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

✓ Approved

Megapharm Ltd · POLA1 · 细胞治疗

什么是 HSV-tk gene therapy？

HSV-tk gene therapy 是一种细胞治疗，由Megapharm Ltd研发。该药已获批，用于治疗相关适应症，给药途径：Injectable (Others)、Intravenous (IV)。

药物档案

商品名HSVtk, Zalmoxis, TK therapy
公司Megapharm Ltd
药物类别细胞治疗, 基因治疗
分子靶点POLA1
给药途径Injectable (Others), Intravenous (IV)
状态Approved
来源： ClinicalTrials.gov, Megapharm Ltd

作用机制

分子靶点

HSV-tk gene therapy 作用于 1 个分子靶点：

POLA1DNA polymerase alpha 1, catalytic subunit (PDR, POLA)
需要更深入的分析？Noah AI 可解释复杂机制并与同类药物比较。

治疗适应症

HSV-tk gene therapy 针对 1 个适应症，涉及 1 个治疗领域。

治疗领域疾病/病症分期
Immune system disordersChronic graft versus host disease✓ Approved

相关研究文献

PubMedEuropean heart journal. Case reports2026-08-06

Syndromic dilated cardiomyopathy suggestive of an oligogenic background with CD36 and TNXB variants: a case report.

Aydin Ipek I, Ebeoglu Sevval Ilke SI, Kaya Melike M, Ebeoglu Abdullah Omer AO et al.

Dilated cardiomyopathy (DCM) is a major cause of heart failure and sudden cardiac death and has traditionally been regarded as a predominantly monogenic disorder. However, advances in next-generation sequencing have revealed a more complex genetic architecture with increasing recognition of oligogenic and polygenic contributions; particularly in patients presenting with extracardiac manifestations. In such cases, careful phenotypic characterization and integrative interpretation of genetic findings are essential for accurate diagnosis and management. We report the case of a 46-year-old man who presented with progressive exertional dyspnoea (the New York Heart Association class II-III). His medical history was notable for childhood-onset epilepsy, visual impairment, musculoskeletal abnormalities, and infertility. Transthoracic echocardiography demonstrated severe left ventricular dilatation with reduced ejection fraction (20%). Cardiac magnetic resonance imaging confirmed severe biventricular systolic dysfunction and revealed mid-to-basal myocardial fibrosis on late gadolinium enhancement imaging. Given the prominent multisystem involvement and exclusion of secondary causes, a syndromic cardiomyopathy was suspected. Comprehensive genetic testing identified likely pathogenic frameshift variants in the CD36 and TNXB genes, while additional variants of uncertain significance were detected in MT-TK and STXBP1. These findings suggested a potential oligogenic contribution involving pathways related to myocardial energy metabolism and extracellular matrix integrity. Guideline-directed medical therapy for heart failure with reduced ejection fraction was initiated, and the patient was enrolled in multidisciplinary follow-up with genetic counselling for first-degree relatives. This case highlights the limitations of a strictly monogenic framework in DCM and underscores the importance of considering oligogenic mechanisms in patients with syndromic features. Integrative evaluation combining detailed phenotyping, advanced cardiac imaging, and genetic analysis may provide valuable insights into complex cardiomyopathy phenotypes and support personalized clinical management.

PMID 42559185
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PubMedScientific reports2026-08-06

Development of an investigational medicinal stem cell gene therapy product to attempt curing human immunodeficiency virus infection.

Weigand Laura L, Herkt Stefanie S, Voges Maike M, Beschorner Niklas N et al.

For most people living with Human immunodeficiency virus (HIV), virus control and sufficient immune function can be achieved with polypharmacotherapy. A minority is intolerant to thereto, and drug-resistant mutants are emerging. Additionally, people living with HIV (PLWH) have significantly higher risk of cardiovascular morbidity and malignant diseases. HIV is in principle immunogenic. If T-cell depletion could be avoided immunological HIV eradication should be achievable. The "Berlin patient" in whom allogeneic stem cell transplantation from a CCR5Δ32/Δ32 donor induced long-term remission without antiviral therapy raised the hope that stem cell gene therapy with CCR5-deleted autologous stem cells could provide a cure, but the strategy did not live up to expectations. We propose to test an alternative strategy, namely expression of a designer recombinase which specifically excises HIV provirus from the genome under a Tat-inducible promoter so that expression is restricted to infected cells. A cGMP-compliant manufacturing protocol and quality control strategy for this investigational medicinal product was developed, validated, and a manufacturing authorization obtained. A First-in-Human-clinical trial, testing engraftment, repopulation of peripheral specific immunity, and ability to control HIV infection without antiviral medication is in preparation. Protocols can be adapted to other stem cell gene therapies by transferring alternative lentviral cargo.

