Bispecific antibodies pairing a shared 4-1BB epitope with non-overlapping HER2 epitopes drove HER2-dependent 4-1BB clustering, amplifying T-cell activation and tumor growth inhibition. In vivo, this pairing enhanced antitumor efficacy and tumor infiltration, while reducing systemic inflammation compared to urelumab - establishing a generalizable strategy for TNFRSF-targeted immunotherapy.

Shim and colleagues develop DLMEH, a metabolically stabilized D-leucine prodrug that bypasses first-pass catabolism. DLMEH activates Sestrin2-dependent mTORC1 signaling, restoring muscle protein synthesis in dexamethasone-induced atrophy. In rat models, DLMEH preserves muscle mass, strength, and endurance superior to L-leucine, supporting DLMEH as a first-in-class candidate for sarcopenia.

Koo and colleagues demonstrate that Un1Cas12f1 recognizes an expanded PAMs, and enables multiplexed genome editing from a single CRISPR array. Delivered as an all-in-one AAV, this compact Un1Cas12f1 system excises Dmd exon 23 in vivo, restores the reading frame and dystrophin expression in a mouse model of Duchenne muscular dystrophy.

Pathogenic variants in the gene encoding 6-pyruvoyl-tetrahydropterin synthase cause primary BH4 deficiency (PBD), leading to hyperphenylalaninemia and reduced monoamine neurotransmitter synthesis. This phase 1/2 study in eight patients with PBD found that sepiapterin increased blood BH4 and rapidly normalized blood phenylalanine levels, with no dose-limiting toxicity or dose-related adverse events.

The recent FDA approval of OTOF gene therapy is a major milestone for the field of hearing loss.1 However, auditory gene therapy still lags behind other fields in terms of clinical trials and approvals. A myriad of promising preclinical studies have been published for pediatric and juvenile-onset hearing loss, but far fewer have demonstrated similar promise for adult-onset hearing disorders. One thing is clear: effective gene delivery to adult hair cells and spiral ganglion neurons remains a key challenge for translating gene therapies for sensorineural hearing loss.