Explore the vast range of titles available.

Elements within the γ-hemoglobin promoters ( and ) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous promoters to de-repress fetal hemoglobin. Transfection of human CD34 cells with TALEN mRNA resulted in indel generation in (43%) and (74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34 cells in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression and , suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia.

arising from N. C. Derecki et al. Nature484, 105–109 (2012); doi:10.1038/nature10907 Rett syndrome is a severe neurodevelopmental disorder caused by mutations in the X chromosomal gene MECP2 (ref. 1 ), and its treatment so far is symptomatic. Mecp2 disruption in mice phenocopies major features of the syndrome 2 that can be reversed after Mecp2 re-expression 3 . Recently, Derecki et al. 4 reported that transplantation of wild-type bone marrow into lethally irradiated Mecp2 -null ( Mecp2 tm1.1Jae/y ) mice prevented neurological decline and early death by restoring microglial phagocytic activity against apoptotic targets 4 , and clinical trials of bone marrow transplantation (BMT) for patients with Rett syndrome have thus been initiated 5 . We aimed to replicate and extend the BMT experiments in three different Rett syndrome mouse models, but found that despite robust microglial engraftment, BMT from wild-type donors did not prevent early death or ameliorate neurological deficits. Furthermore, early and specific Mecp2 genetic expression in microglia did not rescue Mecp2 -deficient mice.

Nature 521, E1–E4 (2015); doi:10.1038/nature14444 In this Brief Communication Arising, the first name of author Sébastien Vingeau was misspelled ‘Sebastian’. In addition, the labels (‘WT→KO’ and ‘KO→WT’) of the two bottom panels in Extended Data Figure 1b were swapped. Both errors have been corrected online.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by mutations in the X chromosomal gene Methyl-CpG-binding Protein 2 (MECP2) (1). RTT treatment so far is symptomatic. Mecp2 disruption in mice phenocopies major features of the syndrome (2) that can be reversed upon re-expression of Mecp2 (3. It has recently been reported that transplantation of wild type (WT) bone marrow (BMT) into lethally irradiated Mecp2tm1.1Jae/y mice prevented neurologic decline and early death by restoring microglial phagocytic activity against apoptotic targets (4). Based on this report, clinical trials of BMT for patients with RTT have been initiated (5). We aimed to replicate and extend the BMT experiments in three different RTT mouse models but found that despite robust microglial engraftment, BMT from WT donors did not rescue early death or ameliorate neurologic deficits. Furthermore, early and specific genetic expression of Mecp2 in microglia did not rescue Mecp2-deficient mice. In conclusion our experiments do not support BMT as therapy for RTT.

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19 + B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 10 7 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 . In the final report of a phase 1/2 trial evaluating allogeneic CD19-specific CAR-NK cells armored with IL-15 in patients with CD19 + hematologic malignancies, the therapy was shown to be safe and efficacious with distinct cord blood features associated with response.

Runoff contributions from glacierized catchments are changing in response to accelerating mass loss. We reconstruct the 1980–2022 mass balance, runoff and water budget of the ∼70% glacierized Kaskawulsh River headwaters in Yukon, Canada, using an enhanced temperature-index model driven by downscaled and bias-corrected reanalysis data. Debris is treated using melt-scaling factors based on site-specific measurements of the critical debris thickness. Accumulation is estimated from downscaled precipitation bias corrected based on in situ measurements. Model tuning incorporates observations of the 2007–18 geodetic mass balance and seasonal snowline positions on the Kaskawulsh Glacier. We assess model sensitivity to the representation of supraglacial debris and accumulation, including treatments of these processes that can be applied in the absence of in situ data. Different representations of debris produce <1% variation in the catchment-wide runoff and water budget. In contrast, accumulation estimates that omit in situ data produce 33–40% variations in modelled runoff relative to those that use these data. This work identifies site-specific measurements of accumulation as critical to accurate estimates of mass balance and runoff for the Kaskawulsh Glacier, in contrast to site-specific characterization of the effects of debris which influence estimated thinning rates at the glacier terminus but have little impact on the glacier-wide runoff.