PMID 42552339
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PubMedCytotherapy2026-08-06

Understanding FDA's reasons for nonapproval: A systematic review of complete response letters in cell and gene therapy.

Babcock Eugene E, Riggins Cindy C

Cell and gene therapy products face unique regulatory challenges due to their biological complexity and the stringent expectations for manufacturing control, analytical testing, and clinical assessment. As the pipeline grows, understanding the drivers of FDA non‑approval is increasingly important for improving first‑cycle success and reducing development delays. In this study, we aimed to characterize the frequency and impact of refuse‑to‑file actions, major amendments, and complete response letters issued for biologics licensing applications; and to identify recurring patterns of deficiencies contributing to delayed approval. Publicly available documents were extracted from the FDA website. Data from each approved cell and gene therapy product's regulatory history-including complete responses, major amendments, inspection timing, and cited deficiencies-were compiled and categorized across clinical, quality, and labeling domains. Analysis showed that informational deficiencies were common across modalities. Major amendments occurred in roughly half of applications, and complete responses had the most significant impact. Quality deficiencies appeared in all complete responses and were the predominant barrier, while clinical and labeling issues were less frequent but meaningful when present. Overall, these findings highlight the need for proactive FDA engagement, comprehensive readiness, and early inspection preparation to reduce regulatory risk and improve first cycle approval outcomes.

PMID 42556171
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PubMedTherapeutic advances in medical oncology2026-08-06

Real-world analysis of perioperative strategies for driver gene-positive resectable non-small cell lung cancer.

Wang Xingpeng X, Wang Kaiyue K, Huang Baiyang B, Zhao Jiarui J et al.

The optimal perioperative treatment strategy for driver gene-positive non-small cell lung cancer (NSCLC) remains unclear. To compare the prognostic outcomes of different perioperative strategies for patients with resectable driver gene-positive NSCLC. Multicenter retrospective observational cohort study. We retrospectively evaluated patients with resectable AJCC 8th clinical stage II-IIIB driver gene-positive NSCLC who underwent neoadjuvant therapy or upfront surgery with adjuvant targeted therapy (US + ATT) at two institutions between 2021 and 2023. Treatment was classified as neoadjuvant targeted therapy (NTT), neoadjuvant chemoimmunotherapy (NCIT), neoadjuvant chemotherapy (NCT), or US + ATT. The primary endpoints were event-free survival (EFS) and overall survival (OS). Survival was estimated using the Kaplan-Meier method and compared with the log-rank test. In total, 290 patients were included; the median follow-up was 31.2 months. Compared with NCT, NCIT was associated with longer EFS (p = 0.048) and a nonsignificant favorable OS trend (p = 0.135). NCIT also achieved higher pathological complete response (29.8% vs 4.9%) and major pathological response (MPR; 52.1% vs 16.4%) rates and comparable R0 resection rates (96.8% vs 93.4%). Survival outcomes were comparable between NCIT and NCT for the epidermal growth factor receptor (EGFR)-mutant subgroup, but NTT showed better EFS (p = 0.093), without an OS advantage. NTT + chemotherapy achieved superior EFS (p = 0.038) and favorable OS trend (p = 0.146) versus NCT alone and longer EFS versus NTT alone (p = 0.062). Postoperative ATT did not confer survival advantage over no ATT in the NTT + chemotherapy subgroup. MPR to NCIT correlated with improved EFS (p = 0.001) and OS (p = 0.009), while MPR to NTT correlated with improved EFS (p = 0.049). NCIT was associated with improved EFS in resectable driver gene-positive NSCLC, although a corresponding OS improvement was not observed. NTT + chemotherapy may offer better prognosis than NCT alone in EGFR‑mutant NSCLC.

PMID 42558961
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PubMedFrontiers in immunology2026-08-06

Splenectomy revisited in Wiskott-Aldrich syndrome in the era of HSCT and gene therapy: a bridge, a rescue, or simply obsolete?

