Genetic newborn screening and digital technologies: A project protocol based on a dual approach to shorten the rare diseases diagnostic path in Europe.

Since 72% of rare diseases are genetic in origin and mostly paediatrics, genetic newborn screening represents a diagnostic "window of opportunity". Therefore, many gNBS initiatives started in different European countries. Screen4Care is a research project, which resulted of a joint effort between the European Union Commission and the European Federation of Pharmaceutical Industries and Associations. It focuses on genetic newborn screening and artificial intelligence-based tools which will be applied to a large European population of about 25.000 infants. The neonatal screening strategy will be based on targeted sequencing, while whole genome sequencing will be offered to all enrolled infants who may show early symptoms but have resulted negative at the targeted sequencing-based newborn screening. We will leverage artificial intelligence-based algorithms to identify patients using Electronic Health Records (EHR) and to build a repository "symptom checkers" for patients and healthcare providers. S4C will design an equitable, ethical, and sustainable framework for genetic newborn screening and new digital tools, corroborated by a large workout where legal, ethical, and social complexities will be addressed with the intent of making the framework highly and flexibly translatable into the diverse European health systems.

Adeno-associated virus serotype 9 antibody seroprevalence for patients in the United States with spinal muscular atrophy.

Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9 (AAV9) vector-based gene therapy for spinal muscular atrophy (SMA). Patients with elevated titers of anti-AAV9 antibodies (AAV9-Ab) should not receive onasemnogene abeparvovec because of potential safety and efficacy implications. We conducted a retrospective study to describe the seroprevalence of anti-AAV9 binding antibodies for pediatric patients with SMA in the United States. At initial testing, 13.0% (115 of 882) of patients (mean [SD] age, 26.29 [33.66] weeks) had elevated AAV9-Ab titers. The prevalence of elevated titers decreased as age increased, with 18.2% (92 of 507) of patients ≤3 months old but only 1.1% (1 of 92) of patients ≥21 months old having elevated titers. This suggests transplacental maternal transfer of antibodies. No patterns of geographic variations in AAV9-Ab prevalence were confirmed. Elevated AAV9-Ab titers in children <6 weeks old decreased in all circumstances. Lower magnitudes of elevated titers declined more rapidly than greater magnitudes. Retesting was completed at the discretion of the treating clinician, so age at testing and time between tests varied. AAV9-Ab retesting should be considered when patients have elevated titers, and elevations at a young age are not a deterrent to eventual onasemnogene abeparvovec administration. Early disease-modifying treatment for SMA leads to optimal outcomes.

Cost-Effectiveness of Newborn Screening for Spinal Muscular Atrophy in The Netherlands.

OBJECTIVES: Spinal muscular atrophy (SMA) is a rare genetic disorder that causes progressive muscle weakness and paralysis. In its most common and severe form, the majority of untreated infants die before 2 years of age. Early detection and treatment, ideally before symptom onset, maximize survival and achievement of age-appropriate motor milestones, with potentially substantial impact on health-related quality of life. Therefore, SMA is an ideal candidate for inclusion in newborn screening (NBS) programs. We evaluated the cost-effectiveness of including SMA in the NBS program in The Netherlands. METHODS: We developed a cost-utility model to estimate lifetime health effects and costs of NBS for SMA and subsequent treatment versus a treatment pathway without NBS (ie, diagnosis and treatment after presentation with overt symptoms). Model inputs were based on literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess model robustness and validity of results. RESULTS: After detection of SMA by NBS in 17 patients, the number of quality-adjusted life-years gained per annual birth cohort was estimated at 320 with NBS followed by treatment compared with treatment after clinical SMA diagnosis. Total healthcare costs, including screening, diagnostics, treatment, and other healthcare resource use, were estimated to be €12 014 949 lower for patients identified by NBS. CONCLUSIONS: NBS for early identification and treatment of SMA versus later symptomatic treatment after clinical diagnosis improves health outcomes and is less costly and, therefore, is a cost-effective use of resources. Results were robust in sensitivity and scenario analyses.

Three years pilot of spinal muscular atrophy newborn screening turned into official program in Southern Belgium.

Three new therapies for spinal muscular atrophy (SMA) have been approved by the United States Food and Drug Administration and the European Medicines Agency since 2016. Although these new therapies improve the quality of life of patients who are symptomatic at first treatment, administration before the onset of symptoms is significantly more effective. As a consequence, newborn screening programs have been initiated in several countries. In 2018, we launched a 3-year pilot program to screen newborns for SMA in the Belgian region of Liège. This program was rapidly expanding to all of Southern Belgium, a region of approximately 55,000 births annually. During the pilot program, 136,339 neonates were tested for deletion of exon 7 of SMN1, the most common cause of SMA. Nine SMA cases with homozygous deletion were identified through this screen. Another patient was identified after presenting with symptoms and was shown to be heterozygous for the SMN1 exon 7 deletion and a point mutation on the opposite allele. These ten patients were treated. The pilot program has now successfully transitioned into the official neonatal screening program in Southern Belgium. The lessons learned during implementation of this pilot program are reported.

Adeno-associated virus serotype 9 antibodies in patients screened for treatment with onasemnogene abeparvovec.

