proteins

2022-10-26 | Findings from the Morquio A Registry Study (MARS) after 6 years: Long-term outcomes of MPS IVA patients treated with elosulfase alfa.

The Morquio A Registry Study (MARS) is an ongoing, multinational, observational study of patients with MPS IVA. Key objectives of MARS are to characterize the heterogeneity and natural history of disease and to evaluate long-term effectiveness and safety of elosulfase alfa enzyme replacement therapy (ERT). Enrollment began in September 2014; data on medical history, clinical outcomes, and safety assessments are collected as part of routine care. As of February 2021, 381 subjects from 17 countries had enrolled in MARS: 58 ERT-naïve subjects and 323 ERT-treated subjects (≥1 infusion), with a mean ERT exposure of 5.5 years (SD 2.8) and median age at first ERT treatment of 9.8 years. ERT-treated subjects were younger at diagnosis (median 3.4 vs 6.5 years) relative to ERT-naïve subjects. Among ERT-treated subjects, urinary keratan sulfate (uKS) levels declined from pre-ERT baseline to last follow-up on treatment (mean % change [95% confidence interval]: -52.5% [-57.5%, -47.4%]; n = 115) and 6-min walk test distance remained stable (mean change: -6.1 [-27.6, 15.5] m; n = 131) over a mean follow-up of 5.5 years. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) increased in subjects who were < 18 years of age at ERT initiation (mean change: +0.3 [0.1, 0.4] L and + 0.4 [0.3, 0.5] L; mean follow-up: ∼6 years; n = 82) and were stable in subjects ≥18 years (mean change: 0.0 [-0.0, 0.1] L and 0.0 [-0.1, 0.1] L; mean follow-up: 4.6 years; n = 38). Overall, 148 (47.1%) ERT-treated subjects experienced ≥1 adverse event (AE) and 110 subjects (35%) reported ≥1 serious AE. Drug-related AEs were reported in 39 (12.4%) subjects; the most common were hypersensitivity (9 subjects [2.9%]), urticaria (8 subjects [2.5%]), and pyrexia (7 subjects [2.2%]). MARS is the longest and largest observational study of MPS IVA patients to date, with a heterogenous population that is representative of the MPS IVA population overall. Data collected over the first 6 years of MARS provide real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients, with no new safety concerns identified.

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2022-04-27 | Comparison of Cosyntropin, Vigabatrin, and Combination Therapy in New-Onset Infantile Spasms in a Prospective Randomized Trial.

Objective: In a randomized trial, we aimed to evaluate the efficacy of cosyntropin injectable suspension, 1 mg/mL, compared to vigabatrin for infantile spasms syndrome. An additional arm was included to assess the efficacy of combination therapy (cosyntropin and vigabatrin) compared with cosyntropin monotherapy. Methods: Children (2 months to 2 years) with new-onset infantile spasms syndrome and hypsarhythmia were randomized into 3 arms: cosyntropin, vigabatrin, and cosyntropin and vigabatrin combined. Daily seizures and adverse events were recorded, and EEG was repeated at day 14 to assess for resolution of hypsarhythmia. The primary outcome measure was the composite of resolution of hypsarhythmia and absence of clinical spasms at day 14. Fisher exact test was used to compare outcomes. Results: 37 children were enrolled and 34 were included in the final efficacy analysis (1 withdrew prior to treatment and 2 did not return seizure diaries). Resolution of both hypsarhythmia and clinical spasms was achieved in in 9 of 12 participants (75%) treated with cosyntropin, 1/9 (11%) vigabatrin, and 5/13 (38%) cosyntropin and vigabatrin combined. The primary comparison of cosyntropin versus vigabatrin was significant (64% [95% confidence interval 21, 82], P < .01). Adverse events were reported in all 3 treatment arms: 31 (86%) had an adverse event, 7 (19%) had a serious adverse event, and 15 (42%) had an adverse event of special interest with no difference between treatment arms. Significance: This randomized trial was underpowered because of incomplete enrollment, yet it demonstrated that cosyntropin was more effective for short-term outcomes than vigabatrin as initial treatment for infantile spasms.

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2021-10-19 | Congenital Glucagon-like Peptide-1 Deficiency in the Pathogenesis of Protracted Diarrhea in Mitchell-Riley Syndrome.

