Publications by authors named "Melita Irving"

81 Publications

A hemizygous mutation in the FOXP3 gene (IPEX syndrome) resulting in recurrent X-linked fetal hydrops: a case report.

BMC Med Genomics 2021 Feb 26;14(1):58. Epub 2021 Feb 26.

Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Background: Fetal hydrops is excessive extravasation of fluid into the third space in a fetus, which could be due to a wide differential of underlying pathology. IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome primarily affects males. It is a monogenic primary immunodeficiency syndrome of X-linked recessive inheritance due to FOXP3 gene variants. It is characterised by the development of multiple autoimmune disorders in affected individuals.

Case Presentation: We present a rare cause of male fetal hydrops in the context of IPEX syndrome and discuss FOXP3 gene variants as a differential for 'unexplained' fetal hydrops that may present after the first trimester.

Discussion And Conclusions: In all similar cases, the pathological process begins during intrauterine life. Furthermore, there are no survivors described. Consequently, this variant should be considered as a severe one, associated with intrauterine life onset and fatal course, i.e., the most severe IPEX phenotype.
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http://dx.doi.org/10.1186/s12920-021-00901-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908803PMC
February 2021

Automated reanalysis, a novel way to diagnose an ultra-rare condition: Fibronectin-1-related spondylometaphyseal dysplasia (SMD-FN1).

Clin Dysmorphol 2021 Feb 17. Epub 2021 Feb 17.

Clinical Genetics Registrar, Guy's and St Thomas' NHS Foundation Trust (London), Birmingham Women's and Children's Hospital NHS Trust & Birmingham Health Partners Medical Student, University of Birmingham, Birmingham Trainee Clinical Bioinformatician, Guy's and St Thomas' NHS Foundation Trust, London East England GLH Bioinformatics Lead, Cambridge University Hospitals NHS FT, Addenbrooke's Hospital, Cambridge Consultant Paediatric Endocrinologist Consultant Clinical Geneticist, Guy's and St Thomas' NHS Foundation Trust, London, UK.

We report a further case of spondylometaphyseal dysplasia - corner fracture type due to the fibronectin-1 gene (SMD-FN1) in a child originally thought to have metaphyseal chondrodysplasia-Brussels type (MCD Brussels). We highlight phenotypic differences with the SMD-FN1 published reports. This case is unique in terms of the method of molecular confirmation. Findings from the 100 000 Genomes Project were originally negative (in both tier 1 and 2); however, subsequent reanalysis, initiated by an automated search for new gene-disease associations in PanelApp, highlighted a candidate diagnostic variant. Our child had short stature, facial dysmorphism, spondylometaphyseal dysplasia and corner fractures and a heterozygous de novo missense variant in FN1 (c.675C>G p.(Cys225Trp), which was likely pathogenic. The variant matched the clinical and radiological features and a diagnosis of SMD-FN1 was confirmed. We explore the diagnostic journey of this patient, compare her findings with the previous 15 patients reported with SMD-FN1 and discuss the diagnostic utility of automated reanalysis. We consider differences and similarities between MCD Brussels and SMD-FN1, by reviewing literature on both conditions and assess whether they are in fact the same disorder.
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http://dx.doi.org/10.1097/MCD.0000000000000369DOI Listing
February 2021

Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

J Med Chem 2021 Feb 8;64(4):2205-2227. Epub 2021 Feb 8.

Molecular Modeling Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.

The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme-ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01968DOI Listing
February 2021

Lifetime Impact of Achondroplasia: Current Evidence and Perspectives on the Natural History.

Bone 2021 Feb 2:115872. Epub 2021 Feb 2.

Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.

Achondroplasia, the most common form of disproportionate short stature, is caused by a variant in the fibroblast growth factor receptor 3 (FGFR3) gene. Advances in drug treatment for achondroplasia have underscored the need to better understand the natural history of this condition. This article provides a critical review and discussion of the natural history of achondroplasia based on current literature evidence and the perspectives of clinicians with extensive knowledge and practical experience in managing individuals with this diagnosis. This review draws evidence from recent and ongoing longitudinal natural history studies, supplemented with relevant cross-sectional studies where longitudinal research is lacking, to summarize the current knowledge on the nature, incidence, chronology and interrelationships of achondroplasia-related comorbidities across the lifespan. Where possible, data related to adults are presented separately from data specific to children and adolescents. Gaps in knowledge regarding clinical care are identified and areas for future research are recommended and discussed.
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http://dx.doi.org/10.1016/j.bone.2021.115872DOI Listing
February 2021

Best practice guidelines in managing the craniofacial aspects of skeletal dysplasia.

