Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome.

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications. METHODS: We are conducting an ongoing study involving eight children with MPSIH. At enrollment, the children lacked a suitable allogeneic donor and had a Developmental Quotient or Intelligence Quotient score above 70 (i.e., none had moderate or severe cognitive impairment). The children received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an α-L-iduronidase (IDUA)-encoding lentiviral vector after myeloablative conditioning. Safety and correction of blood IDUA activity up to supraphysiologic levels were the primary end points. Clearance of lysosomal storage material as well as skeletal and neurophysiological development were assessed as secondary and exploratory end points. The planned duration of the study is 5 years. RESULTS: We now report interim results. The children's mean (±SD) age at the time of HSPC gene therapy was 1.9±0.5 years. At a median follow-up of 2.10 years, the procedure had a safety profile similar to that known for autologous hematopoietic stem-cell transplantation. All the patients showed prompt and sustained engraftment of gene-corrected cells and had supraphysiologic blood IDUA activity within a month, which was maintained up to the latest follow-up. Urinary glycosaminoglycan (GAG) excretion decreased steeply, reaching normal levels at 12 months in four of five patients who could be evaluated. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable after gene therapy and were associated with local clearance of GAGs. Patients showed stable cognitive performance, stable motor skills corresponding to continued motor development, improved or stable findings on magnetic resonance imaging of the brain and spine, reduced joint stiffness, and normal growth in line with World Health Organization growth charts. CONCLUSIONS: The delivery of HSPC gene therapy in patients with MPSIH resulted in extensive metabolic correction in peripheral tissues and the central nervous system. (Funded by Fondazione Telethon and others; ClinicalTrials.gov number, NCT03488394; EudraCT number, 2017-002430-23.).

Mild SARS-CoV-2 Infection After Gene Therapy in a Child With Wiskott-Aldrich Syndrome: A Case Report.

In this work we present the case of SARS-CoV-2 infection in a 1.5-year-old boy affected by severe Wiskott-Aldrich Syndrome with previous history of autoinflammatory disease, occurring 5 months after treatment with gene therapy. Before SARS-CoV-2 infection, the patient had obtained engraftment of gene corrected cells, resulting in WASP expression restoration and early immune reconstitution. The patient produced specific immunoglobulins to SARS-CoV-2 at high titer with neutralizing capacity and experienced a mild course of infection, with limited inflammatory complications, despite pre-gene therapy clinical phenotype.

COVID-19 cardiac involvement in a 38-day old infant.

The spectrum of clinical manifestations of coronavirus disease 2019 in children is yet to be fully elucidated. We report the case of an infant who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developed mild cardiovascular inflammation, a novelty for patients of very young age, that contributes to defining the puzzling nature of this disease in pediatric patients. The potential cardiovascular involvement of SARS-CoV-2 in children should always be taken into account.

Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return.

Total anomalous pulmonary venous return (TAPVR) is a congenital heart defect in which the pulmonary veins fail to enter the left atrium and drain instead into the right atrium or one of its venous tributaries. Although a genetic basis for TAPVR has long been recognized, no single gene involved in the pathogenesis of this disease has been identified to date. We previously reported a TAPVR patient bearing a de novo 10;21 balanced translocation. In this work, we cloned both translocation breakpoints from this patient and mapped the ANKRD1 gene, encoding a cardiac transcriptional regulator, 130 kb proximally to the breakpoint on chromosome 10. In situ hybridization analysis performed on murine embryos showed ANKRD1 expression in the developing pulmonary veins, suggesting a possible role for this gene in TAPVR pathogenesis. Moreover, ANKRD1 expression levels were found to be highly increased in lymphoblastoid cell lines derived from both the translocation-bearing proband and a second independent sporadic TAPVR patient, suggesting that disruption of the normal ANKRD1 expression pattern is associated with TAPVR. Finally, a nonconservative missense mutation in the ANKRD1 gene was found in a third sporadic TAPVR patient. In vitro calpain-mediated degradation assays, coupled to reporter gene analysis in transfected HeLa cells, strongly suggested that this mutation enhances both the stability of the ANKRD1/CARP protein and its transcriptional repression activity upon the cardiac-specific atrial natriuretic factor (ANF) promoter. Taken together, these results define ANKRD1 as a possible candidate gene for TAPVR pathogenesis.

Jugular approach for percutaneous closure of atrial septal defect.

One hundred and forty-two consecutive procedures of percutaneous closure or atrial septal defect were approached by cannulation of the right femoral vein. In 3 of them, the internal jugular vein approach was also necessary because of azygos continuation or unsuccessful device implantation due to inadequate septal alignment. In all of them, device implantation was successfully performed through this alternative percutaneous vascular approach.

Prevalence and prognosis of atrial septal aneurysm in high risk fetuses without structural heart defects.

BACKGROUND: The aim of this study was to evaluate the prevalence and prognostic implications of the association between atrial septal aneurysm (ASA) and fetal arrhythmias in a population of high risk fetuses. METHODS: One thousand three hundred and two fetal echocardiograms performed during high risk pregnancies from the 17th to the 41st week of gestation were retrospectively evaluated for the presence of ASA and/or arrhythmias. An ASA was defined as redundant tissue extending at least halfway across the left atrium. Patients with an ASA were distinguished in two subgroups according to whether there was (subgroup 1) or was not (subgroup 2) cyclical contact of the atrial septum with the left atrial wall or with the mitral valve. Arrhythmias were documented during mono/two-dimensional echocardiography and Doppler evaluation. RESULTS: Out of 1223 patients considered for the study, 93 (7.6%) fetuses had an ASA; among these 93 fetuses, 33 (36%) had premature atrial beats (p < 0.001). Ten of these patients were included in subgroup 1, and 7 of them (70%) exhibited premature atrial beats (p = 0.016 vs subgroup 2). No arrhythmias other than premature atrial beats were observed in these patients. None of them received any therapy during observation. All of them developed a regular sinus rhythm within 3 months of life. CONCLUSIONS: On the basis of these data, we can speculate that, if accurately searched for, ASA is often present (7.6%) and is likely to represent a mechanical stimulus for the generation of premature atrial beats. Indeed, our data show an important correlation between the degree of bulging and the presence of arrhythmias, supporting the hypothesis of a mechanical stimulus. However, the observed arrhythmias did not appear to be prone to degeneration. In conclusion, ASA observed during fetal life is often associated with premature atrial beats, which are apparently in direct relation with the degree of bulging of the atrial septum. On the other hand, an ASA almost invariably disappears at birth and is not associated with major arrhythmias.