Volume 29 Issue 8, August 2023

Nature Medicine explores the latest translational and clinical research news, with a delayed FDA decision on Sarepta’s adeno-associated virus gene therapy SRP-9001.

Nature Medicine explores the latest translational and clinical research news, with results from a small expansion cohort of the phase 2b SYMMETRY trial in patients with type 2 diabetes and non-alcoholic steatohepatitis.

Nature Medicine explores the latest translational and clinical research news, with positive efficacy and safety data from Sanofi’s treatment for autoimmune disease.

Randomization and placebo groups are giving way to biomarkers, real-world data from wearables, and multi-center and adaptive trials.

The entire biotechnology and pharmaceutical industry will be thrown into turmoil if judges can second-guess the scientific expertise of the US Food and Drug Administration.

Women who are pregnant, lactating or of childbearing potential are commonly excluded from cardiovascular randomized controlled trials — this needs to change.

Patients, physicians, and hospital administrators in the USA are often unaware of how legislation governs medical data—but agree that rights over such data should be expanded for patients and curtailed for health systems

Observational studies provide crucial information early during epidemics and pandemics, but they often suffer from methodological shortcomings, which can be resolved.

In individuals with anorexia nervosa, psilocybin therapy comes with specific risks and concerns; but an encouraging phase 1 trial underscores the necessity for more research into classic psychedelics to address the urgent need for effective treatments.

Innovative clinical trial designs with a patient-centered mission are crucial to advancing modern cancer care; the adaptive phase 2 umbrella study CTONG1702 provides one model for this new era of trial design.

Strategies to monitor and modulate gut microorganisms to improve immunity and responses to cancer immunotherapy are increasingly available, with opportunities to expand and iterate on these approaches to treat, intercept and prevent cancer (and other diseases) altogether.

Cost-effective fluid biomarkers for tau aggregate pathology would improve the diagnostic and prognostic work-up of Alzheimer’s disease and facilitate the discovery of anti-tau therapies. We identified MTBR-tau243 as a specific marker for tau aggregate pathology that could be implemented in clinical practice and trials.

We performed gene therapy to induce expression of GDNF in the ventral tegmental area of rhesus monkey brains. Our approach countered the hypodopaminergic state that is associated with chronic alcohol drinking and reduced alcohol intake to fewer than two drinks per day while other ingestive behaviors remained intact. These findings, along with results from our ongoing clinical trials of GDNF gene therapy in other diseases, support future application of this approach in humans with alcohol-use disorder.

Alzheimer’s disease is a complex and chronic disease that evolves over decades. Proteomic analysis of cerebrospinal fluid from people with dominantly inherited forms of the disease reveals the temporal progression of pathological changes in Alzheimer’s disease and identifies extracellular matrix proteins as some of the earliest biomarkers of the disease.

We transplanted gene-edited porcine hearts into two brain-dead human recipients, then evaluated their cardiac function and immune response over the following 66 hours. Both hearts showed sustained cardiac function over the course of the study, without evidence of hyperacute rejection or zoonotic transmission.

OncoNPC, a machine learning classifier developed to predict the primary origin of tumors, made confident predictions for over 40% of cancers of unknown primary (CUP) cases analyzed. Patients with CUP who had received site-specific treatments that retrospectively matched the OncoNPC predictions had better outcomes than patients who had been treated with discordant site-specific therapies. OncoNPC predictions doubled the number of patients with CUP who would be eligible for genomically guided therapies.

The authors generate a checklist of key considerations to guide patient and public involvement and engagement in future research, informed by lessons from the TLC study, which evaluated therapies for long COVID.

This review explains how large language models (LLMs), such as ChatGPT, are developed and discusses their strengths and limitations in the context of potential clinical applications.

A reinforcement learning model developed to adapt artificial intelligence (AI) predictions to human preferences showed better sensitivity for skin cancer diagnoses and improved management decisions compared to a supervised learning model.

Phase 1 trial results demonstrate that psilocybin in conjunction with psychological support is safe, tolerable and deemed acceptable and therapeutically meaningful by female individuals with anorexia nervosa.

