Orphanet J Rare Dis. 2023 Apr 11;18(1):79. doi: 10.1186/s13023-023-02693-7.

ABSTRACT

BACKGROUND: Traditional clinical trials require tests and procedures that are administered in centralized clinical research sites, which are beyond the standard of care that patients receive for their rare and chronic diseases. The limited number of rare disease patients scattered around the world makes it particularly challenging to recruit participants and conduct these traditional clinical trials.

MAIN BODY: Participating in clinical research can be burdensome, especially for children, the elderly, physically and cognitively impaired individuals who require transportation and caregiver assistance, or patients who live in remote locations or cannot afford transportation. In recent years, there is an increasing need to consider Decentralized Clinical Trials (DCT) as a participant-centric approach that uses new technologies and innovative procedures for interaction with participants in the comfort of their home.

CONCLUSION: This paper discusses the planning and conduct of DCTs, which can increase the quality of trials with a specific focus on rare diseases.

PMID:37041605 | PMC:PMC10088572 | DOI:10.1186/s13023-023-02693-7

Orphanet J Rare Dis. 2023 Apr 11;18(1):75. doi: 10.1186/s13023-023-02678-6.

ABSTRACT

BACKGROUND: There are approximately 10,000 rare diseases that affect around 30,000,000 individuals in the U.S.A., most of which do not have an FDA-approved treatment. This fact highlights the failure of traditional research approaches to overcome the unique challenges of developing rare disease treatments. The Castleman Disease Collaborative Network was founded in 2012 to advance research and treatments for Castleman disease, a rare and deadly disease that involves the immune system attacking the body's vital organs for an unknown cause. It has spearheaded a novel strategy for advancing biomedical research, the Collaborative Network Approach. This approach consists of eight steps, one of which is to identify and prioritize high-impact research questions through crowdsourcing ideas from the entire community of stakeholders: patients, loved ones, physicians, and researchers. Rather than hoping that the right researcher will apply for the right research project at the right time, crowdsourcing high-priority research projects into a research strategy ensures that the most high-impact, patient-centered studies are prioritized. The Castleman Disease Collaborative Network launched an initiative in 2021 to systematically generate this list of community-directed studies to focus Castleman disease research efforts.

RESULTS: The Castleman Disease Collaborative Network was able to successfully create a patient-centered research agenda through engaging the entire community of stakeholders. The community contributed important questions about Castleman disease, which were prioritized and reviewed by our Scientific Advisory Board, and the result was a finalized list of studies that address these prioritized questions. We were also able to generate a best practices list which can serve as a model that can be utilized for other rare diseases.

CONCLUSION: Creating a patient-centered research agenda through crowdsourcing research ideas from the community is one of the most important ways that the Castleman Disease Collaborative Network operationalizes its commitment to keeping patients at the center of research and we hope that by sharing these insights we can assist other rare disease organizations to pursue a patient-centric approach.

PMID:37041585 | PMC:PMC10091676 | DOI:10.1186/s13023-023-02678-6

Mediterr J Rheumatol. 2022 Dec 31;33(4):437-443. doi: 10.31138/mjr.33.4.437. eCollection 2022 Dec.

ABSTRACT

BACKGROUND: Anti-Jo1 syndrome is one of the most common amongst the various anti synthetase syndromes (ASS), which forms a subgroup of the idiopathic inflammatory myositis (IIM). It is characterised by myositis, interstitial lung disease (ILD), fever, Raynaud's phenomenon, and mechanic's hands; associated with the presence of anti-Jo1 antibodies in serum. Being an orphan disease, the clinical diagnosis is often delayed.

MATERIALS AND METHODS: In this retrospective study, all patients diagnosed as Anti-Jo1 syndrome, from two tertiary care hospitals in Western Maharashtra, between 01 January 2019 - 31 December 2020, were enrolled. The parameters studied included demographic data, clinical features at presentation, laboratory parameters, spirometry, and radiographic findings, along with treatment instituted.