Orphanet J Rare Dis 2021 Jan 14;16(1):31. Epub 2021 Jan 14.

Department of Orthopedics and Sports Medicine, Seattle Children's Hospital, Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, USA.

Background: Recognition and appropriate management of the craniofacial manifestations of patients with skeletal dysplasia are challenging, due to the rarity of these conditions, and dearth of literature to support evidence-based clinical decision making.

Methods: Using the Delphi method, an international, multi-disciplinary group of individuals, with significant experience in the care of patients with skeletal dysplasia, convened to develop multi-disciplinary, best practice guidelines in the management of craniofacial aspects of these patients.

Results: After a comprehensive literature review, 23 initial statements were generated and critically discussed, with subsequent development of a list of 22 best practice guidelines after a second round voting.

Conclusions: The guidelines are presented and discussed to provide context and assistance for clinicians in their decision making in this important and challenging component of care for patients with skeletal dysplasia, in order standardize care and improve outcomes.
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http://dx.doi.org/10.1186/s13023-021-01678-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809733PMC
January 2021

Chondrodysplasia and growth failure in children after early hematopoietic stem cell transplantation for non-oncologic disorders.

Am J Med Genet A 2021 02 4;185(2):517-527. Epub 2021 Jan 4.

Division of Genetic Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non-oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH-associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants). All children had normal growth and no sign of chondrodysplasia at birth and prior to their primary disease. After HSCT, all children developed growth failure, with standard deviation scores for height at or below -3. Radiographically, all children had changes in the spine, metaphyses and epiphyses, compatible with a spondyloepimetaphyseal dysplasia. Genomic sequencing failed to detect pathogenic variants in genes associated with osteochondrodysplasias. We propose that such chondrodysplasia with growth failure is a novel, rare, but clinically important complication following early HSCT for non-oncologic pediatric diseases. The pathogenesis is unknown but could possibly involve loss or perturbation of the cartilage-bone stem cell population.
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http://dx.doi.org/10.1002/ajmg.a.62021DOI Listing
February 2021

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.

Am J Hum Genet 2021 01 11;108(1):115-133. Epub 2020 Dec 11.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address:

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3 mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820739PMC
January 2021

Welcome to the new genomics: an introduction to the NHS Genomic Medicine Service for oral healthcare professionals.

Br Dent J 2020 Nov 27;229(10):682-686. Epub 2020 Nov 27.

Scientific Director, Genomics Education Programme, Health Education England, St Chad's Court, 213 Hagley Road, Edgbaston, Birmingham, B16 9RG, UK.

Genomic medicine is on the threshold of a significant advance in the United Kingdom (UK) with the introduction of a National Health Service (NHS) Genomic Medicine Service. This world-leading initiative aims to integrate genomic medicine into routine NHS care and has the potential to revolutionise healthcare in the UK, including dentistry. The initial focus will be on increasing diagnostic services for rare diseases and cancer, while also harnessing the use of personalised medicine for therapeutic interventions in multiple disorders. Here, we provide a brief overview of this new service, outlining the historical background that has led to its development and how it will work, as well as discussing some of the wider implications for healthcare within the NHS and highlighting the potential longer-term impact of genomics for oral health.
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http://dx.doi.org/10.1038/s41415-020-2348-2DOI Listing
November 2020

Acromesomelic Dysplasia, Type Maroteaux: Impact of Long-Term (8 Years) High-Dose Growth Hormone Treatment on Growth Velocity and Final Height in 2 Siblings.

Horm Res Paediatr 2020 25;93(5):335-342. Epub 2020 Nov 25.

Department of Child Health, King's College Hospital NHS Foundation Trust, London, United Kingdom.

Introduction: Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare autosomal recessive skeletal dysplasia, characterized by severe dwarfism and disproportionate limb shortening. It results from loss-of-function NPR2 mutations affecting the C-type natriuretic peptide receptor. Resistance to growth hormone (GH) action has previously been suggested. We describe outcomes of 2 siblings with AMDM after prolonged high-dose GH treatment.