Mitchell-Riley syndrome due to RFX6 gene mutations is characterized by neonatal diabetes and protracted diarrhea. The RFX6 gene encodes a transcription factor involved in enteroendocrine cell differentiation required for beta-cell maturation. In contrast to the pathway by which RFX6 mutations leads to diabetes, the mechanisms underlying protracted diarrhea are unknown. To assess whether glucagon-like peptide-1 (GLP-1) was involved in the pathogenesis of Mitchell-Riley syndrome protracted diarrhea. Two case report descriptions. in a tertiary pediatric hospital. "Off-label" treatment with liraglutide. We describe 2 children diagnosed with Mitchell-Riley syndrome, presenting neonatal diabetes and protracted diarrhea. Both patients had nearly undetectable GLP-1 plasma levels and absence of GLP-1 immunostaining in distal intestine and rectum. The main outcome was to evaluate whether GLP-1 analogue therapy could improve Mitchell-Riley syndrome protracted diarrhea. "Off-label" liraglutide treatment, licensed for type 2 diabetes treatment in children, was started as rescue therapy for protracted intractable diarrhea resulting in rapid improvement during the course of 12 months. Congenital GLP-1 deficiency was identified in patients with Mitchell-Riley syndrome. The favorable response to liraglutide further supports GLP-1 involvement in the pathogenesis of protracted diarrhea and its potential therapeutic use.

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2021-06-18 | Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study.

Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa. A total of 33 patients, aged 5-63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease. In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.

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2017-12-05 | Impact of long-term elosulfase alfa treatment on respiratory function in patients with Morquio A syndrome.

To present long-term respiratory function outcomes from an open-label, multi-center, phase 3 extension study (MOR-005) of elosulfase alfa enzyme replacement therapy (ERT) in patients with Morquio A syndrome. In part 1 of MOR-005, patients initially randomized to ERT in the 24-week pivotal study (MOR-004) remained on their regimen (2.0 mg/kg/week or every other week); placebo patients were re-randomized to one of the two regimens. During part 2, all patients received elosulfase alfa 2.0 mg/kg/week. Respiratory function was one of the efficacy endpoints evaluated in MOR-005. Change from MOR-004 baseline to 120 weeks of treatment for the combined population was determined and compared with results from untreated patients from a Morquio A natural history study (MorCAP). Maximum voluntary ventilation (MVV) improved up to week 72 and then stabilized; forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) increased continuously over 120 weeks. Mean increases in the modified per-protocol population was 9.2 % for FVC, 8.8 % for FEV1, and 6.1 % for MVV after 120 weeks. All patients ≤14 years showed respiratory improvements, presumably in part related to growth; however, these were greater in treated patients. For those >14 years, treated patients showed improvements, while deterioration occurred in untreated. Altogether, the improvements were significantly greater (P < 0.05) in treated patients. Long-term ERT is associated with sustained improvements in respiratory function in Morquio A. In younger patients (≤14 years), some improvement may be ascribed to growth. In older patients, other mechanisms, e.g., decreased glycosaminoglycan storage, are likely involved.

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antibodies

2024-06-26 | ACOX1 gain-of-function variation in a 10-years-old patient responsive to immunomodulating therapy.

A heterozygous gain-of-function variant in the acyl-CoA oxidase 1 (ACOX1) gene, c.710A>G (p.Asn237Ser), is known to cause Mitchell syndrome, a very rare progressive disorder characterized by episodic demyelination, sensory polyneuropathy, and hearing loss. Only eight patients have been described so far. A single patient has been treated with intravenous immunoglobulin administration, indicating clinical improvement. In this study, we describe a 10-year-old girl carrying the identical mutation, who presented with progressive sensorineural deafness, visual abnormalities, skin ichthyosis, and gait ataxia from infantile age with progressive worsening and loss of walking ability by the age of 10 years. Antioxidant therapies and monthly intravenous immunoglobulin infusions showed excellent clinical results: after 1 year of treatment, the child is now able to walk, run, and jump. We emphasize the importance of early genetic diagnosis since an effective treatment is available for this rare condition.

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2024-03-05 | [Clinical and prognostic analysis of opsoclonus-myoclonus-ataxia syndrome in children].