RESULT: A total of 17 patients (8 males, 9 females) qualified for inclusion in the study. The mean age of diagnosis was 40 (±13) years with mean time to diagnosis being 2 years (± 0.6 years), from first clinical presentation. The most common presenting symptoms encountered were arthritis (n = 12, 70.5%), fever (n = 16, 70.5%), myositis (n=11, 64.7%) and breathlessness (n=10, 58.8%).10 patients had ILD at presentation on high resolution computerised tomography of chest (n=10, 58.8%) with restrictive lung defect on spirometry. Six patients required induction of immunosuppression using pulse methylprednisolone (n=6) and Rituximab (n=6), while 11 were managed with oral steroids. Mycophenolate mofetil (n=10) and Azathioprine (n=7) were used as maintenance immunosuppression.

CONCLUSION: Anti-Jo1 syndrome is a myositis syndrome, presenting with a multitude of clinical features. Steroids and disease modifying anti rheumatic drugs form mainstay of therapy.

PMID:37034360 | PMC:PMC10075366 | DOI:10.31138/mjr.33.4.437

Orphanet J Rare Dis. 2023 Apr 10;18(1):73. doi: 10.1186/s13023-023-02695-5.

ABSTRACT

INTRODUCTION: The Undiagnosed Diseases Network (UDN), a clinical research study funded by the National Institutes of Health, aims to provide answers for patients with undiagnosed conditions and generate knowledge about underlying disease mechanisms. UDN evaluations involve collaboration between clinicians and researchers and go beyond what is possible in clinical settings. While medical and research outcomes of UDN evaluations have been explored, this is the first formal assessment of the patient and caregiver experience.

METHODS: We invited UDN participants and caregivers to participate in focus groups via email, newsletter, and a private participant Facebook group. We developed focus group questions based on research team expertise, literature focused on patients with rare and undiagnosed conditions, and UDN participant and family member feedback. In March 2021, we conducted, recorded, and transcribed four 60-min focus groups via Zoom. Transcripts were evaluated using a thematic analysis approach.

RESULTS: The adult undiagnosed focus group described the UDN evaluation as validating and an avenue for access to medical providers. They also noted that the experience impacted professional choices and helped them rely on others for support. The adult diagnosed focus group described the healthcare system as not set up for rare disease. In the pediatric undiagnosed focus group, caregivers discussed a continued desire for information and gratitude for the UDN evaluation. They also described an ability to rule out information and coming to terms with not having answers. The pediatric diagnosed focus group discussed how the experience helped them focus on management and improved communication. Across focus groups, adults (undiagnosed/diagnosed) noted the comprehensiveness of the evaluation. Undiagnosed focus groups (adult/pediatric) discussed a desire for ongoing communication and care with the UDN. Diagnosed focus groups (adult/pediatric) highlighted the importance of the diagnosis they received in the UDN. The majority of the focus groups noted a positive future orientation after participation.

CONCLUSION: Our findings are consistent with prior literature focused on the patient experience of rare and undiagnosed conditions and highlight benefits from comprehensive evaluations, regardless of whether a diagnosis is obtained. Focus group themes also suggest areas for improvement and future research related to the diagnostic odyssey.

PMID:37032333 | PMC:PMC10084693 | DOI:10.1186/s13023-023-02695-5

J Biomed Inform. 2023 May;141:104338. doi: 10.1016/j.jbi.2023.104338. Epub 2023 Apr 5.

