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In an analysis of long-term safety events in 783 patients treated with T cell therapy in 38 trials, 2.3% of patients developed second primary malignancies, and vector integration analyses revealed no pathological insertions.

In a first-in-human phase 1/2 study in seven patients with sickle cell disease, autologous hematopoietic stem cell lentiviral gene therapy using reduced-intensity conditioning was considered feasible and safe, achieving >80% reduction in the frequency of vaso-occlusive events.

Human cell engineering has made considerable progress, but where to insert foreign sequences in the human genome to maximize safety and efficacy is still uncertain. This Opinion article discusses genomic safe harbours, which are chromosomal locations where therapeutic transgenes can integrate and function without perturbing endogenous gene activity or promoting cancer.

A statistical analysis of the associations between virus structure and virus transmission suggests that virus structures limit viral transmission routes and have implications for infection prophylaxis and gene therapy strategies.

The DREPAGLOBE lentiviral-based gene therapy for sickle cell disease is safe. However, its efficacy depends on the number of infused hematopoietic stem cells (HSCs) and intrinsic, engraftment impairing inflammatory alterations in HSCs.

A new approach called liquid biopsy integration site sequencing enables monitoring of genetically modified cells in solid tissues of patients receiving gene therapy.

The infant gut is colonized first by temperate bacteriophages induced from pioneer bacteria and later by viruses that replicate in human cells, the populations of which are modulated by breastfeeding.

A gene therapy phase 1 trial in patients with β-thalassemia shows transplantation of autologous CD34⁺ cells transduced with a lentiviral globin vector after reduced-intensity conditioning achieves long-term engraftment, albeit not transfusion independence, with benign clonal expansions, warranting cautious monitoring of patients.

A cell-sorting method leveraging leucine zippers allows for the generation of T cells displaying multiple chimaeric antigen receptors as well as receptors converting inhibitory signals into stimulatory signals.

Affinity tagging, mass spectroscopy and a tailor-made scoring system are used to identify 497 high-confidence interactions between human proteins and human immunodeficiency virus proteins.

The first viruses to colonize the infant gut are shown to arise from bacteria, with human-cell viruses colonizing the gut later, at around four months of age. Exclusive and partial breastfeeding were associated with fewer human viruses in the gut of infants compared with formula-feeding alone.

AAV therapy in dogs leads to clonal expansions of transduced cells.

SourceTracker finds the proportion and origin of contaminants in a given sample. Its database will prove useful in screening of metagenomic datasets for contaminants.

The human body hosts vast numbers of different viruses, collectively termed the virome. In this Review, Liang and Bushman provide an overview of research on the human virome and highlight recent studies that explore the assembly and composition of the human virome as well as host–virome interactions in health and disease.

In a phase 1 dose-escalation trial in patients with nine different types of solid tumors, MAGE-A4-specific T cells had an acceptable safety profile and exhibited an encouraging overall response rate in patients with synovial sarcoma.

Potent chimaeric antigen receptor T cells can be generated within one day from T cells derived from peripheral blood without the need for T-cell activation.

Infusion of CD19-directed chimeric antigen receptor T cells into two patients with chronic lymphocytic leukaemia resulted in complete tumour remission and persistence of the infused cells more than ten years later.

Using a cohort of nearly 1,000 genetically diverse mice undergoing dietary restriction over the lifespan, the authors reveal numerous insights into the interactions between the gut microbiome, host genome, diet, health and longevity.

Enterococci enhance the fitness and pathogenesis of Clostridioides difficile in the gut by altering the amino acid composition and providing signals that increase its virulence towards the host.

CAR T cells targeting PSMA and engineered to be resistant to immunosuppressive TGFβ signaling exhibit dose-dependent toxicity and expansion following infusion, with some transient antitumor activity, in patients with metastatic castration-resistant prostate cancer

Transposons qualify as ‘selfish’ DNA elements, adding new copies of themselves into our genomes without regard for the consequences. This wilful habit may, however, help in normal gene regulation.

A bisulfite-free sequencing method yields high-confidence 5hmC profiles in low-input samples.