Objective: To summarize the clinical and prognostic features of children with opsoclonus-myoclonus-ataxia syndrome (OMAS). Methods: A total of 46 patients who met the diagnostic criteria of OMAS in the Department of Neurology, Beijing Children's Hospital from June 2015 to June 2023 were retrospectively analyzed. Centralized online consultations or telephone visits were conducted between June and August 2023. The data of the children during hospitalization and follow-up were collected, including clinical manifestations, assistant examination, treatment and prognosis. According to the presence or absence of tumor, the patients were divided into two groups. The chi-square test or Mann-Whitney U test was used to compare the differences between the two groups. Univariate Logistic regression was used to analyze the factors related to OMAS recurrence and prognosis. Results: There were 46 patients, with 25 males and the onset age of 1.5 (1.2, 2.4) years. Twenty-six (57%) patients were diagnosed with neuroblastoma during the course of the disease, and no patients were categorized into the high-risk group. A total of 36 patients (78%) were followed up for≥6 months, and all of them were treated with first-line therapy with glucocorticoids, gammaglobulin and (or) adrenocorticotrophic hormone. Among the 36 patients, 9 patients (25%) were treated with second-line therapy for ≥3 months, including rituximab or cyclophosphamide, and 17 patients (47%) received chemotherapy related to neuroblastoma. At the follow-up time of 4.2 (2.2, 5.5) years, 10 patients (28%) had relapsed of OMAS. The Mitchell and Pike OMS rating scale score at the final follow-up was 0.5 (0, 2.0). Seven patients (19%) were mildly cognitively behind their peers and 6 patients (17%) were severely behind. Only 1 patient had tumor recurrence during follow-up. The history of vaccination or infection before onset was more common in the non-tumor group than in the tumor group (55%(11/20) vs. 23%(6/26), χ²=4.95, P=0.026). Myoclonus occurred more frequently in the non-tumor group (40%(8/20) vs. 4%(1/26), χ²=7.23, P=0.007) as the onset symptom. Univariate Logistic regression analysis showed that the tumor group had less recurrence (OR=0.19 (0.04-0.93), P=0.041). The use of second-line therapy or chemotherapy within 6 months of the disease course had a better prognosis (OR=11.64 (1.27-106.72), P=0.030). Conclusions: OMAS in children mostly starts in early childhood, and about half are combined with neuroblastoma. Neuroblastoma in combination with OMAS usually has a low risk classification and good prognosis. When comparing patients with OMAS with and without tumors, the latter have a more common infection or vaccination triggers, and myoclonus, as the onset symptom, is more common. Early addition of second-line therapy is associated with better prognosis in OMAS. 目的： 总结儿童眼球阵挛-肌阵挛-共济失调综合征（OMAS）患儿的临床及预后特征。 方法： 对2015年6月至2023年6月于北京儿童医院神经内科住院的46例OMAS患儿进行回顾性病例分析。并在2023年6至8月对患儿进行集中的互联网诊疗或电话访视。收集患儿住院和门诊随访期间的病例资料，包括临床表现、辅助检查、治疗及预后情况等。根据患儿是否合并肿瘤分为两组，组间比较采用χ²检验或Mann-Whitney U检验。使用单因素Logistic回归分析OMAS复发和预后相关因素。 结果： 46例患儿中男25例，起病年龄1.5（1.2，2.4）岁。26例（57%）患儿病程中确诊神经母细胞瘤，无患儿高危。36例（78%）患儿随访≥6个月，这36例患儿均使用糖皮质激素、丙种球蛋白和（或）促肾上腺皮质激素作为一线治疗，其中9例（25%）使用二线治疗≥3个月（包括利妥昔单抗和环磷酰胺），17例（47%）使用神经母细胞瘤相关的化疗；随访4.2（2.2，5.5）年，10例（28%）患儿出现OMAS复发。36例患儿末次随访时Mitchell and Pike OMS评分量表评分为0.5（0，2.0）分，7例（19%）认知轻度落后于同龄儿，6例（17%）重度落后。仅1例患儿在随访中出现肿瘤复发。未合并肿瘤组起病前疫苗接种或感染病史较合并肿瘤组更多见［55%（11/20）比23%（6/26），χ²=4.95，P=0.026］，首发症状肌阵挛出现更频繁［40%（8/20）比4%（1/26），χ²=7.23，P=0.007］。Logistic单因素回归分析发现，合并肿瘤组比未合并肿瘤组更少出现复发［OR=0.19（0.04~0.93），P=0.041］，病程6个月内使用二线治疗或化疗预后更好［OR=11.64（1.27~106.72），P=0.030］。 结论： 儿童OMAS多于幼儿期起病，约半数合并神经母细胞瘤。合并OMAS的神经母细胞瘤通常危险分级低，预后好。对比合并和未合并肿瘤的OMAS患儿，后者起病前感染或接种疫苗诱因更常见，首发症状肌阵挛更多见。早期加用二线治疗与OMAS更好的预后相关。.

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2021-08-12 | Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2 Macrophages and Accelerated Osteoclastogenesis.

To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin-1 (IL-1)-mediated diseases including neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA). A 4-year-old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute-phase reactants. She had a 17.8-kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long-lasting remission receiving IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL-1β secretion. In contrast, lipopolysaccharide-stimulated, monocyte-derived, M2-like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL-8, IL-6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/β, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL-1 (but not IL-6) blockade. We report 2 novel compound heterozygous disease-causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2-like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1-mediated autoinflammatory diseases.

