Current Gene Therapy - Current Issue

Tumor cells achieve their adaptability through various metabolic reprogramming processes. Among them, ammonia, as a traditional metabolic waste, plays an increasingly important role in the tumor microenvironment along with its associated metabolites. Other cells in the microenvironment can also reshape the immune status of the microenvironment by regulating ammonia-related metabolism, and targeting this metabolic aspect has emerged as a potential strategy for tumor treatment.

In this study, we have systematically reviewed the source and destination of ammonia in tumor cells, as well as the links between ammonia and other biological processes. We have also analyzed the ammonia-related metabolic regulation of other cells (including T cells, macrophages, dendritic cells, natural killer cells, myeloid-derived suppressor cells, and stromal cells) in the tumor microenvironment, and summarized the tumor treatment methods that target this metabolism.

Through ammonia-related metabolic reprogramming, tumor cells obtain the energy they need for rapid growth and proliferation. Multiple immune cells and stromal cells in the microenvironment also interact with each other through this metabolic regulation, ultimately leading to immune suppression. Despite the heterogeneity of tumors and the complexity of cellular functions, further research into therapeutic interventions targeting ammonia-related metabolism is warranted.

This review has focused on the role and regulation of ammonia-related metabolism in tumor cells and other cells in the microenvironment, and highlighted the efficacy and prospects of targeted ammonia-related metabolism therapy.

An analysis of mammalian genomes has revealed a significant number of DNA sequences with transposon or viral origin. Some of these elements encode functional proteins, repurposed during evolution to play significant physiological roles in certain tissues. Some human virus-like proteins, such as Peg10 and Arc/Arg3.1, structurally demonstrate significant similarity with Gag retroviral proteins, while others, like syncytins-1 and -2, resemble envelope viral proteins. In recent years, it has become clear that these proteins can be exploited for bioengineering 'humanized' capsid particles aimed at targeted mRNA delivery. Realizing this idea could provide efficient virus-like particles for gene therapy and address the problem of viral vector immunogenicity. This review provides an overview of the most-studied human proteins of viral or transposon origin and highlights their biological functions. Additionally, recent advances in exploiting these proteins for targeted mRNA delivery and prospects for their clinical application are discussed.

Developing delivery vectors capable of transducing genetic material across the lung epithelia and mucus barrier is a major challenge and of great interest to enable gene therapies to treat pulmonary diseases. Recombinant Adeno-associated Viruses (rAAVs) have emerged as attractive candidates among viral and non-viral vectors due to their broad tissue tropism, ability to transduce dividing and quiescent cells, and their safety profile in current human applications. While rAAVs have demonstrated safety in earlier clinical trials for lung disease applications, there are still some limitations regarding rAAV-transgene delivery in pulmonary cells. Thus, further improvements in rAAV engineering are needed to enhance the effectiveness of rAAV-based therapies for lung diseases. Such therapies could benefit patients with chronic lung diseases, such as asthma, chronic obstructive pulmonary disease, pulmonary hypertension, and cystic fibrosis, among others, by regulating hereditary gene mutations or acquired gene deregulations causing these conditions. Alongside therapeutic development, advances in the rAAV production process are essential to meet increasing production demands, while reducing manufacturing costs. This review discusses current challenges and recent advances in the field of rAAV engineering and manufacturing to encourage the clinical development of new pulmonary gene therapy treatments.

Obsessive-Compulsive Disorder (OCD), a prevalent neuropsychiatric condition, affects approximately 2%-3% of the global population. This paper provides an extensive overview of OCD, detailing its clinical manifestations, neurobiological underpinnings, and therapeutic approaches. It examines OCD's classification shift in the DSM-5, the role of the cortico-striato-thalamo-cortical pathway in its development, and the various factors contributing to its etiology, such as genes, environmental factors, and genetic predispositions. The challenges in diagnosing OCD and the effectiveness of both psychological and pharmacotherapeutic treatments are discussed. The paper also highlights the significant overlap between OCD and other mental health disorders, emphasizing its impact on global disability. Moreover, the role of genetic factors in OCD, including twin studies and gene association studies, is elaborated, underscoring the complex interplay of hereditary and environmental influences in its manifestation. The review further delves into the polygenic nature of OCD, illustrating how multiple genes contribute to its development, and explores the implications of genetic studies in understanding the disorder's complexity. Additionally, this research study delves into the concept of polygenic inheritance in complex diseases, highlighting the role of multiple genes in increasing OCD risk. A Genome-wide Association Study (GWAS) is employed to assess Single Nucleotide Polymorphisms (SNPs) to unearth genetic associations with OCD. This comprehensive analysis provides valuable insights into OCD's genetic landscape, paving the way for enhanced diagnostic approaches and treatment modalities.