Summary Background Effective treatment for metachromatic leukodystrophy (MLD) remains a substantial unmet medical need. In this study we investigated the safety and efficacy of atidarsagene autotemcel (arsa-cel) in patients with MLD. Methods This study is an integrated analysis of results from a prospective, non-randomised, phase 1/2 clinical study and expanded-access frameworks. 29 paediatric patients with pre-symptomatic or early-symptomatic early-onset MLD with biochemical and molecular confirmation of diagnosis were treated with arsa-cel, a gene therapy containing an autologous haematopoietic stem and progenitor cell (HSPC) population transduced ex vivo with a lentiviral vector encoding human arylsulfatase A (ARSA) cDNA, and compared with an untreated natural history (NHx) cohort of 31 patients with early-onset MLD, matched by age and disease subtype. Patients were treated and followed up at Ospedale San Raffaele, Milan, Italy. The coprimary efficacy endpoints were an improvement of more than 10% in total gross motor function measure score at 2 years after treatment in treated patients compared with controls, and change from baseline of total peripheral blood mononuclear cell (PBMC) ARSA activity at 2 years after treatment compared with values before treatment. This phase 1/2 study is registered with ClinicalTrials.gov , NCT01560182 . Findings At the time of analyses, 26 patients treated with arsa-cel were alive with median follow-up of 3·16 years (range 0·64–7·51). Two patients died due to disease progression and one due to a sudden event deemed unlikely to be related to treatment. After busulfan conditioning, all arsa-cel treated patients showed sustained multilineage engraftment of genetically modified HSPCs. ARSA activity in PBMCs was significantly increased above baseline 2 years after treatment by a mean 18·7-fold (95% CI 8·3–42·2; p<0·0001) in patients with the late-infantile variant and 5·7-fold (2·6–12·4; p<0·0001) in patients with the early-juvenile variant. Mean differences in total scores for gross motor function measure between treated patients and age-matched and disease subtype-matched NHx patients 2 years after treatment were significant for both patients with late-infantile MLD (66% [95% CI 48·9–82·3]) and early-juvenile MLD (42% [12·3–71·8]). Most treated patients progressively acquired motor skills within the predicted range of healthy children or had stabilised motor performance (maintaining the ability to walk). Further, most displayed normal cognitive development and prevention or delay of central and peripheral demyelination and brain atrophy throughout follow-up; treatment benefits were particularly apparent in patients treated before symptom onset. The infusion was well tolerated and there was no evidence of abnormal clonal proliferation or replication-competent lentivirus. All patients had at least one grade 3 or higher adverse event; most were...

Objectives Enlarged main pulmonary artery diameter (MPAD) resulted to be associated with pulmonary hypertension and mortality in a non-COVID-19 setting. The aim was to investigate and validate the association between MPAD enlargement and overall survival in COVID-19 patients. Methods This is a cohort study on 1469 consecutive COVID-19 patients submitted to chest CT within 72 h from admission in seven tertiary level hospitals in Northern Italy, between March 1 and April 20, 2020. Derivation cohort (n = 761) included patients from the first three participating hospitals; validation cohort (n = 633) included patients from the remaining hospitals. CT images were centrally analyzed in a core-lab blinded to clinical data. The prognostic value of MPAD on overall survival was evaluated at adjusted and multivariable Cox’s regression analysis on the derivation cohort. The final multivariable model was tested on the validation cohort. Results In the derivation cohort, the median age was 69 (IQR, 58–77) years and 537 (70.6%) were males. In the validation cohort, the median age was 69 (IQR, 59–77) years with 421 (66.5%) males. Enlarged MPAD (≥ 31 mm) was a predictor of mortality at adjusted (hazard ratio, HR [95%CI]: 1.741 [1.253–2.418], p < 0.001) and multivariable regression analysis (HR [95%CI]: 1.592 [1.154–2.196], p = 0.005), together with male gender, old age, high creatinine, low well-aerated lung volume, and high pneumonia extension (c-index [95%CI] = 0.826 [0.796–0.851]). Model discrimination was confirmed on the validation cohort (c-index [95%CI] = 0.789 [0.758–0.823]), also using CT measurements from a second reader (c-index [95%CI] = 0.790 [0.753;0.825]). Conclusion Enlarged MPAD (≥ 31 mm) at admitting chest CT is an independent predictor of mortality in COVID-19. Key Points •Enlargement of main pulmonary artery diameter at chest CT performed within 72 h from the admission was associated with a higher rate of in-hospital mortality in COVID-19 patients. •Enlargement of main pulmonary artery diameter (≥ 31 mm) was an independent predictor of death in COVID-19 patients at adjusted and multivariable regression analysis. •The combined evaluation of clinical findings, lung CT features, and main pulmonary artery diameter may be useful for risk stratification in COVID-19 patients.

