Hidden Gene-Editing Trial Death Raises Oversight Concerns
A six-year-old girl died following an experimental base-editing treatment administered at Xinhua Hospital in Shanghai, China, according to an investigation by science and Retraction Watch.
The personalized therapy was designed to correct a mutation associated with KOS, a rare neurodevelopmental condition. Genes encoding the base-editing components were packaged into adeno-associated virus vectors and delivered into the girl’s cerebrospinal fluid. She reportedly died from a severe treatment-related immune reaction seven days later.
The trial proceeded under a regulatory pathway that did not require approval from China’s national authorities, and the death was not publicly disclosed. An entry on ClinicalTrials.gov has not been updated for more than a year, while a related preclinical paper published in Nature did not refer to the treatment or the family’s financial contribution.
Experts consulted by Science and Retraction Watch raised concerns about the informed-consent process, safety findings from animal studies, and the decision to test the therapy in a child whose condition was not life-threatening. Shanghai Jiao Tong University has since launched an investigation. Source
Deramiocel Meets Phase 3 Duchenne Endpoint
Deramiocel has met the primary endpoint in a Phase 3 trial involving boys and young men with advanced Duchenne muscular dystrophy.
The allogeneic cell therapy consists of cardiosphere-derived cells obtained from donated human hearts. Although the cells persist only briefly after administration, they are intended to produce longer-lasting anti-inflammatory, antifibrotic, and immunomodulatory effects through the release of paracrine factors.
In the HOPE-3 trial, 106 participants aged 10 years or older received deramiocel or placebo intravenously every three months. After 12 months, the treatment produced a 4.55 percent between-group benefit in Performance of the Upper Limb 2.0 scores, corresponding to an approximately 54 percent reduction in disease progression.
The key secondary endpoint assessing left ventricular ejection fraction did not reach statistical significance, although results favored deramiocel. The therapy’s safety profile was similar to placebo. The researchers describe HOPE-3 as the first Phase 3 trial in advanced Duchenne muscular dystrophy to meet a primary efficacy endpoint. Source
Immature Cells May Weaken CAR NK Therapies
A small population of immature natural killer cells in donated cord blood may reduce the effectiveness of off-the-shelf CAR NK therapies.
Researchers at MD Anderson Cancer Center found that cord blood units containing more mature NK cells were associated with stronger treatment responses and better patient outcomes. Higher proportions of immature NK cells were linked to poorer CAR NK activity.
The immature cells acquired cancer-associated proteins through trogocytosis, causing engineered CAR NK cells to mistake them for tumor cells and attack them. This created false targets, weakened the fitter NK-cell population, and reduced its persistence and antitumor activity.
Removing the immature cells before manufacturing improved CAR NK-cell function and strengthened tumor control in preclinical models of lymphoma and ovarian cancer. The findings could inform donor selection and manufacturing strategies for more consistent off-the-shelf products. Source
Inherited Genetics Shapes CAR T Outcomes
Inherited genetic variants may influence both the effectiveness and toxicity of autologous CAR T-cell therapy.
Researchers analyzed whole-genome sequences from more than 200 patients with aggressive lymphoma enrolled in two CAR T clinical trials. Because autologous products are manufactured from each patient’s own T cells, the investigators examined whether germline variation could affect the behavior of the resulting therapy.
Variants that reduced expression of the STXBP2 gene were associated with treatment-related toxicity in one trial. Experiments involving engineered donor cells also indicated that loss or reduced expression of STXBP2 could promote inflammation.
Variants in ADAMTSL3 were associated with protection from toxicity across both trials, while variants in PTPN22 correlated with greater CAR T-cell expansion. The findings could eventually inform donor selection for allogeneic therapies and the design of engineered CAR T cells, although further validation will be required. Source
CRISPR Enzyme Shreds Cancer-Cell DNA
Researchers have repurposed an unusual CRISPR enzyme to kill cancer cells by triggering widespread destruction of their DNA.
Unlike conventional gene-editing enzymes, Cas12a2 is activated when it recognizes a matching RNA sequence. Once activated, it indiscriminately cuts DNA inside the cell, halting growth and causing the cell to die.
Two studies published in Nature programmed Cas12a2 to recognize RNA associated with cancer-driving mutations, including variants of TP53 and KRAS. The approach could provide a means of targeting tumors driven by mutant proteins that have proved difficult to inhibit using conventional drugs.
The work remains at an early preclinical stage. Akribion Therapeutics is developing a Cas12a2-based therapy for human papillomavirus-associated head and neck cancers, with the company aiming to generate initial clinical data by 2030. Source
AAV Gene-Silencing Therapy Extends Survival in ALS Mice
A single intravenous dose of an AAV-delivered microRNA therapy delayed disease progression and extended survival in a mouse model of SOD1-associated amyotrophic lateral sclerosis.
The AAV9 vector carries two artificial microRNAs designed to suppress human SOD1 expression. The microRNAs were incorporated into miR-33 scaffolds intended to reduce vector-genome truncation during manufacturing while maintaining gene-silencing activity.
Treatment before symptom onset delayed disease onset by approximately 66 days and extended median survival by about 100 days. Benefits were also observed when the therapy was administered near or after symptom onset, although the survival gains were smaller.
The treatment preserved motor neurons and neuromuscular junctions, improved motor and respiratory function, and reduced serum neurofilament light levels. The researchers are planning a pre-investigational new drug meeting with the FDA, but the findings have so far been demonstrated only in mice. Source
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