Current Gene Therapy - Volume 20, Issue 2, 2020

The majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage that can only benefit from systemic treatments. Although HCC is highly treatmentresistant, significant achievements have been made in the molecular targeted therapy and immunotherapy of HCC. In addition to regorafenib, cabozantinib and ramucirumab were approved for the second- line targeted treatment by the FDA after disease progression on sorafenib. Nivolumab failed to demonstrate remarkable benefit in overall survival (OS) as first-line therapy, while pembrolizumab did not achieve pre-specified statistical significance in both OS and progression-free survival (PFS) as second-line treatment. Combinations of targeted agents, immune checkpoint inhibitors and other interventions showed favorable results. In this review, we summarized the progress of systemic therapy in HCC and discussed the future directions of the treatment of HCC.

Neurofibromatosis type 1 [NF1] is an autosomal dominant genetic disorder affecting multiple organs. NF1 is well known for its various clinical manifestations, including café-au-late macules, Lisch nodules, bone deformity and neurofibromas. However, there is no effective therapy for NF1. Current therapies are aimed at alleviating NF1 clinical symptoms but not curing the disease. By altering pathogenic genes, gene therapy regulates cell activities at the nucleotide level. In this review, we described the structure and functions of neurofibromin domains, including GAP-related domain [GRD], cysteine-serine rich domain [CSRD], leucine-rich domain [LRD] and C-terminal domain [CTD], which respectively alter downstream pathways. By transfecting isolated sequences of these domains, researchers can partially restore normal cell functions in neurofibroma cell lines. Furthermore, recombinant transgene sequences may be designed to encode truncated proteins, which is functional and easy to be packaged into viral vectors. In addition, the treatment effect of gene therapy is also determined by various factors such as the vectors selection, transgene packaging strategies and drug administration. We summarized multiple NF1 gene therapy strategies and discussed their feasibility from multiple angles. Different protein domains alter the function and downstream pathways of neurofibromin.

CD24, is a mucin-like GPI-anchored molecules. By immunohistochemistry, it is widely detected in many solid tumors, such as breast cancers, genital system cancers, digestive system cancers, neural system cancers and so on. The functional roles of CD24 are either fulfilled by combination with ligands or participate in signal transduction, which mediate the initiation and progression of neoplasms. However, the character of CD24 remains to be intriguing because there are still opposite voices about the impact of CD24 on tumors. In preclinical studies, CD24 target therapies, including monoclonal antibodies, target silencing by RNA interference and immunotherapy, have shown us brighten futures on the anti-tumor application. Nevertheless, evidences based on clinical studies are urgently needed. Here, with expectancy to spark new ideas, we summarize the relevant studies about CD24 from a tumor perspective.

Suppression of TP53 function is nearly ubiquitous in human cancers, and a significant fraction of cancers have mutations in the TP53 gene itself. Therefore, the wild-type TP53 gene has become an important target gene for transformation research of cancer gene therapy. In 2003, the first anti-tumor gene therapy drug rAd-p53 (recombinant human p53 adenovirus), trade name Gendicine™, was approved by the China Food and Drug Administration (CFDA) for treatment of head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy. The recombinant human TP53 gene is delivered into cancer cells by an adenovirus vector constructed to express the functional p53 protein. Although the only currently approved used of Gendicine is in combination with radiotherapy for treatment of HNSCC, clinical studies have been carried out for more than 20 other applications of Gendicine in treating cancer, including treatment of advanced lung cancer, advanced liver cancer, malignant gynecological tumors, and soft tissue sarcomas. Currently more than 30,000 patients have been treated with Gendicine. This review provides an overview of the clinical applications of Gendicine in China. We summarize a total of 48 studies with 2,561 patients with solid tumors, including 34 controlled clinical studies and 14 open clinical studies, i.e., clinical studies without a control group. There are 11 studies for head and neck cancer, 10 for liver cancer, 6 for malignant gynecological tumors, 4 for non-small cell lung cancer, 4 for soft tissue sarcoma, 4 for malignant effusion, 2 for gastrointestinal tumors, and 7 for other types of cancer. In all the reported clinical studies, the most common side effect was self-limited fever. Intratumoral injection and intra-arterial infusion were the most common routes of administration. Overall, Gendicine combined with chemotherapy, radiotherapy, or other conventional treatment regimens demonstrated significantly higher response rates compared to standard therapies alone. Some of the published studies also showed that Gendicine combination regimens demonstrated longer progression-free survival times than conventional treatments alone. To date, Gendicine has been clinically used in China for treatment of cancers other than HNSCC for more than ten years, mainly for patients with advanced or unresectable malignant tumors. However, the establishment of standard treatment regimens using TP53 gene therapy is still needed in order to advance its use in clinical practice.

Hemophilia A (HA) is a hereditary hemorrhagic disease caused by a deficiency of coagulation factor VIII (FVIII) in blood plasma. Patients with HA usually suffer from spontaneous and recurrent bleeding in joints and muscles, or even intracerebral hemorrhage, which might lead to disability or death. Although the disease is currently manageable via delivery of plasma-derived or recombinant FVIII, this approach is costly, and neutralizing antibodies may be generated in a large portion of patients, which render the regimens ineffective and inaccessible. Given the monogenic nature of HA and that a slight increase in FVIII can remarkably alleviate the phenotypes, HA has been considered to be a suitable target disease for gene therapy. Consequently, the introduction of a functional F8 gene copy into the appropriate target cells via viral or nonviral delivery vectors, including gene correction through genome editing approaches, could ultimately provide an effective therapeutic method for HA patients. In this review, we discuss the recent progress of gene therapy for HA with viral and nonviral delivery vectors, including piggyBac, lentiviral and adeno-associated viral vectors, as well as new raising issues involving liver toxicity, pre-existing neutralizing antibodies of viral approach, and the selection of the target cell type for nonviral delivery.

Background: Osteoporosis is the most common metabolic bone disease. There is still an unmet need for novel therapeutic agents that could be beneficial as osteoporosis treatments. It has been reported that the neurotransmitter γ-aminobutyric acid (GABA) might be associated with human bone formation. However, the precise mechanism remains unclear. Objective: To investigate the effect of GABA on bone metabolism and explore the possible role of TNFAIP3 in this process. Methods: GABA had little effect on the proliferation of human mesenchymal stem cells (hMSCs) and RAW 264.7 cells, as indicated by the cell counting kit-8 (CCK-8) assay. The results showed that GABA enhanced the intensity of ALP staining, ALP activity, and accumulation of Ca2+ mineralized nodules in hMSCs during osteogenic induction. Results: The qRT-PCR results indicated that GABA treatment significantly increased the mRNA expression of osteogenic genes in hMSCs. In RAW 264.7 cells, TRAP staining showed that GABA did not alter the number or size of osteoclasts or the expression of osteoclastic genes, which suggests that GABA does not affect osteoclastic differentiation. Mechanistically, GABA treatment significantly induced the sustained expression of TNFAIP3. Furthermore, by knocking down TNFAIP3, the osteogenic effect of GABA was antagonized, which suggests that TNFAIP3 mediates the effects of GABA in hMSCs. Conclusion: Our results suggested that GABA treatment positively regulated osteogenic differentiation by upregulating TNFAIP3, while no obvious effect on osteoclastic differentiation was detected. Therefore, our results provide a potential gene therapy for the treatment of osteoporosis and low bone mineral density.