Molecular Therapy最新文献

Adeno-associated virus (AAV) vectors are a leading gene therapy vector. However, host recognition of AAV induces cytotoxic T lymphocytes (CTLs) and loss of transgene expression over time. Expanding regulatory T cells (Tregs) could suppress such responses, prevent AAV toxicity, and promote persistence of transgene expression. Interleukin-2 (IL-2) treatment can expand Tregs, but it lacks specificity and durability. THOR-834 is a synthetic PEGylated form of IL-2 engineered for enhanced Treg specificity and with improved half-life. In mice, prophylactic use of THOR-834 expands Tregs, reduces CD8⁺ effector memory T cells, ameliorates antibody responses against both AAV capsid and transgene product, and enhances productive gene transfer. THOR-834 can also suppress CD8⁺ T cell responses in a rat model of AAV immunogenicity. In cynomolgus macaques, a single prophylactic dose of THOR-834 expanded Tregs and sustained AAV transgene expression, confirming cross-species efficacy of THOR-834 mediated immunosuppression. These studies represent a novel immunomodulatory strategy that can harness Tregs to enhance the efficacy of gene therapy programs.

A single administration of recombinant adeno-associated viruses (AAVs) has the ability to provide long-term gene expression in the brain, offering promising therapeutic options for neurodegenerative diseases that require decades of intervention. Intra-cerebrospinal fluid (CSF) administration is clinically relevant, and it enables broad transduction of superficial brain areas at lower doses compared with systemic delivery. However, intra-CSF AAV administration remains ineffective at transducing subcortical structures such as the striatum. We demonstrate in rats that following intra-CSF delivery of AAVs, targeting the striatum with focused ultrasound in the presence of intravenous microbubbles significantly enhances transduction in this brain region. When scaled to non-human primates, the AAV delivery to the caudate and putamen was increased up to 100-fold, and transgene expression up to 500-fold. These findings support intra-CSF administration of AAV combined with focused ultrasound as a promising strategy to extend gene delivery from superficial to deep brain structures with anatomical precision and clinical scalability.

Oncolytic viruses offer promising immunotherapy for cancer but face challenges such as delivery, targeting, and immune clearance. Our prior work showed that vaccinia virus (VACV) displaying the complement regulator CD55 evaded complement-mediated clearance, enhancing delivery and targeting in xenograft models. Importantly, this modified VACV also escaped neutralizing antibodies (NAbs) in vitro, a finding with significant implications. To improve translational relevance, we independently evaluated NAb evasion in immunocompetent in vivo models and against human-derived NAbs. Our novel platform virus, SJ-650-a CD55-displaying VACV expressing murine GM-CSF-retained superior antitumor efficacy despite the presence of NAbs in syngeneic breast cancer models. Additionally, SJ-650 effectively evaded NAbs derived from the serum of a clinical VACV trial (REN026). NAb evasion was CD55-dependent, occurred independently of complement activity, and was mediated by steric hindrance via the extracellular CD55 motif. NAb pretreatment masked binding of the key viral entry proteins A27, L1, and H3 in control viruses lacking CD55, but these interactions remained intact in SJ-650. By circumventing both complement and antibody responses, SJ-650 significantly inhibited tumor growth in two metastasis models, inducing immunogenic cell death and reprogramming the tumor microenvironment. These findings support SJ-650's potential as a robust oncolytic platform with broad translational applicability.