In this review Kantor and colleagues highlight some of the current challenges faced in the preclinical and clinical uses of gene therapy with particular emphasis on viral-CRISPR/Cas-based technologies and their future potential. They delve into the assortment of technologies and viral carriers, mostly focusing on lentiviral and adeno-associated vectors.

Ji and colleagues developed a functionalized lipid nanoparticle that efficiently de-targets the liver and presents muscle tropism after systemic delivery in mice. This new vector platform opens new avenues for gene delivery strategies to treat muscle disorders.

In a mouse model of SPG4 Hereditary Spastic Paraplegia that expresses human mutant spastin, this study reports success using AAV9-mediated gene therapy to deplete endogenous spastin and replace it with healthy spastin at physiological levels. When introduced into the presymptomatic mouse, the behavioral and anatomical disease symptoms were entirely prevented.

In RA, nociceptive nerves release CGRP to suppress joint inflammation via CX3CR1+ synovial macrophages. Fang and colleagues found CGRP itself desensitizes these macrophages. A gene therapy restoring macrophage sensitivity to CGRP alleviated arthritis, revealing a novel therapeutic target.

Takagi and colleagues show that excessive pro-inflammatory cytokines reduce vaccine efficacy in mice. They demonstrate that lipid nanoparticle-encapsulated microRNA-192 exhibits anti-inflammatory adjuvant activity by suppressing pro-inflammatory cytokine expression and JAK/STAT signaling, thereby improving vaccine efficacy in aged mice and ameliorating lipid nanoparticle-induced adverse reactions.

Zhao and colleagues reviewed the current situation of CAR-T therapies in the clinical treatment of lymphoma patients, the mechanisms of CAR-T cell exhaustion, and potential strategies to overcome CAR-T cell exhaustion for lymphoma patients.

In 1990, two seminal studies introduced a novel method, systematic evolution of ligands by exponential enrichment (SELEX), to discover and isolate…

Multi-omcis reveals that Epstein-Barr virus–positive B cells upregulate HLA-DQB1 and pro-inflammatory signaling in Hunner-type interstitial cystitis via B-cell–restricted IRF8. The study delineates an immunogenetic circuit linking viral latency, antigen presentation, and epithelial stress, prioritizing candidate biomarkers for precision diagnostics and therapy.

B-cells can serve as immunotherapeutic drug cells, but require integrated safety switches due to oncogenic risks. Inserting an inducible caspase9 (iCasp9) suicide gene enables AP1903 drug-induced apoptosis of edited B-cells in vitro and in vivo, providing a means to control therapy and potentially modulate antibody infusion via the iCasp9/AP1903 system.

Oncolytic viruses are viruses that selectively infect and destroy cancer cells. This process helps the immune system recognize and fight the tumor, acting like an "in-situ vaccine." These viruses can also transform "cold" (immune-ignored) tumors into "hot" (immune-active) ones, making them more receptive to immune cell attack. They show great promise, especially when combined with other cancer treatments.

In this study, Nguyen and colleagues presents bispecific T cell engager receptors (TCERs) designed to target the KRASG12V mutant through HLA-A*11:01, enabling precise T cell-mediated tumor suppression. TCER01 and TCER02 exhibit high specificity and minimal cross-reactivity, offering a promising immunotherapy strategy for KRASG12V-driven cancers, including colorectal tumors.

(Molecular Therapy 32, 2778–2797; August 2024)

CD123-targeting CAR T cells may induce an on-target/off-tumor effect on endothelial cells in connection with the cytokine environment linked to CAR T-cell activation. At low concentrations, dasatinib reduces this effect without impacting anti-tumor efficacy, and at high concentrations, it reversibly controls CAR T-cell functionality.