Using a multi-omics approach to analyse meconium and stool samples from babies during the first few days of life, the authors show that the gut is detectably colonized within 16 h of birth, with Escherichia coli dominating, and that this correlates with proteome and metabolome changes including the fermentation of amino acids.

African apes harbour six Plasmodium species, one of which gave rise to the human malaria parasite. Here, Sundaraman et al. use selective whole-genome amplification to determine genome sequences from two chimpanzee Plasmodiumspecies, shedding light on the evolutionary origin of the human parasite.

Alterations in commensal bacteria are associated with an increased risk of allergic disease. David Artis and his colleagues now report that commensal-derived signals influence basophil development and T_H2 cytokine–dependent allergic airway inflammation by suppressing serum IgE levels. Individuals with hyper IgE syndrome also have elevated circulating basophil numbers, suggesting a mechanistic link between commensal bacteria, B cell–mediated production of IgE and basophil hematopoiesis.

The long-noted association of red meat with an increased risk of cardiovascular disease may be due to ingestion of a specific compound found in red meat, l-carnitine. The ability of this compound to promote atherosclerosis in mice requires that it be further metabolized by the gut microbiota. In humans, omnivores but not vegans or vegetarians metabolize l-carnitine in this manner, a difference which may be explained by effects of diet on the presence of specific types of bacteria in the gut.

A strategy for assessing the effectiveness of different strategies for HIV cure is presented.

A CAR gene unintentionally introduced in a contaminating leukemia cell during the manufacturing of CAR T cells caused a patient to relapse after therapy.

Genetically engineered T cells that induced remission in a patient with chronic lymphocytic leukaemia were found to have disruption of the TET2 gene, which caused T cell changes that potentiated their anti-tumour effects.

Initial results from phase I/II lentiviral gene therapy trials provide early evidence supporting its safety and efficacy in treating patients with X-linked chronic granulomatous disease.

The STORMS tool provides guidance for concise and complete reporting of microbiome studies to facilitate manuscript preparation, peer review, reader comprehension of publications, and comparative analysis of published results.

An assay to measure the latent HIV-1 reservoir that separately quantifies intact and defective proviruses will facilitate evaluation of HIV-1 cure strategies by measuring the provirues that pose a barrier to cure.

Disorders caused by abnormal β-globin, such as β-thalassaemia, are the most prevalent inherited disorders worldwide. For treatment, many patients are dependent on blood transfusions; thus far the only cure has involved matched transplantation of haematopoietic stem cells. Here it is shown that lentiviral β-globin gene transfer can be an effective substitute for regular transfusions in a patient with severe β-thalassaemia.

This work identifies a role for intestinal epithelial cell (IEC)-intrinsic expression of histone deacetylase 3 in regulating commensal-bacteria-dependent gene expression and intestinal homeostasis; IEC-specific HDAC3 deficiency gives rise to Paneth cell abnormalities, impaired intestinal barrier function, and increased DSS-induced intestinal inflammation in commensal-bacteria-containing, but not germ-free, mice.

Group 3 innate lymphoid cells are shown to process and present antigen and to control CD4⁺ T-cell responses to intestinal commensal bacteria through an MHC-class-II-dependent mechanism.

If transgenes are to be introduced into the genome for cell therapies, the integration events should permit high transgene expression without altering the expression of endogenous genes. Papapetrou et al. propose five criteria to define such 'safe harbors' in the human genome and demonstrate high A-globin expression from a safe-harbor site in erythroid-lineage cells derived from induced pluripotent stem (iPS) cells.

Advances in the design of vectors based on retroviruses, such as lentiviruses and gammaretroviruses, have led to improvements in the safety and stability of gene therapies directed at haematopoietic stem and progenitor cells. In this Review, Cavazzana and colleagues discuss the results from recent clinical trials of retroviral vectors for the treatment of genetic disorders, including severe combined immunodeficiencies and β-haemoglobinopathies (β-thalassaemia and sickle cell disease). They highlight the progress made and the remaining challenges in applying gene therapies more broadly.