ABSTRACT

Federated learning initiatives in healthcare are being developed to collaboratively train predictive models without the need to centralize sensitive personal data. GenoMed4All is one such project, with the goal of connecting European clinical and -omics data repositories on rare diseases through a federated learning platform. Currently, the consortium faces the challenge of a lack of well-established international datasets and interoperability standards for federated learning applications on rare diseases. This paper presents our practical approach to select and implement a Common Data Model (CDM) suitable for the federated training of predictive models applied to the medical domain, during the initial design phase of our federated learning platform. We describe our selection process, composed of identifying the consortium's needs, reviewing our functional and technical architecture specifications, and extracting a list of business requirements. We review the state of the art and evaluate three widely-used approaches (FHIR, OMOP and Phenopackets) based on a checklist of requirements and specifications. We discuss the pros and cons of each approach considering the use cases specific to our consortium as well as the generic issues of implementing a European federated learning healthcare platform. A list of lessons learned from the experience in our consortium is discussed, from the importance of establishing the proper communication channels for all stakeholders to technical aspects related to -omics data. For federated learning projects focused on secondary use of health data for predictive modeling, encompassing multiple data modalities, a phase of data model convergence is sorely needed to gather different data representations developed in the context of medical research, interoperability of clinical care software, imaging, and -omics analysis into a coherent, unified data model. Our work identifies this need and presents our experience and a list of actionable lessons learned for future work in this direction.

PMID:37023843 | DOI:10.1016/j.jbi.2023.104338

Swiss Med Wkly. 2023 Mar 31;153:40048. doi: 10.57187/smw.2023.40048.

ABSTRACT

AIMS OF THE STUDY: Acquired haemophilia A is a rare disease with an annual incidence of 1.48 per million. Based on clinical observations, we suspect a higher incidence in southern Switzerland, and aimed at providing local epidemiological data, and clinical information regarding diagnosis, treatment and outcome in our region.

METHODS: All adult patients with acquired haemophilia A treated between 2013 and 2019 in our facility were included in the present retrospective analysis.

RESULTS: We treated 11 patients with acquired haemophilia A between 2013 and 2019, resulting in an annual incidence of 4.5 per million (95% confidence interval [CI] 0-9.0). Median delay from first symptoms to diagnosis was 4.5 days, and the median age at diagnosis was 79 years (range 23-87). Possible causative conditions were: pregnancy (n = 1), polyarteritis nodosa (n = 1), myelodysplastic syndrome (n = 1), chronic human immunodeficiency virus (HIV) (n = 1), and HIV postexposure prophylaxis (n = 1). In five patients no underlying or associated condition was identified. Median activated partial thromboplastin time (aPTT)) at baseline was 79 seconds (65-117; ref. value <38 sec), and FVIII:C 2.15% (<1-3.75%). A FVIII:C <1% was present in 4/10 patients. Median FVIII-inhibitor titre was 10.3 BU/ml (2.4-75.0 BU/ml). All patients had bleeding symptoms, 5/10 patients had major bleedings, and 7/10 patients were treated with bypassing agents. All patients received corticosteroids; 7/10 patients received immunosuppressive combination therapy. FVIII levels of ≥50% were achieved after a median of 40 days (8-62). One patient had a severe immunosuppressive therapy-related infection. An 87-years-old woman died for reasons not related to acquired haemophilia A or immunosuppressive therapy.

CONCLUSIONS: Acquired haemophilia A is a rare disease, but manageable despite the advanced patient age and comorbidities. Its incidence in Southern Switzerland is higher than previously suspected.

PMID:37021783 | DOI:10.57187/smw.2023.40048

Orphanet J Rare Dis. 2023 Apr 5;18(1):71. doi: 10.1186/s13023-023-02685-7.

ABSTRACT

BACKGROUND: In many countries worldwide orphan drug regulations are installed but only the United States of America and Japan have an orphan device regulation. For many years surgeons have used off-label or self-assembled medical devices for the prevention, diagnosis or treatment of rare disorders. Four examples are given: an external cardiac pacemaker, a metal brace for clubfoot in newborns, a transcutaneous nerve stimulator and a cystic fibrosis mist tent.

CONCLUSION: In this article we argue that we need authorized medical devices as well as medicinal products to prevent, diagnose and treat patients with life-threatening or chronically debilitating disorders with a low prevalence/incidence. Several arguments are given to support this statement.