Rancati and colleagues report that restoring a combination of microRNAs (miRNAs) yields synergistic suppression of glioblastoma progression. This multimodal, miRNA-based strategy offers a conceptual advance by demonstrating combinatorial miRNA restoration as an anticancer approach and identifying actionable targets for future diagnostic and therapeutic development.

mRNA vaccines reshape the entire body's immune landscape to fight cancer. Ren and colleagues discovered a rapid, innate immune program in lymph nodes and a coordinated burst of antigen-specific cell cycling. These findings reveal how mRNA vaccines orchestrate a systemic attack on tumors, advancing immunotherapy for HPV-related cancers.

Judge and colleagues demonstrated mutation-agnostic therapeutic gene editing using induced pluripotent stem cell (iPSC) models of Charcot-Marie-Tooth type 2E. They targeted common variants to inactivate dominant NEFL missense mutations and rescue phenotypes in iPSC-motor neurons. This haplotype editing approach could streamline therapeutic development for CMT2E and other genetic diseases.

Lyu and colleagues identified 272 cancer-specific ER genes that were dysregulated in cancer, as determined using a proposed dysregulation score method. The dysregulated gene list is a valuable resource for cancer immunotherapy research, with implications for precision oncology and the development of more effective, individualized treatment strategies.

This study evaluates AAV9-U7–mediated exon 51 skipping to restore brain dystrophin in mdx52 mice. Bilateral intracerebroventricular delivery induced partial Dp427 restoration (6–12%) but no behavioral improvement, highlighting current limitations of vectorized exon skipping while providing key insights into CNS gene delivery strategies for Duchenne muscular dystrophy.

Directed evolution of Sindbis virus generated the P438L variant, which shows enhanced replication and selective oncolysis in osteosarcoma and hepatocellular carcinoma models. These findings highlight the potential of viral evolution strategies to tailor oncolytic viruses for precision cancer therapy.

The editorial team at Molecular Therapy is very grateful to our many reviewers who unselfishly devoted their time and expertise to achieve the publication of exciting, first-rate basic and applied medical science. We thank you so very much for engaging in rigorous scientific discussion and deep and insightful judgment and for providing our editorial board and our authors with expert opinions and constructive criticism. Your contributions are crucial for the advancement of our science and for upholding the high standards to which we aspire to make Molecular Therapy a leading journal in molecular and cellular medicines.

At first glance, arthritis seems an unlikely target for gene therapy. Only in extremely rare cases is the disease caused by a single gene mutation; most forms of arthritis are complex diseases where the genetic contribution is polygenic and complicated. Nevertheless, as illustrated by the paper of Yang et al.1 in this issue of Molecular Therapy, arthritis is receiving increasing attention from gene therapists.2

Microglial depletion and subsequent repopulation represent a promising treatment for various neurological disorders, including Alzheimer disease, multiple sclerosis, and leukodystrophies. Microglia replacement therapy can be used to treat neuroinflammation and genetic disorders by replacing morphologically or genetically abnormal cells with healthy microglia.1 Past research has largely focused on the therapeutic potential of microglia replacement to treat these disorders; however, the long-term effects of donor cell type remain largely unknown.

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disorder of the immune system caused by bi-allelic mutations in the ADA2 gene. This disorder causes vasculitis/vasculopathy, systemic inflammation, mild immunodeficiency, and hematologic abnormalities. Untreated or undiagnosed DADA2 has an estimated lethality rate of 8% and a mean survival age of 35 years. At present, the standard of care is anti-tumor necrosis factor agents, which can reduce inflammation, keep vasculitis in check, and prevent strokes.

Blanquart and colleagues identified Afftins, derived from extremophilic archaea, for the targeting of human mesothelin, a well-known tumor associated antigen. The authors demonstrated their advantageous properties (high affinity, specificity and stability), and also produced and characterized Affitin-based bispecific NK cell engagers and showed their high efficiency to induce the death of mesothelin-expressing cells.

This study elucidates the mechanism of D1 of MSLN in promoting tumor progression (e.g., migration, invasion, signaling pathway), and how the D1-targeting antibody W1 inhibits tumor activity and reduces tumor burden in vivo, offering novel insights into MSLN function and a new therapeutic strategy for tumors.