Background Host inflammation contributes to determine whether SARS-CoV-2 infection causes mild or life-threatening disease. Tools are needed for early risk assessment. Methods We studied in 111 COVID-19 patients prospectively followed at a single reference Hospital fifty-three potential biomarkers including alarmins, cytokines, adipocytokines and growth factors, humoral innate immune and neuroendocrine molecules and regulators of iron metabolism. Biomarkers at hospital admission together with age, degree of hypoxia, neutrophil to lymphocyte ratio (NLR), lactate dehydrogenase (LDH), C-reactive protein (CRP) and creatinine were analysed within a data-driven approach to classify patients with respect to survival and ICU outcomes. Classification and regression tree (CART) models were used to identify prognostic biomarkers. Results Among the fifty-three potential biomarkers, the classification tree analysis selected CXCL10 at hospital admission, in combination with NLR and time from onset, as the best predictor of ICU transfer (AUC [95% CI] = 0.8374 [0.6233–0.8435]), while it was selected alone to predict death (AUC [95% CI] = 0.7334 [0.7547–0.9201]). CXCL10 concentration abated in COVID-19 survivors after healing and discharge from the hospital. Conclusions CXCL10 results from a data-driven analysis, that accounts for presence of confounding factors, as the most robust predictive biomarker of patient outcome in COVID-19. Graphic abstract

In this study, we characterize the natural course of metachromatic leukodystrophy (MLD), explore intra/inter group differences, and identify biomarkers to monitor disease progression. This is a longitudinal observational study. Genotype and characteristics at disease onset were recorded. Time‐to‐event analyses were performed to assess time to major disease‐related milestones in different subgroups. Longitudinal trajectories of nerve conduction velocities (NCV), brain MRI score, and brainstem auditory evoked responses (BAERs) were described. We recruited 22 late‐infantile, 14 early‐juvenile, 5 late‐juvenile, and 4 adult MLD patients. Thirty‐four were prospectively evaluated (median FU time 43 months). In late‐infantile patients, the attainment of independent walking was associated with a later age at dysphagia. In early‐juvenile, the presence of isolated cognitive impairment at onset was not a favorable prognostic factor. Late‐infantile and early‐juvenile subjects showed similar rapid loss of ambulation and onset of seizures, but late‐infantile displayed earlier loss of trunk control, dysphagia, and death. We found significant differences in all major disease‐related milestones (except death) between early‐juvenile and late‐juvenile patients. Late‐juvenile and adult patients both presented with a predominant cognitive impairment, mild/no peripheral neuropathy, lower brain MRI score at plateau compared to LI/EJ, and later cerebellar involvement. NCV and BAER were consistently severely abnormal in late‐infantile but not in older subjects, in whom both NCV and BAER were variably affected, with no deterioration over time in some cases. This study clarifies intra/inter group differences between MLD subtypes and provides additional indications regarding reliable clinical and instrumental tools to monitor disease progression and to serve as areference to evaluate the efficacy of future therapeutic interventions inthe different MLD variants.