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2016-03-15 | Effect of Increased Immunosuppression on Developmental Outcome of Opsoclonus Myoclonus Syndrome (OMS).

Opsoclonus myoclonus syndrome (OMS) produces long-term cognitive, behavioral, and motor deficits. Objective was to see if more aggressive treatment improved outcome. Assessment included opsoclonus myoclonus syndrome rating, developmental/cognitive and motor assessment, and adaptive behavior. Fourteen subjects completed testing. Nine had neuroblastoma. Onset was at 10 to 35 months; onset to diagnosis: 2 days to 14 months, and onset to first treatment: 5 days to 15 months. Initial treatment was corticotropin (12), oral steroids (3), plus intravenous immunoglobulin in all. Ten received rituximab, 5 cyclophosphamide. Age at testing ranged from 2.5 to 10.3 years. Adaptive Behavior Score (11 subjects), mean 93.5; estimated Intelligence Quotient/Developmental Quotient mean 93.5; Motor: mean 92.8. Residual opsoclonus myoclonus syndrome symptoms at the time of the evaluation were generally minor; opsoclonus myoclonus syndrome scores ranged from 0 to 6. Comparison to previously reported opsoclonus myoclonus syndrome subjects showed improved outcomes: Adaptive behavior, cognitive and motor scores were significantly higher (P < .001) in new subjects. Outcomes have improved with more aggressive immunosuppression, with most opsoclonus myoclonus syndrome survivors now functioning at or near normal.

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small molecules

2026-04-03 | Abstract 7086: Preclinical characterization of a potent and selective Werner helicase (WRN) inhibitor with activity in low-TA repeat microsatellite instability-high (MSI-H) cancers

Abstract Werner syndrome helicase (WRN), a member of the RecQ family of DNA helicases, is a synthetic-lethal dependency in DNA mismatch repair-deficient cancers that exhibit high microsatellite instability (MSI-H). Here, we characterize Compound 1, a potent and selective small molecule WRN inhibitor. Compound 1 binds within an allosteric pocket in the helicase domain of WRN and forms an irreversible covalent interaction with cysteine 727 (C727), a residue not conserved in other RecQ helicases. In vitro, Compound 1 potently inhibited WRN’s helicase activity and was confirmed to be a highly selective covalent inhibitor of WRN C727 by mass spectrometry-based cysteine profiling in human MSI-H cancer cells. Consequently, Compound 1 potently impacted the viability of a broad panel of MSI-H cell lines, including colorectal SW48 and RKO (IC50 = &lt; 10 nM and &lt; 100 nM, respectively), and ovarian TOV-21G (IC50 &lt; 300 nM) cells. Treatment with Compound 1 elicited robust induction of pharmacodynamic (PD) biomarkers including sensors of DNA damage and the proteasome-dependent degradation of WRN across the panel. Notably, these responses were selective for MSI-H cells and were not observed in microsatellite-stable (MSS) cells nor in cell lines derived from normal tissues up to the highest concentration tested (5 μM). In vivo, Compound 1 treatment resulted in a dose-dependent modulation of PD biomarkers, which correlated with strong anti-tumor efficacy in SW48, RKO, and TOV-21G MSI-H cell line-derived xenograft (CDX) models. Covalent engagement of WRN by Compound 1 was measurable in tumor tissue and in peripheral blood monocytes. The exposure and target occupancy of Compound 1 required for efficacy strongly correlated with the expansion of repetitive thymine-adenine (TA) nucleotide DNA microsatellites. These repeats form non-canonical secondary structures that interfere with DNA replication in MSI-H cells and require unwinding by WRN. Long-read DNA sequencing confirmed that the extent of TA-repeat expansion was associated with Compound 1 activity in MSI-H CDX models. An analysis of primary MSI-H tumor cohorts revealed that the majority of patient tumor samples exhibited TA-repeat expansions within the range of Compound 1 efficacy observed in cell-based models. Importantly, dosing of Compound 1 was sufficient to elicit tumor regression in low-TA repeat CDX MSI-H models (RKO, TOV-21G), which have proven to be refractory to WRN inhibitors advanced previously. Together, these data demonstrate that covalent inhibition of WRN by Compound 1 is an effective strategy to selectively kill MSI-H tumor cells with expanded TA repeats. Citation Format: Pablo E. Hollstein, Daniel A. Aiello, Anne Y. Saiki, Keegan S. Cooke, Petia Mitchell, Xiang Yi, Ishwar N. Kohale, Matthew J. Rardin, John Rodgers, Mauro Poggio, Chun Su, Sigurgeir Olaffson, Doruk Beyter, Jennifer A. Roth, Andrew J. Holland, Paul E. Hughes. Preclinical characterization of a potent and selective Werner helicase (WRN) inhibitor with activity in low-TA repeat microsatellite instability-high (MSI-H) cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7086.