Patients/methods: Two siblings (Pt-A and Pt-B; consanguineous parents) presented in early childhood with severe disproportionate short stature and radiological features of AMDM. Subsequent genetic testing identified a novel homozygous NPR2 mutation. GH provocation testing showed relatively high GH levels. Serum insulin-like growth factor 1 (IGF-1) was ∼2 SD below age/sex-specific mean. High-dose GH (0.075 mg/kg/day) was started. Pre-GH height velocities were 3.7 (Pt-A) and 4.5 (Pt-B) cm/year. GH dose was adjusted to sustain serum IGF-1 towards +3 SDS for age/sex. Annualized height velocities for first 3 years on GH were 7.0, 5.4, and 4.7 cm/year for patient A and 9.4, 8.0, and 5.9 cm/year for patient B. Height gain during puberty was 10.6 (Pt-A) and 5.9 (Pt-B) cm. Final heights after 8.5 years of GH treatment were 130.5 cm (-6.57 SDS, Pt-A) and 134 cm (-4.58 SDS, Pt-B).

Conclusions: To the best of our knowledge, this is the first report of final height in patients with AMDM after long-term GH treatment. Our results confirm the finding of relative GH resistance in AMDM, which when overcome with high-dose GH treatment resulted in improved height SDS during childhood and adolescence and associated quality of life. The final height of our patients was significantly higher than average reported final height (120 cm) of AMDM patients.
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http://dx.doi.org/10.1159/000511874DOI Listing
November 2020

Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression.

J Exp Med 2021 Feb;218(2)

Department of Oncology, Ludwig Institute for Cancer Research Lausanne, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Limited clinical benefit has been demonstrated for chimeric antigen receptor (CAR) therapy of solid tumors, but coengineering strategies to generate so-called fourth-generation (4G) CAR-T cells are advancing toward overcoming barriers in the tumor microenvironment (TME) for improved responses. In large part due to technical challenges, there are relatively few preclinical CAR therapy studies in immunocompetent, syngeneic tumor-bearing mice. Here, we describe optimized methods for the efficient retroviral transduction and expansion of murine T lymphocytes of a predominantly central memory T cell (TCM cell) phenotype. We present a bicistronic retroviral vector encoding both a tumor vasculature-targeted CAR and murine interleukin-15 (mIL-15), conferring enhanced effector functions, engraftment, tumor control, and TME reprogramming, including NK cell activation and reduced presence of M2 macrophages. The 4G-CAR-T cells coexpressing mIL-15 were further characterized by up-regulation of the antiapoptotic marker Bcl-2 and lower cell-surface expression of the inhibitory receptor PD-1. Overall, this work introduces robust tools for the development and evaluation of 4G-CAR-T cells in immunocompetent mice, an important step toward the acceleration of effective therapies reaching the clinic.
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http://dx.doi.org/10.1084/jem.20192203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653685PMC
February 2021

Pediatric radiology in the diagnosis and management of skeletal dysplasias - welcome to the era of genomic medicine and modern drug pipelines.

Pediatr Radiol 2020 11 2;50(12):1648-1649. Epub 2020 Nov 2.

Department of Clinical Genetics, Guys and St Thomas' NHS Foundation Trust, London, UK.

Radiologists have long played a key role in the diagnosis and management of children with suspected skeletal dysplasia. Advancing molecular sciences, including the emergence of next generation sequencing and the development of modern rapid drug pipelines have the potential to transform this role.
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http://dx.doi.org/10.1007/s00247-020-04858-zDOI Listing
November 2020

Earlier detection of hypochondroplasia: A large single-center UK case series and systematic review.

Am J Med Genet A 2021 01 14;185(1):73-82. Epub 2020 Oct 14.

Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Hypochondroplasia (HCH) is a rare autosomal dominant skeletal dysplasia condition caused by FGFR3 mutations leading to disproportionate short stature. Classically HCH presents in toddlers or school-age children, as limb-to-trunk disproportion and is often mild and easily overlooked during infancy. We report experiences from a single-center UK HCH-cohort of 31 patients, the rate of antenatal HCH detection in our cohort (13/31, 41.9%) and describe relevant case-data for this subset of 13 patients. Inclusion criteria were patients with confirmed molecular HCH diagnosis (by age 3 years) and presenting with short long-bones or large head size on antenatal ultrasound scan. We then conducted a systematic literature review using PUBMED and MEDLINE, analyzing patients with HCH and related antenatal findings. Antenatally suspected (with subsequent molecular confirmation) HCH has been reported 15 times in the literature (2004-2019). Key markers (consistent in both groups) included reduced; femur length, humeral length and increased; biparietal diameter and head circumference. HCH is increasingly detected both antenatally and in infancy, contrary to previous descriptions. This is likely due to greater HCH awareness, improved imaging, and easier molecular testing. Thus, one should consider HCH outside the classical presenting period. Studying the natural history of younger patients with HCH is important with the advent of several targeted FGFR3 therapies currently in trials for Achondroplasia, that may soon be trialed in HCH.
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http://dx.doi.org/10.1002/ajmg.a.61912DOI Listing
January 2021

