Focus |

Therapeutics

Ross Cloney: synthetic biology and genome engineering. 

Francesco Conti: musculoskeletal biology and gene therapy.

Sonja Schmid: therapeutics for infectious diseases. 

Aishwarya Sundaram: cancer metastasis, models, drug discovery and nanotherapy.

Welcome to the Nature Communications Editors’ Highlights webpage on therapeutics. Each month our editors select a small number of Articles recently published in Nature Communications that they believe are particularly interesting or important.

The aim is to provide a snapshot of some of the most exciting work published in the area of therapeutics at Nature Communications.

Make sure to check the Editors' Highlights page each month for new featured articles.

Ross Cloney

Mucopolysaccharidosis type I (MPSI) is a lysosomal storage disease caused by insufficient iduronidase (IDUA) activity. Here, the authors use an ex vivo genome editing approach to overexpress IDUA in human hematopoietic stem and progenitor cells and show it can phenotypically correct MSPI in mouse model.

Article | Open Access | | Nature Communications

Cochlear implant spectral resolution is limited by current spread from each stimulation electrode. Here the authors compare optogenetic, electric and acoustic stimulation in gerbils and demonstrate improved spectral resolution of optogenetic over conventional electric stimulation.

Article | Open Access | | Nature Communications

Gene correction in hematopoietic stem cells could be a powerful way to treat monogenic diseases of the blood and immune system. Here the authors develop a strategy using CRISPR-Cas9 and an aAdeno-Associated vVirus(AAV)-delivered IL2RG cDNA to correct X-linked sSevere Ccombined iImmunodeficiency (SCID-X1) with a high success rate.

Article | Open Access | | Nature Communications

Francesco Conti

Non-alcoholic fatty liver (NAFLD) disease causes degeneration of the liver, affects about 25% of people globally, and has no approved treatment. Here, the authors show that the therapeutic siRNA-driven silencing of MCJ in the liver is an effective and safe treatment for NAFLD in multiple mouse models.

Article | Open Access | | Nature Communications

Bone marrow adipose tissue (BMAT) comprises over 10% of total fat mass but its systemic metabolic role is unclear. Here, the authors show that BMAT glucose uptake is not insulin or cold responsive; however, BMAT basal glucose uptake is higher than in white adipose tissue or skeletal muscle, underscoring BMAT’s potential to influence systemic glucose homeostasis.

Article | Open Access | | Nature Communications

Unruptured intracranial aneurysm (UIA) is a life-threatening cerebrovascular condition. Here the authors report altered gut microbiota including low abundance of Hungatella hathewayi in patients with UIAs, and show that supplementation with Hungatella hathewayi or the metabolite taurine prevents UIAs in mice.

Article | Open Access | | Nature Communications

One potential approach for the treatment of Duchenne muscular dysrophy is to increase expression of the dystrophin homolog utrophin. Here, the authors show that eEF1A2 regulates utrophin expression, and show that 2 FDA-approved drugs upregulate eEIF1A2 and utrophin level in mice, leading to improvement of the dystrophic phenotype.

Article | Open Access | | Nature Communications

Fibroblast hyper-activation and proliferation is a major feature in arthritis, yet scarcely addressed for anti-arthritic therapies. Here, the authors show that activation of the MC1 receptor induces fibroblast senescence associated with a reparative phenotype, ultimately regulating experimental inflammatory arthritis.

Article | Open Access | | Nature Communications

Neovascular age-related macular degeneration and diabetic retinopathy are currently treated with repeated intravitreous injections of VEGF neutralizing proteins. Here the authors develop a microparticle-loaded tyrosine kinase inhibitor therapy, which is effective for six months after a single injection in preclinical models.

Article | Open Access | | Nature Communications

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease and adult lung spheroid cells have been shown to promote regeneration in animal models of IPF. Here the authors show that the secretome and exosomes of lung spheroid cells is effective as inhalation treatment in rodent models of lung injury and fibrosis and superior to the counterparts derived from mesenchymal stem cells.

Article | Open Access | | Nature Communications

Reconstructive microsurgery is limited by the precision that human hands can achieve. Here, the authors demonstrate in a randomized clinical pilot trial the feasibility of robot-assisted supermicrosurgery using a dedicated microsurgical robot for the completion of lymphatico-venous anastomosis in the treatment of breast cancer-related lymphedema

Article | Open Access | | Nature Communications

Sonja Schmid

During an ongoing Ebola virus outbreak, infection before onset of protective immunity from vaccination is a possible scenario. Here the authors show in non-human primates that vaccination shortly before treatment with a monoclonal antibody does not negatively affect effectiveness of the antibody therapy.

Article | Open Access | | Nature Communications

Peptide antibiotics often display a very narrow therapeutic index. Here, the authors present an optimized peptide antibiotic with broad-spectrum in vitro activities, in vivo efficacy in multiple disease models against multidrug-resistant Gram-negative infections, and reduced toxicity.