PMID:37020310 | PMC:PMC10077604 | DOI:10.1186/s13023-023-02685-7

PLoS One. 2023 Apr 5;18(4):e0281892. doi: 10.1371/journal.pone.0281892. eCollection 2023.

ABSTRACT

BACKGROUND: Genotype-phenotype analyses of rare diseases often suffer from a lack of power, due to small sample size, which makes identifying significant associations difficult. Sinusoidal obstruction syndrome (SOS) of the liver is a rare but life-threatening complication of hematopoietic stem cell transplantation (HSCT). The alkylating agent busulfan is commonly used in HSCT and known to trigger SOS. We developed a novel pipeline to identify genetic determinants in rare diseases by combining in vitro information with clinical whole-exome sequencing (WES) data and applied it in SOS patients and controls.

METHODS: First, we analysed differential gene expression in six lymphoblastoid cell lines (LCLs) before and after incubation with busulfan. Second, we used WES data from 87 HSCT patients and estimated the association with SOS at the SNP and the gene levels. We then combined the results of the expression and the association analyses into an association statistic at the gene level. We used an over-representation analysis to functionally characterize the genes that were associated with a significant combined test statistic.

RESULTS: After treatment of LCLs with busulfan, 1708 genes were significantly up-, and 1385 down-regulated. The combination of the expression experiment and the association analysis of WES data into a single test statistic revealed 35 genes associated with the outcome. These genes are involved in various biological functions and processes, such as "Cell growth and death", "Signalling molecules and interaction", "Cancer", and "Infectious disease".

CONCLUSIONS: This novel data analysis pipeline integrates two independent omics datasets and increases statistical power for identifying genotype-phenotype associations. The analysis of the transcriptomics profile of cell lines treated with busulfan and WES data from HSCT patients allowed us to identify potential genetic contributors to SOS. Our pipeline could be useful for identifying genetic contributors to other rare diseases where limited power renders genome-wide analyses unpromising.

TRIAL REGISTRATION: For the clinical dataset: Clinicaltrials.gov: NCT01257854. https://clinicaltrials.gov/ct2/history/NCT01257854.

PMID:37018234 | PMC:PMC10075428 | DOI:10.1371/journal.pone.0281892

J Palliat Med. 2023 Apr;26(4):599-600. doi: 10.1089/jpm.2022.0521.

NO ABSTRACT

PMID:37011294 | DOI:10.1089/jpm.2022.0521

Mol Genet Metab. 2023 Apr;138(4):107558. doi: 10.1016/j.ymgme.2023.107558. Epub 2023 Mar 8.

ABSTRACT

Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases caused by a deficiency of one of the enzymes or transporters that constitute the urea cycle. Defects in these enzymes lead to acute accumulation (hyperammonemic crises, HAC) or chronically elevated levels (hyperammonemia) of ammonia in the blood and/or various tissues including the brain, which can cause persistent neurological deficits, irreversible brain damage, coma, and death. Ongoing treatment of UCDs include the use of nitrogen-scavenging agents, such as sodium phenylbutyrate (salt of 4-phenylbutyric acid; NaPBA) or glycerol phenylbutyrate (GPB). These treatments provide an alternative pathway for nitrogen disposal through the urinary excretion of phenylacetylglutamine. ACER-001 is a novel formulation of NaPBA with polymer coated pellets in suspension, which is designed to briefly mask the unpleasant bitter taste of NaPBA and is being developed as a treatment option for patients with UCDs. Four Phase 1 studies were conducted to characterize the bioavailability (BA) and/or bioequivalence (BE) of ACER-001 (in healthy volunteers) and taste assessment relative to NaPBA powder (in taste panelists). ACER-001 was shown to be bioequivalent to NaPBA powder under both fed and fasting conditions. Lower systemic exposure of phenylacetate (PAA) and phenylbutyrate (PBA) was observed when ACER-001 was administered with a high-fat meal relative to a fasting state suggesting that the lower doses of PBA administered under fasting conditions may yield similar efficacy with potentially fewer dose dependent adverse effects relative to higher doses with a meal. ACER-001 appeared to be adequately taste-masked, staying below the aversive taste threshold for the first 3 min after the formulation was prepared and remaining palatable when taken within 5 min.