Centrally mediated obstructive apnoea and restenosis of the foramen magnum in an infant with achondroplasia.

Br J Neurosurg 2020 Sep 12:1-4. Epub 2020 Sep 12.

Guy's and Saint Thomas' NHS Foundation Trust, London, United Kingdom of Great Britain and Northern Ireland.

Achondroplasia is associated with foramen magnum stenosis. We report a male infant with achondroplasia and centrally mediated obstructive apnoea who underwent two foramen magnum decompression due to bone regrowth. He presented at six weeks of age with breath holding and apnoeic episodes associated with significant desaturation, requiring non-invasive ventilation. Craniospinal imaging revealed a narrow foramen magnum without signal change in the spinal cord. Sleep studies showed obstructive, but not central, apnoea. Respiratory abnormalities persisted and reimaging at two months showed development of significant signal changes at the cervicomedullary junction (CMJ). He underwent emergency foramen magnum decompression with initial clinical improvement. Ten days later he relapsed with further apnoeic episodes requiring respiratory support. After extensive re-investigations including CT and MRI, incomplete initial decompression and foramen magnum restenosis were considered and confirmed with a CT head scan 15 weeks after the initial operation. Repeat decompression of bone and removal of thickened dural bands resulted in complete resolution of the apnoeic episodes. Obstructive sleep apnoea can be centrally mediated and further decompression of foramen magnum stenosis should be considered, especially if significant respiratory compromise persists or recurs.
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http://dx.doi.org/10.1080/02688697.2020.1817315DOI Listing
September 2020

Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial.

Lancet 2020 09;396(10252):684-692

BioMarin (UK), London, UK.

Background: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings.

Methods: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 μg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11.

Findings: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred.

Interpretation: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be.

Funding: BioMarin Pharmaceutical.
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http://dx.doi.org/10.1016/S0140-6736(20)31541-5DOI Listing
September 2020

Achondroplasia Foramen Magnum Score: screening infants for stenosis.

Arch Dis Child 2021 02 3;106(2):180-184. Epub 2020 Sep 3.

Department of Paediatric Neurosurgery, Great Ormond Street Hospital, London, UK.

Background: Achondroplasia is associated with foramen magnum stenosis (FMS) and significant risk of morbidity and sudden death in infants. A sensitive and reliable method of detecting infants who require decompressive surgery is required. This study aims to describe the incidence and severity of FMS in an unselected, sequential series of infants using a novel MRI score and retrospectively correlate severity with clinical examination and cardiorespiratory sleep (CRS) studies.

Methods: The Achondroplasia Foramen Magnum Score (AFMS) was developed and scores were retrospectively correlated with clinical and CRS data over a 3-year period.

Results: Of 36 infants (M:F, 18:18), 2 (5.6%) did not have FMS (AFMS0); 13 (36.1%) had FMS with preservation of the cerebrospinal fluid (CSF) spaces (AFMS1); 3 (8.3%) had FMS with loss of the CSF space but no spinal cord distortion (AFMS2); 13 (36.1%) had FMS with flattening of the cervical cord without signal change (AFMS3); and 5 (13.9%) had FMS resulting in cervical cord signal change (AFMS4). Mean Total Apnea and Hypopnea Index (TAHI) for AFMS0-4 was 3.4, 6.41, 2.97, 10.5 and 25.8, respectively. Severe TAHI had a specificity of 89% but only a 59% sensitivity for AFMS3-4. Neurological examination was normal in 34/36 (94%) patients. Overall, 9/36 (25%) infants required neurosurgery with minimal surgical complications.