Khanafer Youssuf Y, Al-Naemi Ahmad A, Khayyat Layan L, Cyprian Farhan F

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency caused by mutations in the WAS gene, classically presenting with microthrombocytopenia, eczema, and recurrent infections, with an incidence of approximately 1 per 100, 000 live births. At the mechanistic level, deficiency of the WAS protein (WASp) disrupts actin cytoskeleton remodeling across hematopoietic cells, impairing immune synapse formation, T-cell receptor signaling, natural killer cell cytotoxicity, B-cell activation, and dendritic cell migration. Concurrently, these cytoskeletal defects compromise megakaryocyte proplatelet formation, producing structurally fragile platelets that are rapidly cleared by the spleen and further targeted by immune-mediated destruction, culminating in thrombocytopenia. This pathophysiological basis explains the historical use of splenectomy to control life-threatening bleeding in refractory cases, as removal of the spleen reduces platelet sequestration and destruction, leading to reliable increases in platelet counts, often exceeding 150 × 109/L, and improved bleeding outcomes. However, the durability of this response is phenotype-dependent, with sustained benefit more common in X-linked thrombocytopenia and relapse occurring in up to 56% of classical WAS cases within the first year. Despite these hematologic benefits, splenectomy does not correct the underlying immune defect and is limited by a substantial risk of overwhelming infection, necessitating lifelong antibiotic prophylaxis, vaccination, and often immunoglobulin replacement. Consequently, with the advent of hematopoietic stem cell transplantation (HSCT) and gene therapy as curative approaches, the role of splenectomy has markedly declined and is now largely restricted to specific scenarios, including as a bridge to HSCT in severe thrombocytopenia, a rescue option when definitive therapies are inaccessible, and a post-HSCT intervention for persistent thrombocytopenia due to mixed donor chimerism. Nonetheless, global disparities in access to HSCT and gene therapy (driven by donor availability, financial constraints, and health system limitations), preserve a limited but important role for splenectomy in resource-constrained settings, underscoring the need for standardized, evidence-based guidelines to ensure its use only when the anticipated benefits outweigh the risks.

PMID 42558364
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PubMedCytotherapy2026-08-06

A scoping review of gene editing in clinical trials: identifying aspects of trial design to accelerate clinical adoption.

Khare Gabrielle G, Duong An A, Hanotaux Justine J, Shorr Risa R et al.

Initial clinical trials of gene editing have recently emerged and generated significant interest in this promising therapy. A scoping review is needed to understand aspects of study design that may accelerate further clinical translation. A systematic search of published clinical trials was conducted to May 22, 2025. Twenty-nine published trials were identified for analysis (420 patients; median ages 6 months to 90 years). The most common gene editing technology used was CRISPR-Cas9 (23 studies, 79%). Hematopoietic cells were targeted most frequently, and leukemias and lymphomas were the most common clinical indications (8 studies; 27.5%), followed by hemoglobin disorders (6; 20.6%), solid tumors (6; 20.6%), rare genetic diseases (5; 17.2%), and others (4; 13.8%). All trials were early-phase (Phase I/II) with only 1 controlled study (29 patients). Six studies used in vivo approaches while all others performed gene editing ex vivo. Gene transfection was by electroporation (9 studies; 31.0%), viral-mediated transfection (6; 20.7%), or by lipid nanoparticles (3; 10.3%). Commonly reported outcomes included early safety and adverse events, mortality, persistence of edited cells, clinical and functional responses. Studies of leukemia/lymphoma reported rates of complete remission in 15-92% while we identified important and sustained increases in mean hemoglobin levels in studies of hemoglobin disorders. Edited cells were detected in most studies at 3 and 6 months but later timepoints were reported less frequently. While early serious adverse events were infrequently observed, reporting of longer-term outcomes was lacking. Gene editing appears feasible and generally safe in humans although important safety outcomes such as long-term oncogenic surveillance outcomes remain to be addressed. A broad range of conditions have been treated, and most often leverages the CRISPR-Cas9 technology with transfection by electroporation. The persistence of edited cells remains ill-defined and longer-term safety outcomes are needed. Studies optimizing CART therapy for leukemia/lymphoma and treatment of hemoglobin disorders appear poised for significant clinical adoption.

PMID 42556172
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