PMID:37004302 | DOI:10.1016/j.ymgme.2023.107558

BMC Musculoskelet Disord. 2023 Mar 31;24(1):247. doi: 10.1186/s12891-023-06371-4.

ABSTRACT

BACKGROUND: Progressive osseous heteroplasia (POH) is a rare genetic condition that causes progressive ossification. This usually results from an inactivating mutation of the paternal GNAS gene. Herein, we report a case of POH caused by a novel mutation in exon 2 of the GNAS gene.

CASE PRESENTATION: A 5-year-old Chinese boy was referred to our hospital for a growing mass in his right foot. Although laboratory findings were normal, radiographic imaging revealed severe ossification in his right foot and smaller areas of intramuscular ossification in his arms and legs. A de novo mutation (c.175C > T, p.Q59X) in exon 2 of the GNAS gene was identified, prompting a diagnosis of POH. We conducted a systematic literature review to better understand this rare disease.

CONCLUSION: We have discovered that a de novo nonsense mutation in exon 2 of GNAS can lead to POH. Our literature review revealed that ankylosis of the extremities is the primary clinical outcome in patients with POH. Unlike other conditions such as fibrodysplasia ossificans progressiva (FOP), patients with POH do not experience respiratory failure. However, much remains to be learned about the relationship between the type of GNAS gene mutation and the resulting POH symptoms. Further research is needed to understand this complex and rare disease. This case adds to our current understanding of POH and will contribute to future studies and treatments.

PMID:37003989 | PMC:PMC10064707 | DOI:10.1186/s12891-023-06371-4

Medicine (Baltimore). 2023 Mar 31;102(13):e32662. doi: 10.1097/MD.0000000000032662.

ABSTRACT

Pseudomonas aeruginosa infective endocarditis (IE) is a rare disease associated with high mortality and complications. Here, we describe a contemporary set of patients aiming to improve the understanding of risk factors, clinical features, treatments, and outcomes. This retrospective case series reviewed cases from 3 tertiary metropolitan hospitals between January 1999 and January 2019. prespecified data were collected for each case, with a review of risk factors, valve involvement, acquisition, treatment, and complications. Fifteen patients were identified over a 20 years period. All patients presented with fever, 5/15 had preexisting prosthetic valve with valvular heart disease in 7/15 patients making it the most common risk factor. Intravenous drug use (IVDU) was the source in only 6/15 cases with healthcare associated infection and left-sided valvular involvement being more common than previous reports both occurring in 9/15 cases. Complications occurred in 11/15 patients with a 30 days mortality of 13%. Surgery was performed in 7/15 patients and 9/15 patients received antibiotic combination therapy. One year mortality was higher in those with increasing age, comorbidities, left-sided valve involvement, presence of predefined complications, and antibiotic monotherapy. Development of resistance occurred in 2 cases that received monotherapy. P aeruginosa IE remains a rare disease with high mortality and secondary complications.

PMID:37000062 | PMC:PMC10063303 | DOI:10.1097/MD.0000000000032662

Turk Kardiyol Dern Ars. 2023 Apr;51(3):212-216. doi: 10.5543/tkda.2022.23460.

ABSTRACT

This article presents the case of a 24-year-old woman with Poland syndrome who developed primary right atrial cardiac angiosarcoma. The patient presented to the hospital with dyspnea and chest pain, and imaging studies revealed a large mass attached to the right atrium. Urgent surgery was performed to remove the tumor, and the patient underwent adjuvant chemotherapy afterward. Follow-up exams showed no signs of the tumor or any complications from treatment. Poland syndrome is a rare congenital disorder characterized by the absence of unilateral large pectoral muscle, ipsilateral symbrachydactyly, and other malformations of the anterior chest wall and breast. Although the condition does not predispose patients to malignancy, different pathologies can be seen in these patients due to the unknown etiology of the syndrome. Primary right atrial cardiac angiosarcoma is a rare malignancy, and its coexistence with Poland syndrome has not been well established in the literature. This case report highlights the need to consider cardiac angiosarcoma as a possible diagnosis in patients with Poland syndrome who present with cardiac symptoms.

