.05.

CONCLUSIONS: Among other factors, an orphan drug's cost-effectiveness was associated with health plan drug coverage restrictiveness.

PMID:34697718 | DOI:10.1007/s40273-021-01096-5

Viruses. 2021 Oct 19;13(10):2103. doi: 10.3390/v13102103.

ABSTRACT

The Zika virus (ZIKV) has shown a promising oncolytic effect against embryonal CNS tumors. However, studies on the effect of different administration routes and the ideal viral load in preclinical models are highly relevant aiming for treatment safety and efficiency. Here, we investigated the effect and effectiveness of different routes of administration, and the number of ZIKVBR injections on tumor tropism, destruction, and side effects. Furthermore, we designed an early-stage human brain organoid co-cultured with embryonal CNS tumors to analyze the ZIKVBR oncolytic effect. We showed that in the mice bearing subcutaneous tumors, the ZIKVBR systemically presented a tropism to the brain. When the tumor was located in the mice's brain, serial systemic injections presented efficient tumor destruction, with no neurological or other organ injury and increased mice survival. In the human cerebral organoid model co-cultured with embryonal CNS tumor cells, ZIKVBR impaired tumor progression. The gene expression of cytokines and chemokines in both models suggested an enhancement of immune cells recruitment and tumor inflammation after the treatment. These results open new perspectives for virotherapy using the ZIKVBR systemic administration route and multiple doses of low virus load for safe and effective treatment of embryonal CNS tumors, an orphan disease that urges new effective therapies.

PMID:34696533 | DOI:10.3390/v13102103

Orphanet J Rare Dis. 2021 Oct 23;16(1):446. doi: 10.1186/s13023-021-02048-0.

ABSTRACT

BACKGROUND: Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have linked this disease to mutations in GPX4, with consequences in the resulting enzyme, glutathione peroxidase 4. This offers potential diagnostic and therapeutic avenues for those suffering from this disease, though the steps toward these treatments is often convoluted, expensive, and time-consuming.

MAIN BODY: The CureGPX4 organization was developed to promote awareness of GPX4-related diseases like SSMD, as well as support research that could lead to essential therapeutics for patients. We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis. We outline in detail the steps CureGPX4 has taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies.

CONCLUSION: The primary aim of this review is to provide a roadmap for therapy development for rare, ultra-rare, and difficult to diagnose diseases, as well as increase awareness of the genetic component of SSMD. This work will offer a better understanding of GPx4-related diseases, and help guide researchers, clinicians, and patients interested in other rare diseases find a path towards treatments.

PMID:34688299 | PMC:PMC8542321 | DOI:10.1186/s13023-021-02048-0

J Clin Med. 2021 Oct 14;10(20):4720. doi: 10.3390/jcm10204720.

ABSTRACT

Hereditary hemorrhagic telangiectasia (HHT; Rendu-Osler-Weber syndrome) affects the capillary and larger vessels, leading to arteriovenous shunts. Epistaxis is the main symptom impairing quality of life. The aim of the Osler Calendar is to offer information about the extent of the systemic disease and the current state of treatment. A care plan with information on the rare disease and self-treatment of epistaxis was created. Organ examinations and ongoing treatments were recorded. A questionnaire documents the treatment success, including patient satisfaction, frequency of hemorrhage and hemoglobin levels. The patients using the Osler Calendar for at least one year (n = 54) were surveyed. Eighty-five percent of patients (n = 46) used the calendar to gain information about HHT. Seventy-two percent (n = 39) used the Osler Calendar for instructions on the self-treatment of nosebleeds. The calendar increased patients' understanding for the need for organ screenings from 48% (n = 26) to 81% (n = 44). Seventy-nine percent (n = 43) of patients confirmed that the Osler Calendar documented their therapeutic process either well or very well. Fifty-two percent (n = 28) saw an improvement in the therapeutic process due to the documentation. The Osler Calendar records the individual intensity of the disease and facilitates the communication between attending physicians. It is a tool for specialists to review treatment strategies. Furthermore, the calendar enhances patients' comprehension of their condition.

