HSV-tk gene therapy (HSVtk / Zalmoxis / TK therapy)

Personalized gene therapy relieves severe epilepsy in two boys.

Inhalable Mucoadhesive Redox-Triggered Nanotherapeutics for p53-Mediated Lung Cancer Therapy and Metastasis Suppression.

Shim Yun Seop YS, Han Sung Min SM, Jo Yun Kee YK

Lung cancer remains a leading cause of cancer-related mortality worldwide, with metastatic disease accounting for ∼90% of deaths. While p53 gene therapy offers promise for restoring tumor suppressor function, its clinical translation has been hindered by inefficient delivery systems and pulmonary administration challenges. Here, we developed redox-responsive thiolated chitosan nanoparticles (TCS NPs) as the first inhalable nanotherapeutic platform for tumor-selective p53 gene delivery to treat metastatic lung cancer. Our system exploits elevated glutathione levels in cancer cells to trigger selective gene release, while mucoadhesive properties ensure prolonged pulmonary retention. The p53 DNA-loaded TCS NPs demonstrated exceptional cancer selectivity, exhibiting significant cytotoxicity against lung cancer cells while maintaining biocompatibility with normal tissues. Treatment restored p53-mediated pathways, upregulating metastasis suppressors (KLF6 and E-cadherin) and apoptotic factors (Bax and cleaved caspase-3), thereby inhibiting migration, invasion, and metastatic progression. In vivo studies using ectopic xenograft and experimental metastasis models confirmed robust therapeutic efficacy, with inhaled TCS@p53 NPs achieving significant tumor suppression and reduced metastatic nodule formation while maintaining excellent safety profiles. This work presents a transformative inhalable gene therapy platform that overcomes traditional delivery limitations through tumor-selective targeting.

Out of Reach: Understanding Resource Barriers to Gene Therapy for Pediatric Patients With Sickle Cell Disease.

Kelly Colleen A CA, Paul Morgan A MA, Griffin McKenzie M, Kang Sunyu S et al.

Sickle cell disease (SCD) is a highly morbid condition resulting in poor quality of life and early death. Gene therapy offers opportunity for cure, but its resource‑ and time‑intensive nature may limit access. We conducted a single-center, cross-sectional study to determine the proportion of families with a child with SCD who report the ability to access a hypothetical curative therapy and to identify family-reported resource barriers. A single-timepoint survey was administered to 100 families with children aged 2-17 years receiving sickle cell care at a quaternary care center. The survey queried parent-reported household characteristics and unmet basic needs in food, housing, utilities, or transportation (household material hardship [HMH]) and assessed parent-reported ability to access a hypothetical curative treatment based on a vignette. Multivariable logistic regression examined associations of HMH and disease severity with family-reported access. Of the evaluable 82 families, 60% experienced HMH over the prior 12 months despite robust social work involvement (78%) and participation in means-tested benefits (59%). Forty percent of parents reported an ability to obtain curative therapy with current resources. Upon adjustment for key covariates, HMH exposure was independently associated with 95% lower odds of family-reported ability to obtain curative therapy. Although gene therapy offers a potential cure for SCD, fewer than half of families reported ability to access it with current supports. HMH exposure affected nearly two-thirds of families and was independently associated with lower odds of access. As highly centralized, resource-intensive treatments expand, resource-targeted interventions are needed to ensure equitable access and receipt.

The cell-mediated adaptive immune response to herpes simplex virus type 1 encephalitis: mechanisms and clinical implications.

Osborne Louise L, Dunai Cordelia C, Huang Yun Y, Egbe Franklyn N FN et al.

Herpes simplex virus (HSV) encephalitis is the most frequent cause of sporadic encephalitis globally. Despite the emergence of the antiviral drug aciclovir curtailing mortality, this disease remains a clinical challenge due to its rapid progression and associated neurological sequelae; indicating the urgent requirement for adjunctive neuroprotective treatment options. Recent studies using both human samples and murine models have highlighted how cell mediated immune cells including CD8+, CD4+ and brain tissue-resident memory T cells have the capacity to act as a 'double-edged sword'; both serving to protect the host against HSV encephalitis, but also increasing neuroglial injury by inflammation. Factors which impair cell-mediated immunity may predispose individuals to herpes simplex encephalitis, including defects in viral immune evasion strategies (infected cell protein 47, UL13 kinase), host genetic pre-disposition (toll-like receptor 3 deficiency, lymphotoxin-α deficiency, Rel mutations) and external factors such as stress. Additionally, there is a particular need for clinical vigilance for patients on immunosuppressive treatments which impair cell-mediated immunity, including azathioprine, hydroxychloroquine and methotrexate. Conversely, understanding these molecular mechanisms may provide new insights into the use of immunomodulatory strategies including anakinra, tocilizumab, and the implementation of targeted vaccination. This review summarises the current state of knowledge of how an impaired cell-mediated immune response could promote herpes simplex virus encephalitis, followed by an exploration of the clinical applications and therapeutic interventions which could viably be implemented to ameliorate immune-mediated tissue injury.