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Gene therapy (GT) has rapidly attracted renewed interest as a treatment for otherwise incurable diseases, with several GT products already on the market and many more entering clinical testing for selected indications. Clonal tracking techniques based on vector integration enable monitoring of the fate of engineered cells in the blood of patients receiving GT and allow assessment of the safety and efficacy of these procedures. However, owing to the limited number of cells that can be tested and the impracticality of studying cells residing in peripheral organs without performing invasive biopsies, this approach provides only a partial snapshot of the clonal repertoire and dynamics of genetically modified cells and reduces the predictive power as a safety readout. In this study, we developed liquid biopsy integration site sequencing, or LiBIS-seq, a polymerase chain reaction technique optimized to quantitatively retrieve vector integration sites from cell-free DNA released into the bloodstream by dying cells residing in several tissues. This approach enabled longitudinal monitoring of in vivo liver-directed GT and clonal tracking in patients receiving hematopoietic stem cell GT, improving our understanding of the clonal composition and turnover of genetically modified cells in solid tissues and, in contrast to conventional analyses based only on circulating blood cells, enabling earlier detection of vector-marked clones that are aberrantly expanding in peripheral tissues. A new approach called liquid biopsy integration site sequencing enables monitoring of genetically modified cells in solid tissues of patients receiving gene therapy.

Christoph Klein and colleagues identify loss-of-function mutations in SMARCD2 ( BAF60b ) that lead to neutropenia, specific granule deficiency and myelodysplasia. They show that SMARCD2 controls differentiation of myeloid–erythroid progenitor cells through interaction with CEBPɛ and that reduced SMARCD2 levels cause transcription and chromatin alterations in acute myeloid leukemia cells. We identify SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2), also known as BAF60b (BRG1/Brahma-associated factor 60b), as a critical regulator of myeloid differentiation in humans, mice, and zebrafish. Studying patients from three unrelated pedigrees characterized by neutropenia, specific granule deficiency, myelodysplasia with excess of blast cells, and various developmental aberrations, we identified three homozygous loss-of-function mutations in SMARCD2 . Using mice and zebrafish as model systems, we showed that SMARCD2 controls early steps in the differentiation of myeloid–erythroid progenitor cells. In vitro , SMARCD2 interacts with the transcription factor CEBPɛ and controls expression of neutrophil proteins stored in specific granules. Defective expression of SMARCD2 leads to transcriptional and chromatin changes in acute myeloid leukemia (AML) human promyelocytic cells. In summary, SMARCD2 is a key factor controlling myelopoiesis and is a potential tumor suppressor in leukemia.

Background Concentrations of neurofilament light chain (NfL), a neuroaxonal damage marker, increase with age. Therefore, age-dependent reference values are important in clinical practice. However, so far these have only been established with a bead-based system and age-dependent z-scores for CSF are missing. In addition, we here propose how the combined analysis of CSF and serum NfL could help in the discrimination between central (CNS) and peripheral nervous system (PNS) axonal degeneration. Methods For the calculation of age reference values, serum and CSF NfL concentrations from 1,514 control subjects, measured using the microfluidic Ella system, were applied. Results Age-dependent NfL levels were calculated with additive quantile regression and presented with percentiles and z-scores. We observed a non-linear increase of NfL in serum and CSF. The spearman r of the association with age was 0.81 (95% CI 0.78–0.83), p  < 0.0001 and 0.82 (95% CI 0.79–0.85), p  < 0.0001 for serum and CSF NfL, respectively. Serum and CSF NfL levels were also associated with each other ( r  = 0.68 (95%CI 0.62–0.73), p  < 0.0001). Furthermore, we used this association to establish a bi-compartmental CSF and serum NfL model allowing to differentiate between peripheral or central origin of neurodegeneration. Conclusions The age reference curves corroborate findings of an exponential elevation of NfL in serum and CSF with increasing age. As NfL values from different platforms are not interchangeable, this is of additional high relevance. Moreover, the association between CSF and serum NfL values could be applied for clinical use regarding overlapping symptoms of CNS and PNS-based neurological diseases.

Pathogenic variants in the Cu/Zn superoxide dismutase ( SOD1 ) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1 -ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89–20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55–11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07–0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5–11.5) and therefore shorter compared to 57.5 months (IQR 14.0–83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8–38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1 -ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.

Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023. This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS.

HintergrundEs besteht ein zunehmender Bedarf an Untersuchungen von Patienten mit Hauterkrankungen und Hauttumoren durch Hautärzte. Teledermatologische und teledermatoskopische Diagnosestellungen sind mit guten Ergebnissen möglich.Ziel der ArbeitDiese deskriptive Studie soll beantworten, ob eine zunehmende hautfachärztliche Unterversorgung mittels einer teledermatologischen und teledermatoskopischen Triage-Vernetzung zwischen Hausärzten und Hautärzten regional verbessert werden kann.Material und MethodenSechs Hausärzte sendeten über eine Internetplattform Bilder von unklaren Hauterkrankungen bzw. Hautläsionen an eine Hautarztpraxis (2 Hautärzte) über 9 Monate. Als Triage-Antworten waren möglich: (1) beim Hausarzt bleiben, (2) rasche Vorstellung beim Hautarzt (Tage) oder (3) spätere Vorstellung beim Hautarzt (Wochen/Monate), jeweils mit Diagnose und therapeutischen Empfehlungen. Vom Hautarzt gab es Feedback (Noten 1–6) über die Bildqualität und vom Hausarzt über die Befundung. Die Befundung der Hautärzte erfolgte unabhängig, und alle Antworten wurden von einem externen dritten Hautarzt auditiert.ErgebnisseBei hoher Patientenakzeptanz (100 %) wurde eine sehr gute bis gute Bildqualität in 94 % erreicht; 66,3 % der Patienten konnten beim Hausarzt verbleiben, und 20,7 % der Patienten sollten sich rasch bei Hautarzt vorstellen. Die Tele-Triage-Entscheidung einer raschen Vorstellung beim Hautarzt wurde in der Face-to-face-Begutachtung in 41,5 % bestätigt. Das Feedback der Hausärzte über die Tele-Triage wurde mit der Durchschnittsnote 1,1 bewertet.DiskussionEine erfolgreiche regionale teledermatologische und teledermatoskopische Triage-Vernetzung zwischen niedergelassenen Hausärzten und Hautärzten ist möglich. Datenschutzrechtliche Vorgaben sind einzuhalten, und eine angemessene Vergütung ist wünschenswert.