PMID:34682843 | PMC:PMC8541180 | DOI:10.3390/jcm10204720

Orphanet J Rare Dis. 2021 Oct 22;16(1):429. doi: 10.1186/s13023-021-02061-3.

ABSTRACT

BACKGROUND: Rare diseases (RD) are a diverse collection of more than 7-10,000 different disorders, most of which affect a small number of people per disease. Because of their rarity and fragmentation of patients across thousands of different disorders, the medical needs of RD patients are not well recognized or quantified in healthcare systems (HCS).

METHODOLOGY: We performed a pilot IDeaS study, where we attempted to quantify the number of RD patients and the direct medical costs of 14 representative RD within 4 different HCS databases and performed a preliminary analysis of the diagnostic journey for selected RD patients.

RESULTS: The overall findings were notable for: (1) RD patients are difficult to quantify in HCS using ICD coding search criteria, which likely results in under-counting and under-estimation of their true impact to HCS; (2) per patient direct medical costs of RD are high, estimated to be around three-fivefold higher than age-matched controls; and (3) preliminary evidence shows that diagnostic journeys are likely prolonged in many patients, and may result in progressive, irreversible, and costly complications of their disease CONCLUSIONS: The results of this small pilot suggest that RD have high medical burdens to patients and HCS, and collectively represent a major impact to the public health. Machine-learning strategies applied to HCS databases and medical records using sentinel disease and patient characteristics may hold promise for faster and more accurate diagnosis for many RD patients and should be explored to help address the high unmet medical needs of RD patients.

PMID:34674728 | PMC:PMC8532301 | DOI:10.1186/s13023-021-02061-3

Am J Hematol. 2021 Oct 22. doi: 10.1002/ajh.26382. Online ahead of print.

ABSTRACT

Septins play key roles in mammalian cell division and cytokinesis but have not previously been implicated in a germline human disorder. A male infant with severe neutropenia and progressive dysmyelopoiesis with tetraploid myeloid precursors was identified. No known genetic etiologies for neutropenia or bone marrow failure were found. However, next-generation sequencing of germline samples from the patient revealed a novel, de novo germline stop-loss mutation in the X-linked gene SEPT6 that resulted in reduced SEPT6 staining in BM granulocyte precursors and megakaryocytes. Patient skin fibroblast-derived induced pluripotent stem cells (iPSCs) produced reduced myeloid colonies, particularly of the granulocyte lineage. CRISPR/Cas9 knock-in of the patient's mutation or complete knock-out of SEPT6 was not tolerated in non-patient derived iPSCs or human myeloid cell lines, but SEPT6 knock-out was successful in an erythroid cell line and resulting clones revealed a propensity to multinucleation. In silico analysis predicts the mutated protein hinders the dimerization of SEPT6 coiled coils in both parallel and antiparallel arrangements, which could in turn impair filament formation. These data demonstrate a critical role for SEPT6 in chromosomal segregation in myeloid progenitors that can account for the unusual predisposition to aneuploidy and dysmyelopoiesis. This article is protected by copyright. All rights reserved.

PMID:34677878 | DOI:10.1002/ajh.26382

Orphanet J Rare Dis. 2021 Oct 19;16(1):439. doi: 10.1186/s13023-021-02022-w.

ABSTRACT

BACKGROUND AND AIM: Evidence on determinants of prices for orphan medicines is scarce and not available for Italy. The aim of this paper is to provide an evidence on variables affecting the annual treatment cost of orphan drugs in Italy, testing the hypothesis of a negative correlation with the dimension of the target population and a positive correlation with the added therapeutic value of the drug and the quality of the evidence of pivotal studies.

METHODS: Drugs with a European orphan designation reimbursed in Italy in the last 6 years (2014-2019) were considered. Univariate, cluster analysis and multiple regression models were used to investigate the correlation between the annual treatment cost and, as explanatory variables, the dimension of the target population, the existence of Randomized Clinical Trials as a proxy of the quality of the pivotal studies, the added therapeutic value.