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2025-05-28 | Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review.

Background and Objectives: Erythromelalgia (EM) is an uncommon condition marked by recurring redness, intense burning sensations, and elevated limb warmth. This syndrome can be significantly debilitating, and finding effective treatment options often proves to be quite difficult. The symptoms can severely impact the quality of life of those affected, resulting in considerable disability. This systematic review aims to compare available medical treatments for EM by evaluating their efficacy and safety. Materials and Methods: Following PRISMA guidelines, the search included the PubMed, Medline, and Web of Science databases, using the keywords ("Erythromelalgia" OR "Mitchell's Disease") AND ("Erythromelalgia Treatment" OR "Erythromelalgia Management"). Results: From the 103 papers extracted through the database search, six articles were considered suitable for the systematic review. The included studies investigated various interventions used for a total of 120 patients, including iloprost (n = 8), misoprostol (n = 21), topical amitriptyline-ketamine (n = 36), lidocaine (n = 27), chemical lumbar sympathectomy (CLS, n = 13), and various pharmacological agents (n = 11). The outcomes showed significant improvements in areas like pain reduction, cooling scores, and temperature regulation. Iloprost and misoprostol exhibited notable benefits in cooling scores, sympathetic dysfunction, and EM severity compared to placebos. About 75% of the patients reported pain relief with topical amitriptyline-ketamine, while lidocaine reduced nociceptive feelings in a dose-dependent manner. Conclusions: Comparing interventions demonstrated consistent clinical benefit with varied tolerability. However, adverse events ranged from mild gastrointestinal symptoms to severe complications such as disability and depression, requiring careful monitoring. Given EM's diverse symptoms and comorbidities, treatment efficacy varies among individuals. A personalized approach incorporating genetic testing, multidisciplinary care, and long-term monitoring is essential to optimize outcomes. Continued research is vital to advance understanding of EM's pathophysiology and improve patient care.

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2025-02-28 | A clinical case of secondary erythromelalgia

Background. Angiotrophoneuroses treatment is supposed to be one of the most sophisticated tasks for neurologists. This is the group of diseases, characterized by impairment of vascular tone regulation. The particular example of angiotrophoneuroses is erythromelalgia (also known as Mitchell syndrome), which results into neuropathic pain, autonomic dysfunction, and dystrophic changes in tissues, therefore poor level of life quality of patients with this condition. Unfortunately, comprehensive understanding of its pathophysiology is missing in view of the fact that itʼs rare and can be masked at the background of other myeloproliferative, demyelinating, metabolic, autoimmune and other diseases. Performing analysis of the clinical case of the secondary form of erythromelalgia gives an opportunity to attract attention of many healthcare specialists, such as neurologists, dermatologists, haematologists, vascular surgeons, etc. It is exceptionally important to highlight this topic, because patients with Mitchell syndrome can search for help visiting the doctors of different specialties. Purpose – to describe the clinical case of erythromelalgia, occurred in the patient with erythremia. Materials and Methods. The results of an objective neurological examination, the DN4 neuropathic pain diagnostic questionnaire and the TSS (Total Symptoms Score) assessment, as well as the reporting of laboratory and instrumental diagnostic examinations of a patient with Mitchellʼs syndrome, were used. Results. Neurological examination and paraclinical tests implied the patient had erythromelalgia, polyneuropathy (with vegetative-trophic and sensitive disorders, as well as movement disorders in the limbs, mainly in the distal parts), and erythremia. The use of complex therapy (gabapentin, L-lysine escinate, keltican, propranolol, suprastin, alerzin, methotrexate, acetylsalicylic acid) made it possible to improve the patientʼs condition. Conclusions. Erythromelalgia is a severe disease with high resistance to existent pharmacological approaches and unfavorable outcome. Although the modern drugs make it possible to reduce the subjective severity of symptoms, the frequency of paroxysms is hard to be controlled. Therefore, there is an urgent need to find new therapeutic approaches to the treatment of Mitchellʼs disease and the development of new methods that allow the detection of secondary forms of erythromelalgia.

