Gene Therapy最新文献

Inherited retinal diseases are a devasting and incurable cause of blindness which frequently affect patients at a young age, and developing effective treatments has been an important research priority in recent decades. Treatments must be validated in randomised-control trials, which involve measuring benefit according to prospectively defined endpoints. A wide variety of conventional clinical endpoints and emerging anatomical, physiological, and functional biomarkers may be selected. Different options may be better or worse at capturing clinically significant differences and identifying real differences between experimental groups. This review provides an overview of some proven and potential endpoints for randomised-control trials involving inherited retinal disease patients. Clinical endpoints and biomarkers are discussed, and the work required to validate biomarkers for use in trials is outlined. Unlike in general medicine, ophthalmological clinical endpoints may all be conceptualised as surrogates for maintained vision. Selecting optimal endpoints is essential to ensure that treatments are assessed fairly, such that resources are directed towards interventions that stand to truly benefit patients with inherited retinal diseases.

Rod-cone dystrophies (RCD) are caused by mutations in over 100 genes associated with photoreceptor function, leading to progressive and sequential loss of rod and cone photoreceptors. These mutations generally disrupt retinal metabolism and oxidative stress response accelerating disease progression and vision loss. SPVN06 is an adeno-associated virus (AAV)-based gene- and mutation-agnostic investigational therapy designed to slow cone degeneration by delivering long-term expression of rod-derived cone viability factor (RdCVF) and its full-length isoform, thioredoxin RdCVFL, following a single subretinal administration. These proteins support cone survival by promoting glucose metabolism and reducing oxidative damage, respectively, providing a gene and mutation independent therapeutic approach for RCD. SPVN06 IND-enabling program included pharmacology evaluation in the rd10/rd10 mouse model of RCD (1.0 × 10⁸ vector genomes (vg)/eye up to 1 month) along with systemic and ocular safety and biodistribution evaluation in non-human primates (NHPs, 6.0 × 10⁹ to 3.0 × 10¹¹ vg/eye up to 3 months). In the rd10/rd10 mice, SPVN06 showed preserved vision, as assessed by optokinetic tracking. In NHPs, SPVN06 was well-tolerated up to 6.0 × 10¹⁰ vg/eye, with high and stable RdCVF and RdCVFL mRNA expression levels in the retina and retinal pigment epithelium. These results supported the initiation of the ongoing Phase I/II PRODYGY trial with RCD (NCT05748873).

The selection of an appropriate promoter is important to the design and optimisation of adeno-associated viral (AAV) vector-based cardiac gene therapies. The expression cassette design can impact efficacy and safety of the vector. This study is the first to use a novel AAV barcode-seq method for the simultaneous evaluation of a panel of cardiac-specific promoters in a high-throughput manner. Functional analyses of our cardiac promoter kit packaged in three different capsids were performed using neonatal rat ventricular myocytes (NRVM), human iPSC-derived cardiomyocytes (hiPSC-CMs), HuH7 hepatocellular carcinoma cells, as well as mouse, rat, sheep and pig models. The cardiac troponin T (cTnT) promoter showed the most promise overall as a cardiac-specific promoter across all cardiac models tested. The results validate the barcode-seq technique as a powerful and versatile approach that enables high-throughput, quantitative analysis of various expression cassettes in commonly used models of cardiac gene therapy.

Due to the poor healing capacity of tendons, the healing process is slow, with a risk of re-rupture post-injury. In this study, we found that miR-494-3p was one of the miRNAs with significant expression differences after tendon injury by sequencing in the rat Achilles tendon injury model. Therefore, we hypothesized that regulating miR-494-3p expression in tendons could improve tendon healing. Considering the long healing process of the tendons and the short half-life of miRNA, we hope to achieve the best efficacy by delivering miR-494-3p using a sustained-release nanoparticle hydrogel system. In the results, with an increase in miR-494-3p, the tendon biomechanics were significantly improved after 2-week repair, and the content of collagen I (Col I) also increased. Through bioinformatics prediction, double luciferase, and immunohistochemistry experiments, we confirmed that miR-494-3p targeting CXXC finger protein 4 (CXXC4) promoted tendon healing. In conclusion, the miR-494-3p/nanoparticles hydrogel delivery system can protect and sustainedly transfer miR-494-3p into tenocytes, block the translation of CXXC4, increase the expression of Col I, and ultimately improve tendon healing. A nanoparticle hydrogel delivery system of miRNA was constructed and applied to injured tendons. Finally, we confirmed that the miR-494-3p/nanoparticles hydrogel delivery system can protect and sustainedly transfer miR-494-3p into tenocytes, block the translation of CXXC4, increase the expression of Col I, and ultimately improve tendon healing.