Current Issue : January-March Volume : 2026 Issue Number : 1 Articles : 5 Articles
Precision oncology has seen significant progress with oligonucleotide-based therapies, which provide a novel approach to gene expression silencing. These therapies, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and microRNAs (miRNAs), target specific genetic sequences with high precision. They offer promising solutions for cancers resistant to conventional treatments due to their ability to modulate previously “undruggable” targets and their reduced toxicity. However, challenges such as susceptibility to degradation, poor cellular uptake, and off-target effects have hindered their clinical application. Advances in chemical modifications and delivery systems, like lipid nanoparticles and GalNAc conjugates, have improved the stability and efficacy of these therapies. This review discusses the structural features, mechanisms of action, and clinical applications of ASOs, siRNAs, and miRNAs, focusing on gastrointestinal and genitourinary cancers. We highlight successful oncology applications, such as siRNA-based therapies targeting specific oncogenes, which have shown promise in clinical trials. Continued advancements in this field are paving the way for more effective and safer cancer treatments....
The prevalence of wet age-related macular degeneration (AMD) in the US is expected to increase to 82 million by 2050. Addressing the specialized needs for this population will become increasingly challenging as prevalence rises. Frequent anti-vascular endothelial growth factor (anti-VEGF) injections have been the recourse for this population; however, the burden wet AMD places on patients underscores the critical need for durable therapeutic approaches. Gene therapy is a bioengineered treatment that has transformed the management of previously untreatable disorders. Ongoing advancements and refinements in its biomechanism could lead to more sustainable treatment options for wet AMD. In this article, we provide recent updates on gene therapy trials for wet AMD....
X-linked agammaglobulinemia (XLA) is a rare inborn error of immunity caused by loss-of-function mutations in the gene encoding Bruton’s tyrosine kinase (BTK). XLA patients lack mature B cells and have negligible antibody levels, leaving them susceptible to recurrent bacterial and chronic viral infections. Autologous hematopoietic stem cell gene therapy with gene-corrected HSC may serve as a promising treatment of XLA; this therapy would provide a one-time cure and would replace lifelong immunoglobulin replacement therapy. Due to the requirement of strict physiological regulation of BTK gene expression, a site-specific editing strategy was designed to insert a BTK cDNA transgene directly into its endogenous locus. To study the effectiveness of this therapy, murine lineage- negative hematopoietic cells from a murine model of XLA were edited using CRISPR-Cas9/rAAV6 then transplanted into recipient XLA mice. Myeloablated XLA mice that received transplantation of Btk-corrected Lin- cells displayed high levels of engraftment, significant increases in their B cell levels, increased production of various immunoglobulins, improved B cell development in the bone marrow, increased B cell receptor diversity, and the ability to produce antigen-specific antibodies following immunization. Collectively, we have modeled a gene therapy strategy in a disease model of XLA and extensively validated the site-specific genome editing approach....
Surfeit locus protein 1 (SURF1)-related Leigh syndrome is an early-onset neurodegenerative disorder characterized by a reduction in complex IV activity that disrupts mitochondrial function. Currently, there are no disease-modifying treatments available. Previously, we reported that a gene replacement therapy for SURF1-related Leigh syndrome was developed, which showed improved complex IV activity and restored exercise-induced lactate acidosis, as well as a high safety profile in wild-type (WT) mice. However, further investigations of this original SURF1 vector design uncovered cytotoxicity in multiple tissues of WT rats despite having minimal immune responses. We hypothesized that this cytotoxicity was elicited by SURF1 protein overexpression driven by a strong ubiquitous promoter, CBh. Here, we report the development of an improved gene therapy for SURF1 Leigh syndrome by utilizing a different promoter and polyadenylation sequence. Our data showed that, with lower SURF1 protein expression, the new design conferred a similar level of efficacy, but with minimal cytotoxicity in mice or rats. We propose this new vector design as a promising therapeutic candidate for SURF1- related Leigh syndrome, warranting further translational studies....
Genetic hearing loss, caused by mutations in critical auditory genes, has seen promising advances through gene therapy, yet the temporal dynamics of early-stage auditory functional recovery and therapeutic transgene expression patterns following intervention remain uncharacterized in preclinical deafness models. This study systematically investigates the post-treatment progression of cochlear functional restoration and spatially resolved transgene expression kinetics in adult Vglut3 knockout (Vglut3KO) mice following adeno-associated virus (AAV)-mediated inner ear gene therapy. AAV8 vectors delivering Vglut3 were injected via the posterior semicircular canal (PSCC), with auditory brainstem response (ABR) thresholds and cochlear transgene expression assessed at days 1–14 post-injection. VGLUT3 expression in Vglut3KO mice revealed rapid transduction, detectable in inner hair cells (IHCs) by day 1, peaking at day 14. Remarkably, hearing recovery commenced as early as day 1 post-injection, and plateaued near wild-type (WT) levels by day 5. Functional correlation analysis demonstrated a robust inverse relationship between FLAG expression and hearing thresholds. This study provides critical insights into the dynamic processes underlying cochlear gene therapy and challenges the conventional paradigm that 1–2 weeks are required for functional recovery....
Loading....