Spinal muscular atrophy is a progressive, recessively inherited monogenic neurologic disease, the genetic root cause of which is the absence of a functional survival motor neuron 1 gene. Onasemnogene abeparvovec (formerly AVXS-101) is an adeno-associated virus serotype 9 vector-based gene therapy that delivers a fully functional copy of the human survival motor neuron gene. We report anti-adeno-associated virus serotype 9 antibody titers for patients with spinal muscular atrophy when they were screened for eligibility in the onasemnogene abeparvovec clinical trials (intravenous and intrathecal administration) and managed access programs (intravenous). Through December 31, 2019, 196 patients and 155 biologic mothers were screened for anti-adeno-associated virus serotype 9 binding antibodies with an enzyme-linked immunosorbent assay. Of these, 15 patients (7.7%) and 23 biologic mothers (14.8%) had titers >1:50 on their initial screening tests. Eleven patients (5.6%) had elevated titers on their final screening tests. The low percentage of patients with exclusionary antibody titers indicates that most infants with spinal muscular atrophy type 1 should be able to receive onasemnogene abeparvovec. Retesting may identify patients whose antibody titers later decrease to below the threshold for treatment, and retesting should be considered for patients with anti-adeno-associated virus serotype 9 antibody titers >1:50.

Corrigendum: Core competencies for pharmaceutical physicians and drug development scientists.

[This corrects the article on p. 105 in vol. 4, PMID: 23986704.].

Core competencies for pharmaceutical physicians and drug development scientists.

Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine), are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes (LO) of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain LO anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide.

Acute effects of high-dose furosemide on residual renal function in CAPD patients.

BACKGROUND: High doses of furosemide can increase urine volume in chronic peritoneal dialysis (CAPD) patients. However, no information is available about effects on urinary solute excretion in relation to residual glomerular filtration rate (GFR), urinary furosemide excretion, and peritoneal solute kinetics. METHODS: Diuretic response and the effect on peritoneal fluid and solute transport parameters were investigated in 7 stable CAPD patients with residual renal function (median urine volume 350 mL/24 hours, range 140- 1900 mL/24 hours). Comparisons were made during two clearance periods of 24 hours: one without (P1) and one during 2 g furosemide (P2). RESULTS: The median increase in urine volume was 400 mL (range 270 - 910 mL, p < 0.02) and the increase in sodium excretion was 54 mmol (range 25 - 118 mmol, p < 0.02). No change in GFR was found between P1 (2.4 mL/ minute, range 0.6 - 5.7 mL/min) and P2 (2.0 mL/min, range 1.0 - 4.8 mL/min). An increase in fractional clearance was found for volume, sodium, potassium, and osmolality (p < 0.02). No change was found in the fractional clearance of urea and electrolyte-free water. Furosemide excretion in urine was 8.7 mg/24 hours (range 2.1 - 38 mg/24 hours) and in dialysate 4.9 mg/24 hours (range 1.9 - 7.8 mg/ 24 hours). Plasma furosemide concentration was 29.5 mg/L (range 6.2 - 43.9 mg/L). A positive correlation was found between residual GFR and total urine furosemide excretion (r = 0.93, p < 0.005). Efficiency, expressed as the increase in fractional sodium clearance (percent) per milligram of furosemide excreted per 24 hours, was 1.2%/mg (range 0.3% - 11.3%/mg). CONCLUSION: High-dose furosemide is effective in CAPD patients in increasing urine volume and electrolyte excretion without affecting urea and creatinine clearance. In CAPD patients, the individual response to an identical high dose of furosemide is dependent on the magnitude of residual GFR.

Plasma thrombopoietin levels in patients with chronic renal failure.

INTRODUCTION: Thrombopoietin (Tpo) is the most important regulator of thrombocytopoiesis. The main sites of Tpo production are the liver and the kidney produce Tpo. In the current study, the influence of renal failure on overall Tpo production was evaluated. MATERIALS AND METHODS: Tpo levels were measured in 23 patients on hemodialysis (HD) and 16 patients on chronic ambulatory peritoneal dialysis (CAPD). Plasma glycocalicin (GC) levels and platelet counts were measured as parameters of platelet mass and platelet turnover. RESULTS: Platelet counts were significantly lower in the HD group, both before 207+/-98 x 10(9)/l (P<0.001) and after hemodialysis 202+/-102 x 10(9)/l (P<0.001) when compared to healthy controls, 293+/-79 x 10(9)/l. No significant difference was found between platelet counts in patients on CAPD and healthy donors. Mean plasma Tpo levels of HD patients were higher both before 23+/-18 AU/ml (P<0.0001) and after dialysis 25+/-26 AU/ml (P<0.0001), as compared to Tpo levels in healthy controls (11+/-8 AU/ml). Patients on CAPD had significantly higher Tpo concentrations, 29+/-25 AU/ml than healthy controls (P<0.0001). There was no difference in Tpo level between the HD and CAPD group. No correlation was found between Tpo concentration and platelet count, hematocrit, creatinine or uremia levels. The GC concentration was significantly higher in HD patients and CAPD patients when compared to healthy controls. There was no correlation between GC and Tpo level or platelet count. CONCLUSION: These results confirm the increased platelet turnover in patients with chronic renal failure. Moreover this study shows that the kidney does not seem to play a major role in the overall Tpo production in the body.