PMID:36999325 | DOI:10.5543/tkda.2022.23460

Ann Clin Transl Neurol. 2023 Mar 31. doi: 10.1002/acn3.51767. Online ahead of print.

ABSTRACT

OBJECTIVE: The goal of this study is to demonstrate the utility of a growth assay to quantify the functional impact of single nucleotide variants (SNVs) in SLC2A1, the gene responsible for Glut1DS.

METHODS: The functional impact of 40 SNVs in SLC2A1 was quantitatively determined in HAP1 cells in which SLC2A1 is required for growth. Donor libraries were introduced into the endogenous SLC2A1 gene in HAP1-Lig4KO cells using CRISPR/Cas9. Cell populations were harvested and sequenced to quantify the effect of variants on growth and generate a functional score. Quantitative functional scores were compared to 3-OMG uptake, SLC2A1 cell surface expression, CADD score, and clinical data, including CSF/blood glucose ratio.

RESULTS: Nonsense variants (N = 3) were reduced in cell culture over time resulting in negative scores (mean score: -1.15 ± 0.17), whereas synonymous variants (N = 10) were not depleted (mean score: 0.25 ± 0.12) (P < 2e-16). Missense variants (N = 27) yielded a range of functional scores including slightly negative scores, supporting a partial function and intermediate phenotype. Several variants with normal results on either cell surface expression (p.N34S and p.W65R) or 3-OMG uptake (p.W65R) had negative functional scores. There is a moderate but significant correlation between our functional scores and CADD scores.

INTERPRETATION: Cell growth is useful to quantitatively determine the functional effects of SLC2A1 variants. Nonsense variants were reliably distinguished from benign variants in this in vitro functional assay. For facilitating early diagnosis and therapeutic intervention, future work is needed to determine the functional effect of every possible variant in SLC2A1.

PMID:37000947 | DOI:10.1002/acn3.51767

Res Sq. 2023 Mar 20:rs.3.rs-2566253. doi: 10.21203/rs.3.rs-2566253/v1. Preprint.

ABSTRACT

Objective: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) has enabled development of novel therapeutic approaches that are currently undergoing clinical evaluation or are proposed to move into clinical development. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top clinical concerns in order to gain information to guide the development and selection of outcome measures for future clinical trials. Methods: Caregivers of participants enrolled in the US Natural History Study of RTT and related disorders were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for Classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2 . Results: The top caregiver concerns for Classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The rank order of the frequency of the top caregiver concerns for Classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. The frequency of caregiver concern for seizures, hand use, and spoken language increased in relation to clinician assessed severity in these clinical domains, showing consistency between clinician assessments and caregiver concerns. Comparison across disorders found commonalities in the top caregiver concerns between Classic RTT, Atypical RTT, MECP2 Duplication Syndrome, CDKL5 Deficiency Disorder, and FOXG1 Syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features. Conclusion: The top caregiver concerns for individuals with RTT and the RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers.

PMID:36993737 | PMC:PMC10055548 | DOI:10.21203/rs.3.rs-2566253/v1

Rofo. 2023 Apr;195(4):333-334. doi: 10.1055/a-2030-1114. Epub 2023 Mar 30.

NO ABSTRACT

PMID:36996825 | DOI:10.1055/a-2030-1114

Diabetologia. 2023 Mar 30. doi: 10.1007/s00125-023-05905-8. Online ahead of print.

ABSTRACT

AIMS/HYPOTHESIS: Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons.

METHODS: The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice.

RESULTS: Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons.