Conclusions: Clinical examination and CRS have a low sensitivity for predicting the effects of foramen stenosis on the spinal cord. Routine screening with MRI using AFMS can aid in detecting early spinal cord changes and has the potential to reduce infant morbidity and mortality.
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http://dx.doi.org/10.1136/archdischild-2020-319625DOI Listing
February 2021

High versus low dose irradiation for tumor immune reprogramming.

Curr Opin Biotechnol 2020 10 1;65:268-283. Epub 2020 Sep 1.

Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland; Radiation Oncology Service, Lausanne University Hospital, and University of Lausanne, Lausanne, Switzerland; Department of Oncology, Lausanne University Hospital, and University of Lausanne, Lausanne, Switzerland. Electronic address:

Local administration of ionizing radiation to tumors can promote anticancer immune responses that lead to the abscopal regression of distant metastases, especially in patients receiving systemic immune-checkpoint inhibitors. Growing preclinical evidence indicates that high-dose irradiation administered locally to destroy malignant lesions, can promote the release of danger-associated molecular patterns that lead to the recruitment of immune cells, thus inducing a systemic response against tumor antigens that protects against local disease relapse and also mediates distant antineoplastic effects. An accumulating body of preclinical evidence supports also the implementation of low-dose irradiation to induce tumor immune reprogramming. Here, we provide the rationale for a clinical research agenda to refine future clinical practice based on innovative combinations of radiation-immunotherapy.
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http://dx.doi.org/10.1016/j.copbio.2020.08.001DOI Listing
October 2020

Arthrogryposis as a presenting feature of nail-patella syndrome: a lesser-known feature and the perils of negative whole-genome sequencing.

Clin Dysmorphol 2020 Oct;29(4):177-181

Guy's and St Thomas' NHS Foundation Trust, London.

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http://dx.doi.org/10.1097/MCD.0000000000000334DOI Listing
October 2020

Best practice guidelines for management of spinal disorders in skeletal dysplasia.

Orphanet J Rare Dis 2020 06 24;15(1):161. Epub 2020 Jun 24.

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, University of Melbourne, Parkville, Victoria, Australia.

Background: Disorders of the spine present a common and difficult management concern in patients with skeletal dysplasia. Due to the rarity of these conditions however, the literature, largely consisting of small, single institution case series, is sparse in regard to well-designed studies to support clinical decision making in these situations.

Methods: Using the Delphi method, an international, multi-disciplinary group of individuals, with significant experience in the care of patients with skeletal dysplasia, convened to develop multi-disciplinary, "best practice" guidelines in the care of spinal disorders in patients with skeletal dysplasia.

Results: Starting with 33 statements, the group a developed a list of 31 "best practice" guidelines.

Conclusions: The guidelines are presented and discussed to provide context for clinicians in their decision making in this often-challenging realm of care.
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http://dx.doi.org/10.1186/s13023-020-01415-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313125PMC
June 2020

Hip displacement in Wolf-Hirschhorn syndrome: Report on three cases and review of associated musculoskeletal pathologies.

Am J Med Genet A 2020 06 7;182(6):1449-1453. Epub 2020 Apr 7.

Department of Orthopaedic Surgery, Great Ormond Street Hospital, London, UK.

Wolf-Hirschhorn syndrome is a rare genetic disease caused by a chromosomal deletion of the distal short arm of Chromosome 4. It is associated with multisystem abnormalities, including delayed growth, characteristic facial features, epilepsy, and skeletal abnormalities. We report three patients who developed hip displacement, and describe the occurrence of delayed and nonunion in patients who underwent corrective proximal femoral osteotomy for hip displacement. We also performed a literature review identifying common musculoskeletal presentations associated with the condition. Patients with Wolf-Hirschhorn Syndrome are at risk of hip displacement (subluxation), and we would advocate annual hip surveillance in this patient group.
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http://dx.doi.org/10.1002/ajmg.a.61573DOI Listing
June 2020

Correction to: Preclinical Evaluation and Dosimetry of [In] CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1).

Mol Imaging Biol 2020 Aug;22(4):992

Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

In the original article, some numerical values in the following paragraph were reported incorrectly.
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http://dx.doi.org/10.1007/s11307-020-01493-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645449PMC
August 2020

Author Correction: A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy.

Nat Biotechnol 2020 Apr;38(4):503

Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41587-020-0461-zDOI Listing
April 2020

All systems go: converging synthetic biology and combinatorial treatment for CAR-T cell therapy.