Article | Open Access | | Nature Communications

Drugs for filariases are under development and clinical trial simulators could help to inform the design of clinical trials. Here, Walker et al. use an individual-based onchocerciasis transmission model to project trial outcomes of a hypothetical macrofilaricidal drug, resolving key design choices.

Article | Open Access | | Nature Communications

Here, the authors report the results of a randomized, placebo controlled trial of children with acute gastroenteritis who were treated with a probiotic and find no virus-specific beneficial effects attributable to the probiotic, either in reducing clinical symptoms or clearance of viral nucleic acid from stool specimens.

Article | Open Access | | Nature Communications

Vaccines and targeted therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently lacking. Here, the authors report a human monoclonal antibody capable of neutralizing both authentic SARS-CoV and SARS-CoV-2 by targeting a common epitope.

Article | Open Access | | Nature Communications

SARS-CoV-2 uses ACE2 as the entry receptor. Here, the authors show that an ACE2-Ig fusion protein inhibits entry of virus pseudotyped with the SARS-CoV-2 spike protein, show differential binding kinetics of SARS-CoV and SARSCoV-2 spike proteins to ACE2, and determine pharmakocinetic parameters of ACE2-Ig in mice.

Article | Open Access | | Nature Communications

Antibiotic-resistant bacteria are an urgent threat to human health. Here, Roberts et al. characterise and monitor an ongoing hospital outbreak of carbapenemase-producing Enterobacter hormaechei by integrating several technologies for whole-genome sequencing and shotgun metagenomics.

Article | Open Access | | Nature Communications

Cases of C. difficile (CD) resistant to metronidazole have been reported but the mechanism remains enigmatic. Here the authors identify a plasmid, which correlates with metronidazole resistance status in a large international collection of CD isolates, and demonstrate that the plasmid can confer metronidazole resistance.

Article | Open Access | | Nature Communications

The mechanism of action of daptomycin, a lipopeptidic antibiotic, is unclear. Here, the authors show that Ca2+-daptomycin simultaneously interacts with lipid-coupled precursors of the bacterial cell envelope and with the anionic phospholipid phosphatidylglycerol, forming a tripartite complex.

Article | Open Access | | Nature Communications

Remdesivir (RDV) is a broad-spectrum antiviral drug with activity against MERS coronavirus, but in vivo efficacy has not been evaluated. Here, the authors show that RDV has superior anti-MERS activity in vitro and in vivo compared to combination therapy with lopinavir, ritonavir and interferon beta and reduces severe lung pathology.

Article | Open Access | | Nature Communications

Aishwarya Sundaram

Depletion of tribbles pseudokinase 3 (TRIB3) is known to suppress the expression of several tumor-promoting factors, including EGFR. Here, the authors show that TRIB3 interacts with EGFR and regulates its stability and activity, and perturbing EGFR-TRIB3 interaction attenuates NSCLC progression by accelerating EGFR degradation.

Article | Open Access | | Nature Communications

Metastatic dissemination contributes to the lethality in pancreatic ductal adenocarcinoma (PDAC). Here, the authors perform RNA-sequencing on patient derived circulating tumor cells (CTCs) and identify three major CTC subgroups, and show the therapeutic potential of targeting LIN28B/let-7 pathway to halt cancer metastasis.

Article | Open Access | | Nature Communications

Penile squamous cell carcinoma (PSCC) is a cancer that is associated with significant mortality. Here, the authors develop a mouse model of PSCC by co-deletion of Smad4 and Apc in the androgen-responsive penile epithelium, and show synergistic efficacy of checkpoint therapy with cabozantinib or celecoxib in their model.

Article | Open Access | | Nature Communications

Interleukin-2 can induce an anti-tumour response, but is associated with toxicity. Here, the authors demonstrate that an engineered interleukin-2 promotes intratumoral T regulatory cell depletion while enhancing effective anti-tumour CD8+ T cell responses that result in potent tumor suppression.

Article | Open Access | | Nature Communications

Elevated expression of ULK1 is known to be inversely correlated with breast cancer metastasis. Here, the authors report Exo70 as a substrate of ULK1 that suppresses cancer metastasis, and show that ERK1/2 mediated phosphorylation of Exo70 leads to opposing effects on tumour cell invasion.

Article | Open Access | | Nature Communications

The progress in pre-clinical drug discovery for Wilms tumor (WT) is limited by a lack of disease models. Here, the authors develop 45 heterotopic WT patient-derived xenografts including several anaplastic models that recapitulate the biological heterogeneity of WT, and propose this as a resource for evaluating future therapeutics for WT.

Article | Open Access | | Nature Communications

Tobacco use is one of the major risk factors for Head and neck squamous cell carcinoma (HNSCC). Here, the authors report an immune-competent syngeneic mouse model that mimics human tobacco-related HNSCC, and develops tumors in the tongue, and report a high response rate to anti-CTLA-4 therapy.

Article | Open Access | | Nature Communications