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2023-09-04 | Early Treatment of Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe hyperinflammatory illness occurring after severe acute respiratory syndrome coronavirus 2 infection. The optimal treatment of MIS-C is unknown, although prior studies have indicated benefits of intravenous immunoglobulin (IVIG) and glucocorticoids. We hypothesize that early treatment with glucocorticoids is associated with shorter hospital length of stay (LOS). This study is a multicenter retrospective cohort study of patients hospitalized with MIS-C over a roughly 1-year period. The primary outcome was hospital LOS comparing subjects who received glucocorticoids within 48 hours of arrival to the treating hospital to those who did not. Secondary outcomes included ICU LOS. Unadjusted and adjusted analyses were performed. The final analysis included 131 subjects. Subjects who received early glucocorticoids were more likely to receive early IVIG and to require ICU admission. Early glucocorticoid administration was associated with shorter ICU LOS (4 vs 9 days, P = .004) in the unadjusted analysis. In the adjusted analysis, early glucocorticoid administration and early IVIG administration were both independently associated with shorter hospital LOS (incidence rate ratio 0.75, P = .025; incidence rate ratio 0.56, P = .026, respectively). Glucocorticoids and intravenous immunoglobulin were independently associated with shorter hospital length of stay when given early in hospitalization to MIS-C patients after accounting for potential confounding factors. The optimal dose and duration of treatment require further investigation, but this study supports early combination therapy with both IVIG and glucocorticoids for all children hospitalized with MIS-C.

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2023-06-23 | Lineage-Specific Induced Pluripotent Stem Cell-Derived Smooth Muscle Cell Modeling Predicts Integrin Alpha-V Antagonism Reduces Aortic Root Aneurysm Formation in Marfan Syndrome Mice.

The role of increased smooth muscle cell (SMC) integrin αv signaling in Marfan syndrome (MFS) aortic aneurysm remains unclear. Herein, we examine the mechanism and potential efficacy of integrin αv blockade as a therapeutic strategy to reduce aneurysm progression in MFS. Induced pluripotent stem cells (iPSCs) were differentiated into aortic SMCs of the second heart field (SHF) and neural crest (NC) lineages, enabling in vitro modeling of MFS thoracic aortic aneurysms. The pathological role of integrin αv during aneurysm formation was confirmed by blockade of integrin αv with GLPG0187 in Fbn1C1039G/+ MFS mice. iPSC-derived MFS SHF SMCs overexpress integrin αv relative to MFS NC and healthy control SHF cells. Furthermore, integrin αv downstream targets (FAK [focal adhesion kinase]/AktThr308/mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment of MFS SHF SMCs with GLPG0187 reduced p-FAK/p-AktThr308/mTORC1 activity back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS NC SMCs and control SMCs, which normalized with GLPG0187 treatment. In the Fbn1C1039G/+ MFS mouse model, integrin αv, p-AktThr308, and downstream targets of mTORC1 proteins were elevated in the aortic root/ascending segment compared to littermate wild-type control. Mice treated with GLPG0187 (age 6-14 weeks) had reduced aneurysm growth, elastin fragmentation, and reduction of the FAK/AktThr308/mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing. The integrin αv-FAK-AktThr308 signaling pathway is activated in iPSC SMCs from MFS patients, specifically from the SHF lineage. Mechanistically, this signaling pathway promotes SMC proliferation and migration in vitro. As biological proof of concept, GLPG0187 treatment slowed aneurysm growth and p-AktThr308 signaling in Fbn1C1039G/+ mice. Integrin αv blockade via GLPG0187 may be a promising therapeutic approach to inhibit MFS aneurysmal growth.

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gene therapies

2025-12-21 | Multifaceted functions of transcription regulatory factor X6 (RFX6): from pancreatic development to cancer progression.

Regulatory factor X6 (RFX6) is defined as the sixth member of the RFX family based on its highly conserved and specific wing-helix DNA-binding domain. Its expression in adults is predominantly localized to pancreatic islets, small intestine, and colon. Extensive research has demonstrated that RFX6 regulates cellular processes, such as pancreatic development, differentiation of islet progenitor cells, and insulin secretion, through the modulation of specific miRNAs (such as miR145 and miR195) and mRNAs (such as Pdx1, Neurod1, GCK, and Abcc8). Hence, mutations and deletions in RFX6 have been linked to the onset of various types of diabetes, including type 2 diabetes, Maturity-onset diabetes of the young, neonatal diabetes mellitus, especially Mitchell-Riley Syndrome (MRS). Specifically, homozygous mutations in RFX6 impede the proper differentiation of pancreatic progenitor cells, leading to inhibition of pancreatic head-tail development and endocrine cell formation, thereby contributing to the pathogenesis of MRS. Furthermore, examination of RFX6 target genes reveals a potential association with tumor development, indicating that RFX6 may play a role in cancer progression. Dysregulated expression or mutations of the RFX6 gene in prostate cancer, hepatocellular carcinoma, gastric cancer, melanoma, and other tumors have garnered significant interest, with studies showing that such alterations affect tumor cell proliferation, migration, and invasion, and are correlated with an unfavorable clinical prognosis in patients carrying RFX6 mutations. This review delves into the various functions of RFX6, emphasizing its crucial regulatory roles in pancreatic development, tumorigenesis, and progression. In addition, recent advancements in MRS therapy are outlined, underscoring the importance of RFX6-targeted therapy in MRS and cancer.