CSF MTBR-tau243 is more related to tau tangles and clinical cognitive impairment in Alzheimer’s disease than phospho-tau biomarkers, which are more related to amyloid plaques.

Prospective and longitudinal analyses of patients with cognitive impairment reveal that in vivo detection of Lewy body pathology is independently associated with hallucinations, worse attention/executive, visuospatial and motor function and predicted future cognitive decline.

A longitudinal study of clinically unimpaired individuals reveals that Lewy body pathology measured in vivo is associated with worse smell and cognitive functions and predicted subsequent cognitive decline and progression to Parkinson’s disease or dementia with Lewy bodies.

Proteomic analysis of cerebrospinal fluid from individuals with autosomal dominant Alzheimer’s disease reveals how this complex and chronic disease evolves over many decades.

In a short-term study in which hearts from gene-edited pigs were transplanted into two recently deceased human recipients, the hearts were able to function for the duration of the study without signs of rejection and without evidence of pig virus transmission, encouraging further clinical study of cardiac xenotransplantation.

A newly developed hemodynamic parameter, termed tissue perfusion pressure, can be determined from standard blood pressure monitors and has additive value compared to mean arterial pressure for predicting the risk of mortality and other outcomes for patients in the cardiac intensive care unit.

Based on a newly developed deep-learning model for predicting the binding affinities of protein–protein interactions, the effects of SARS-CoV-2 spike protein variants on binding to the ACE2 receptor and neutralizing antibodies were analyzed and used to predict immune escape and viral evolution.

Adoptive transfer of convalescent donor-derived SARS-CoV-2-specific T cells was safe and conferred faster recovery in patients with severe COVID-19 compared to standard of care.

In a preclinical study, the delivery of an AAV-based gene therapy encoding GDNF in the brain prevented the return to alcohol use behaviors in a non-human primate model.

In a case series of six patients with refractory lupus nephritis who were treated off-label with an anti-CD38 monoclonal antibody, five patients achieved complete or partial renal responses by 12 months of follow-up.

UK Biobank moement tracking data show increased performance as compared to symptoms and genetic and lifestyle factors in identifying prodromal Parkinson’s disease in the general population.

A machine-learning classifier predicts the origin of cancer of unknown primary based on electronic health records and next-generation sequencing data, showing that patients treated accordingly to model predictions had significantly better outcomes.

In the NATION-1907 trial, treatment of patients with resectable esophageal squamous cell carcinoma with the anti-PD-L1 agent adebrelimab was safe and showed preliminary overall survival efficacy, with responders exhibiting an immune-enriched tumor microenvironment phenotype at baseline.

Treatment of patients with HER2-mutant non-small-cell lung cancer with the pan-HER inhibitor pyrotinib in a phase 2 trial or compassionate use showed a favorable objective response rate, whereas patients treated in parallel by physician’s choice in a real-world study did not.

Treatment with anti-PDL1 and anti-CTLA4 in combination with mFOLFOX6 chemotherapy for patients with treatment-naive microsatellite stable metastatic colorectal cancer is safe, shows encouraging progression-free survival and induces a tumor-specific immune response.

T cells containing an anti-mesothelin single-domain antibody fused to a component of the endogenous T cell receptor signaling complex exhibit notable toxicities but encouraging clinical responses in patients with treatment-refractory mesothelioma and ovarian cancer.

Trastuzumab deruxtecan, an anti-HER2–drug conjugate, exhibits the highest objective response rate in patients with HER2-overexpressing metastatic breast cancer, but clinical activity is also observed in patients with HER2-low or non-expressing tumors, potentially pointing to additional determinants of drug efficacy.

In patients with advanced melanoma, fecal microbiota transplantation from healthy donors combined with the anti-PD-1 inhibitors nivolumab or pembrolizumab was well tolerated with an encouraging objective response rate of 65% in the first-line treatment setting.

In the randomized, double-blind, phase 3 GLOW trial, capecitabine and oxaliplatin combined with zolbetuximab, a monoclonal antibody that targets CLDN18.2, significantly improved progression-free survival and overall survival in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.