CONCLUSIONS/INTERPRETATION: Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome.

PMID:36995380 | DOI:10.1007/s00125-023-05905-8

bioRxiv. 2023 Mar 19:2023.02.01.526672. doi: 10.1101/2023.02.01.526672. Preprint.

ABSTRACT

Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, and in part because of this AA remains an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases, but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given its localization to the peritoneal space we hypothesized that intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here we tested the efficacy paclitaxel given by IP administration using three orthotopic PDX models of AA established in NSG mice. Weekly treatment of 25.0 mg/kg of IP paclitaxel dramatically reduced AA tumor growth in TM00351 (81.9% reduction vs. control), PMP-2 (98.3% reduction vs. control), and PMCA-3 (71.4% reduction vs. control) PDX models. Comparing the safety and efficacy of intravenous (IV) to IP administration in PMCA-3, neither 6.25 nor 12.5 mg/kg of IV paclitaxel significantly reduced tumor growth. These results suggest that IP administration of paclitaxel is favorable to IV administration. Given the established safety record of IP paclitaxel in gastric and ovarian cancers, and lack of effective chemotherapeutics for AA, these data showing the activity of IP paclitaxel in orthotopic PDX models of mucinous AA support the evaluation of IP paclitaxel in a prospective clinical trial.

PMID:36993681 | PMC:PMC10055008 | DOI:10.1101/2023.02.01.526672

Int J Environ Res Public Health. 2023 Mar 8;20(6):4732. doi: 10.3390/ijerph20064732.

ABSTRACT

This document provides a comprehensive summary of evidence on the current situation of rare diseases (RDs) globally and regionally, including conditions, practices, policies, and regulations, as well as the challenges and barriers faced by RD patients, their families, and caregivers. The document builds on a review of academic literature and policies and a process of validation and feedback by a group of seven experts from across the globe. Panelists were selected based on their academic merit, expertise, and knowledge regarding the RD environment. The document is divided into five main sections: (1) methodology and objective; (2) background and context; (3) overview of the current situation and key challenges related to RDs covering six dimensions: burden of disease, patient journey, social impact, disease management, RD-related policies, and research and development; (4) recommendations; and (5) conclusions. The recommendations are derived from the discussion undertaken by the experts on the findings of this review and provide a set of actionable solutions to the challenges and barriers to improving access to RD diagnosis and treatment around the world. The recommendations can support critical decision-making, guiding efforts by a broad range of RDs stakeholders, including governments, international organizations, manufacturers, researchers, and patient advocacy groups.

PMID:36981643 | DOI:10.3390/ijerph20064732

Genes (Basel). 2023 Mar 16;14(3):727. doi: 10.3390/genes14030727.

ABSTRACT

Ancient anatomically modern humans (AMHs) encountered other archaic human species, most notably Neanderthals and Denisovans, when they left Africa and spread across Europe and Asia ~60,000 years ago. They interbred with them, and modern human genomes retain DNA inherited from these interbreeding events. High quality (high coverage) ancient human genomes have recently been sequenced allowing for a direct estimation of individual heterozygosity, which has shown that genetic diversity in these archaic human groups was very low, indicating low population sizes. In this study, we analyze ten ancient human genome-wide data, including four sequenced with high-coverage. We screened these ancient genome-wide data for pathogenic mutations associated with monogenic diseases, and established unusual aggregation of pathogenic mutations in individual subjects, including quadruple homozygous cases of pathogenic variants in the PAH gene associated with the condition phenylketonuria in a ~120,000 years old Neanderthal. Such aggregation of pathogenic mutations is extremely rare in contemporary populations, and their existence in ancient humans could be explained by less significant clinical manifestations coupled with small community sizes, leading to higher inbreeding levels. Our results suggest that pathogenic variants associated with rare diseases might be the result of introgression from other archaic human species, and archaic admixture thus could have influenced disease risk in modern humans.

PMID:36980999 | DOI:10.3390/genes14030727