RESULTS: In the univariate analysis prevalence and added therapeutic value, as expected, have a negative and positive correlation with cost respectively. The correlation with RCT is not significant. In the multivariate model, coefficients for prevalence and added value are confirmed but for the latter are not significant anymore. We also found, through an interaction analysis, that the existence of an RCT has a positive impact on annual treatment cost when the target population is very small.

CONCLUSIONS: Our results suggest that value arguments and sustainability (dimension of the target population and its impact on budget impact) issues are considered for orphan drugs pricing: the role played by sustainability is systematically supported by our results. A more transparent and reproducible price negotiation process for orphan drugs is needed in Italy. This paper has contributed to highlight the implicit drivers of this process.

PMID:34666819 | PMC:PMC8527608 | DOI:10.1186/s13023-021-02022-w

Clin Cancer Res. 2021 Oct 19:clincanres.2639.2021. doi: 10.1158/1078-0432.CCR-21-2639. Online ahead of print.

ABSTRACT

Real-world evidence (RWE) has garnered great interest to support registration of new therapies and label expansions by the United States Food and Drug Administration (FDA). Currently, practical insights on the design and analysis of regulatory-grade RWE are lacking. This study aimed to analyze attributes of real-world studies in FDA's decision-making and characteristics of full versus accelerated approvals through a systematic review of oncology product approvals. Oncology approvals from 2015-2020 were reviewed from FDA.gov. Applications were screened for inclusion of RWE, and variables related to regulatory designations of the application, pivotal clinical trial, and real-world studies were extracted. FDA feedback was reviewed to identify takeaways and best practices for adequate RWE. Among 133 original and 573 supplemental approvals for oncology, 11 and 2, respectively, included RWE; none predated 2017. All realworld studies were retrospective in nature; the most common data source was chart review, and the most common primary endpoint was overall response rate, as in the pivotal trial. FDA critiqued lack of the following: a pre-specified study protocol, inclusion/exclusion criteria matching to the trial, comparability of endpoint definitions, methods to minimize confounding and address unmeasured confounding, and plans to handle missing data. All full (vs. accelerated) approvals shared the following characteristics: high magnitude of efficacy in the pivotal trial, designations of orphan disease, breakthrough therapy, and priority review, and no advisory committee meeting held. This study found that findings from external control real-world studies complemented efficacy data from single-arm trials in successful oncology product approvals.

PMID:34667027 | DOI:10.1158/1078-0432.CCR-21-2639

Mob DNA. 2021 Oct 18;12(1):22. doi: 10.1186/s13100-021-00250-2.

ABSTRACT

Transposable elements (TEs) significantly contribute to shaping the diversity of the human genome, and lines of evidence suggest TEs as one of driving forces of human brain evolution. Existing computational approaches, including cross-species comparative genomics and population genetic modeling, can be adapted for the study of the role of TEs in evolution. In particular, diverse ancient and archaic human genome sequences are increasingly available, allowing reconstruction of past human migration events and holding the promise of identifying and tracking TEs among other evolutionarily important genetic variants at an unprecedented spatiotemporal resolution. However, highly degraded short DNA templates and other unique challenges presented by ancient human DNA call for major changes in current experimental and computational procedures to enable the identification of evolutionarily important TEs. Ancient human genomes are valuable resources for investigating TEs in the evolutionary context, and efforts to explore ancient human genomes will potentially provide a novel perspective on the genetic mechanism of human brain evolution and inspire a variety of technological and methodological advances. In this review, we summarize computational and experimental approaches that can be adapted to identify and validate evolutionarily important TEs, especially for human brain evolution. We also highlight strategies that leverage ancient genomic data and discuss unique challenges in ancient transposon genomics.

PMID:34663455 | DOI:10.1186/s13100-021-00250-2