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2024-05-20 | Exploiting fly models to investigate rare human neurological disorders.

Rare neurological diseases, while individually are rare, collectively impact millions globally, leading to diverse and often severe neurological symptoms. Often attributed to genetic mutations that disrupt protein function or structure, understanding their genetic basis is crucial for accurate diagnosis and targeted therapies. To investigate the underlying pathogenesis of these conditions, researchers often use non-mammalian model organisms, such as Drosophila (fruit flies), which is valued for their genetic manipulability, cost-efficiency, and preservation of genes and biological functions across evolutionary time. Genetic tools available in Drosophila, including CRISPR-Cas9, offer a means to manipulate gene expression, allowing for a deep exploration of the genetic underpinnings of rare neurological diseases. Drosophila boasts a versatile genetic toolkit, rapid generation turnover, and ease of large-scale experimentation, making it an invaluable resource for identifying potential drug candidates. Researchers can expose flies carrying disease-associated mutations to various compounds, rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and, ultimately, clinical trials. In this comprehensive review, we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis, pathophysiology, and potential therapeutic implications. We discuss rare diseases associated with both neuron-expressed and glial-expressed genes. Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay, mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay, and mutations in IRF2BPL causing seizures, a neurodevelopmental disorder with regression, loss of speech, and abnormal movements. And we explore mutations in EMC1 related to cerebellar atrophy, visual impairment, psychomotor retardation, and gain-of-function mutations in ACOX1 causing Mitchell syndrome. Loss-of-function mutations in ACOX1 result in ACOX1 deficiency, characterized by very-long-chain fatty acid accumulation and glial degeneration. Notably, this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology, offering a platform for the rapid identification of potential therapeutic interventions. Rare neurological diseases involve a wide range of expression systems, and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia. Furthermore, mutations within the same gene may result in varying functional outcomes, such as complete loss of function, partial loss of function, or gain-of-function mutations. The phenotypes observed in patients can differ significantly, underscoring the complexity of these conditions. In conclusion, Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases. By facilitating the modeling of these conditions, Drosophila contributes to a deeper understanding of their genetic basis, pathophysiology, and potential therapies. This approach accelerates the discovery of promising drug candidates, ultimately benefiting patients affected by these complex and understudied diseases.

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2022-08-26 | Embryologic Origin Influences Smooth Muscle Cell Phenotypic Modulation Signatures in Murine Marfan Syndrome Aortic Aneurysm.

Aortic root smooth muscle cells (SMC) develop from both the second heart field (SHF) and neural crest. Disparate responses to disease-causing Fbn1 variants by these lineages are proposed to promote focal aortic root aneurysm formation in Marfan syndrome (MFS), but lineage-stratified SMC analysis in vivo is lacking. We generated SHF lineage-traced MFS mice and performed integrated multiomic (single-cell RNA and assay for transposase-accessible chromatin sequencing) analysis stratified by embryological origin. SMC subtypes were spatially identified via RNA in situ hybridization. Response to TWIST1 overexpression was determined via lentiviral transduction in human aortic SMCs. Lineage stratification enabled nuanced characterization of aortic root cells. We identified heightened SHF-derived SMC heterogeneity including a subset of Tnnt2 (cardiac troponin T)-expressing cells distinguished by altered proteoglycan expression. MFS aneurysm-associated SMC phenotypic modulation was identified in both SHF-traced and nontraced (neural crest-derived) SMCs; however, transcriptomic responses were distinct between lineages. SHF-derived modulated SMCs overexpressed collagen synthetic genes and small leucine-rich proteoglycans while nontraced SMCs activated chondrogenic genes. These modulated SMCs clustered focally in the aneurysmal aortic root at the region of SHF/neural crest lineage overlap. Integrated RNA-assay for transposase-accessible chromatin analysis identified enriched Twist1 and Smad2/3/4 complex binding motifs in SHF-derived modulated SMCs. TWIST1 overexpression promoted collagen and SLRP gene expression in vitro, suggesting TWIST1 may drive SHF-enriched collagen synthesis in MFS aneurysm. SMCs derived from both SHF and neural crest lineages undergo phenotypic modulation in MFS aneurysm but are defined by subtly distinct transcriptional responses. Enhanced TWIST1 transcription factor activity may contribute to enriched collagen synthetic pathways SHF-derived SMCs in MFS.