Curr Opin Biotechnol 2020 10 25;65:75-87. Epub 2020 Feb 25.

Ludwig Institute for Cancer Research, University of Lausanne, and Department of Oncology, University of Lausanne and University Hospital of Lausanne (CHUV), Switzerland. Electronic address:

Synthetic biology has been transformative to the treatment of advanced hematological malignancies by chimeric antigen receptor (CAR)-engineered T cells. A range of obstacles are now understood to limit the responses of solid epithelial-derived tumors to CAR therapy. For example, inefficient tumor homing and a fortified stroma can restrain the number of CAR-T cells reaching the tumor bed. Upon transendothelial migration across the tumor vasculature, CAR-T cells face a highly suppressive microenvironment that can quickly render them hypofunctional. Safety also remains a critical issue for advancing CAR therapy of solid tumors. Innovative CAR design as well as coengineering and combinatorial treatment strategies with oncolytic adenovirus, radiotherapy, vaccines, chemotherapy, small molecules and monoclonal antibodies hold tremendous potential to support CAR-T cell control of solid tumors, either by directly promoting CAR-T cell function, or/and by re-programming the TME and harnessing the endogenous immune system against the tumor.
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http://dx.doi.org/10.1016/j.copbio.2020.01.009DOI Listing
October 2020

miR-155 Overexpression in OT-1 CD8 T Cells Improves Anti-Tumor Activity against Low-Affinity Tumor Antigen.

Mol Ther Oncolytics 2020 Mar 25;16:111-123. Epub 2019 Dec 25.

Department of Fundamental Oncology and Ludwig Cancer Center, Faculty of Biology and Medicine, University of Lausanne, 1066 Epalinges, Switzerland.

Therapy by adoptive transfer of -expanded tumor-infiltrating or genetically modified T cells may lead to impressive clinical responses. However, there is a need to improve persistence and functionality of the transferred T cells, in particular, to face the highly immunosuppressive environment of solid tumors. Here, we investigate the potential of miR-155, a microRNA known to play an important role in CD8 T cell fitness. We show that forced expression of miR-155 in tumor antigen-specific T cells improves the tumor control of B16 tumors expressing a low-affinity antigen ligand. Importantly, miR-155-transduced T cells exhibit increased proliferation and effector functions associated with a higher glycolytic activity independent of exogenous glucose. Altogether, these data suggest that miR-155 may optimize the antitumor activity of adoptively transferred low-affinity tumor-infiltrating lymphocytes (TILs), in particular, by rendering them more resistant to the glucose-deprived environment of solid tumors. Thus, transgenic expression of miR-155 may enable therapeutic targeting of self-antigen-specific T cells in addition to neoantigen-specific ones.
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http://dx.doi.org/10.1016/j.omto.2019.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994712PMC
March 2020

A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy.

Nat Biotechnol 2020 04 3;38(4):426-432. Epub 2020 Feb 3.

Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3ζ- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.
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http://dx.doi.org/10.1038/s41587-019-0403-9DOI Listing
April 2020

Preclinical Evaluation and Dosimetry of [In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1).

Mol Imaging Biol 2020 08;22(4):979-991

Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Purpose: Endosialin/tumor endothelial marker-1 (TEM1) is an attractive theranostic target expressed by the microenvironment of a wide range of tumors, as well as by sarcoma and neuroblastoma cells. We report on the radiolabeling and preclinical evaluation of the scFv78-Fc, a fully human TEM1-targeting antibody fragment cross-reactive with mouse TEM1.

Procedures: The scFv78-Fc was conjugated with the chelator p-SCN-Bn-CHX-A"-DTPA, followed by labeling with indium-111. The number of chelators per molecule was estimated by mass spectrometry. A conventional saturation assay, extrapolated to infinite antigen concentration, was used to determine the immunoreactive fraction of the radioimmunoconjugate. The radiopharmaceutical biodistribution was assessed in immunodeficient mice grafted with Ewing's sarcoma RD-ES and neuroblastoma SK-N-AS human TEM1-positive tumors. The full biodistribution studies were preceded by a dose-escalation experiment based on the simultaneous administration of the radiopharmaceutical with increasing amounts of unlabeled scFv78-Fc. Radiation dosimetry extrapolations to human adults were obtained from mouse biodistribution data according to established methodologies and additional assumptions concerning the impact of the tumor antigenic sink in the cross-species translation.