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2025-07-01 | A single-dose intranasal immunization with a novel bat influenza A virus-vectored MERS vaccine provides effective protection against lethal MERS-CoV challenge.

The threat to global health security posed by Middle East respiratory syndrome coronavirus (MERS-CoV) and emerging MERS-like coronaviruses highlights the need to develop safe and efficient vaccines. Viral vector vaccines have been shown to be effective and are widely used to prevent various viral diseases because they mimic natural infection and induce a more comprehensive immune response. Herein, we developed a novel bat influenza A virus-based vaccine vector by replacing the open reading frame of either bat influenza hemagglutinin or neuraminidase with that of the hemagglutinin-esterase-fusion gene from influenza D virus, which can infect multiple species, including humans and camels. We then generated a temperature-sensitive, cold-adapted, and attenuated MERS vaccine candidate expressing the clade A MERS-CoV spike S1, referred to as Len_S1, using the developed bat influenza vector and demonstrated its safety and immunogenicity. A single-dose intranasal immunization with Len_S1 protected human dipeptidyl-peptidase-4 (hDPP4) transgenic mice from a lethal MERS-CoV challenge. Notably, a two-dose immunization with Len_S1 completely blocked viral replication and lung damage in challenged mice. Further studies revealed that intranasal immunization with Len_S1 in mice elicited mucosal, humoral, and cellular immune responses. Moreover, sera collected from Len_S1-immunized mice were able to cross-neutralize multiple clades of MERS-CoVs. Collectively, these results indicate that Len_S1 is a safe and effective MERS vaccine that induces a comprehensive immune response and provides cross-protection against diverse clades of MERS-CoVs.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is an important zoonotic virus with pandemic potential that continues to evolve within dromedary camels. However, no licensed vaccine is currently available. Viral vector-based vaccines represent a promising platform, with demonstrated efficacy in preventing viral diseases. In this study, we developed a bat influenza virus-vectored MERS vaccine, Len_S1, that is safe and immunogenic. Intranasal immunization of human dipeptidyl-peptidase-4 (hDPP4)-transgenic mice with Len_S1 induced humoral, mucosal, and cellular immune responses and provided effective protection against a lethal MERS-CoV challenge. Importantly, sera collected from immunized mice cross-neutralized three distinct clades of MERS-CoVs. Our results indicate that Len_S1 is a promising vaccine candidate with the potential to prevent MERS-CoV infection and mitigate the risk of future epidemics and pandemics.

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2025-06-21 | Allogeneic haematopoietic stem cell transplantation for STAT3 hyper-IgE syndrome: a worldwide study.

STAT3 hyper-IgE syndrome (STAT3-HIES) is a multisystem disorder causing recurrent skin and respiratory infection with bronchiectasis, pneumatocoeles, and aspergillosis; lymphoma; and extra-immune manifestations including fractures and vasculopathy. Published data on immune and extra-immune HSCT outcomes focus on case reports or small cohorts. International multicentre retrospective study of HSCT in STAT3-HIES. Primary endpoints were overall survival (OS) and event-free survival (EFS; events were death, graft failure, chronic GvHD). We identified 41 patients over a 28-year period. HSCT indication was infection (93%) or lymphoma (7%). Median age at HSCT was 14 (4-45) years. Most patients had pre-HSCT respiratory disease (93%) including parenchymal lung disease (68%) and prior suspected/confirmed pulmonary fungal infection (32%). Patients received peripheral blood stem cell (51%) or marrow (49%) from HLA 10/10-MUD (44%), MFD (44%), MMFD (10%), or one 9/10 MMUD (2%). Median CD34+ stem cell dose was 6.2 (0.05-22.0) cells x106/kg. Conditioning regimens were predominantly treosulfan-based (59%; with thiotepa, 34%); other patients received busulfan-based (24%) or melphalan-based (17%) regimens. Median follow-up for surviving patients was 5 (0.8-28) years. 5-year OS was 93% and 5-year EFS 90%. Cumulative incidence of grade II-IV acute GvHD was 22%. Median whole blood donor chimerism at latest follow up was 100%. 87% of patients have reduced or no bacterial or fungal respiratory infection. Post-HSCT, 20% developed new skeletal fractures. This worldwide study expand data on HSCT for STAT3-HIES to 41 patients. Despite significant pre-HSCT pulmonary morbidity, OS was high, and patients have improved skin and respiratory disease, though the impact on extra-immune manifestations appears limited.

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