Results: [In]CHX-DTPA-scFv78-Fc was obtained with a radiochemical purity > 98 % after 1 h incubation at 42 °C and ultrafiltration. It showed good stability in human serum and > 70 % immunoreactive fraction. Biodistribution data acquired in tumor-bearing mice confirmed fast blood clearance and specific tumor targeting in both xenograft models. The radiopharmaceutical off-target uptake was predominantly abdominal. After a theoretical injection of [In]CHX-DTPA-scFv78-Fc to the reference person, the organs receiving the highest absorbed dose would be the spleen (0.876 mGy/MBq), the liver (0.570 mGy/MBq) and the kidneys (0.298 mGy/MBq). The total body dose and the effective dose would be 0.058 mGy/MBq and 0.116 mSv/MBq, respectively.

Conclusions: [In]CHX-DTPA-scFv78-Fc binds specifically to endosialin/TEM1 in vitro and in vivo. Dosimetry estimates are in the range of other monoclonal antibodies radiolabeled with indium-111. [In]CHX-DTPA-scFv78-Fc could be potentially translated into clinic.
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http://dx.doi.org/10.1007/s11307-020-01479-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343747PMC
August 2020

CD8 Binding of MHC-Peptide Complexes in cis or trans Regulates CD8 T-cell Responses.

J Mol Biol 2019 12 5;431(24):4941-4958. Epub 2019 Nov 5.

Ludwig Institute for Cancer Research, University of Lausanne, and Department of Oncology, University Hospital of Lausanne, 1009, Lausanne, Switzerland. Electronic address:

The coreceptor CD8αβ can greatly promote activation of T cells by strengthening T-cell receptor (TCR) binding to cognate peptide-MHC complexes (pMHC) on antigen presenting cells and by bringing p56 to TCR/CD3. Here, we demonstrate that CD8 can also bind to pMHC on the T cell (in cis) and that this inhibits their activation. Using molecular modeling, fluorescence resonance energy transfer experiments on living cells, biochemical and mutational analysis, we show that CD8 binding to pMHC in cis involves a different docking mode and is regulated by posttranslational modifications including a membrane-distal interchain disulfide bond and negatively charged O-linked glycans near positively charged sequences on the CD8β stalk. These modifications distort the stalk, thus favoring CD8 binding to pMHC in cis. Differential binding of CD8 to pMHC in cis or trans is a means to regulate CD8 T-cell responses and provides new translational opportunities.
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http://dx.doi.org/10.1016/j.jmb.2019.10.019DOI Listing
December 2019

C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. Reply.

N Engl J Med 2019 09;381(13):1291-1292

BioMarin, London, United Kingdom.

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http://dx.doi.org/10.1056/NEJMc1910394DOI Listing
September 2019

The phenotype of Sotos syndrome in adulthood: A review of 44 individuals.

Am J Med Genet C Semin Med Genet 2019 12 3;181(4):502-508. Epub 2019 Sep 3.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

Sotos syndrome is an overgrowth-intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the published Sotos syndrome clinical descriptions are based on studies of children; the phenotype in adults with Sotos syndrome is not yet well described. Given that it is now 17 years since disruption of NSD1 was shown to cause Sotos syndrome, many of the children first reported are now adults. It is therefore timely to investigate the phenotype of 44 adults with Sotos syndrome and NSD1 pathogenic variants. We have shown that adults with Sotos syndrome display a wide spectrum of intellectual ability with functioning ranging from fully independent to fully dependent. Reproductive rates are low. In our cohort, median height in adult women is +1.9 SD and men +0.5 SD. There is a distinctive facial appearance in adults with a tall, square, prominent chin. Reassuringly, adults with Sotos syndrome are generally healthy with few new medical issues; however, lymphedema, poor dentition, hearing loss, contractures and tremor have developed in a small number of individuals.
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http://dx.doi.org/10.1002/ajmg.c.31738DOI Listing
December 2019

The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.

Genet Med 2020 02 7;22(2):389-397. Epub 2019 Aug 7.

Wessex Clinical Genetics Service, University Hospital Southampton NHS Trust. Department of Human Genetics and Genomic Medicine, Southampton University, Southampton, UK.

Purpose: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function.

Methods: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains.

Results: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains.

Conclusion: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
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http://dx.doi.org/10.1038/s41436-019-0612-0DOI Listing
February 2020