Current Gene Therapy - Volume 23, Issue 2, 2023

Hemophilia A, a single gene disorder leading to deficient Factor VIII (FVIII), is a suitable candidate for gene therapy. The aspiration is for single administration of a genetic therapy that would allow the production of endogenous FVIII sufficient to restore hemostasis and other biological processes. This would potentially result in reliable protection from bleeding and its associated physical and emotional impacts. Gene therapy offers the possibility of a clinically relevant improvement in disease phenotype and transformational improvement in quality of life, including an opportunity to engage in physical activities more confidently. Gene therapy products for hemophilia A in advanced clinical development use adeno-associated viral (AAV) vectors and a codon-optimized B-domain deleted FVIII transgene. However, the different AAV-based gene therapies have distinct design features, such as choice of vector capsid, enhancer and promoter regions, FVIII transgene sequence and manufacturing processes. These, in turn, impact patient eligibility, safety and efficacy. Ideally, gene therapy technology for hemophilia A should offer bleed protection, durable FVIII expression, broad eligibility and limited response variability between patients, and long-term safety. However, several limitations and challenges must be overcome. Here, we introduce the characteristics of the BAY 2599023 (AAVhu37.hFVIIIco, DTX 201) gene therapy product, including the low prevalence in the general population of anti-AAV-hu37 antibodies, as well as other gene therapy AAV products and approaches. We will examine how these can potentially meet the challenges of gene therapy, with the ultimate aim of improving the lives of patients with hemophilia A.

Chronic hyperglycemia damages the nerves and blood vessels, culminating in other vascular complications. Such complications enhance cytokine, oxidative and endoplasmic reticulum (ER) stress. ER is the primary organelle where proteins are synthesised and attains confirmatory changes before its site of destination. Perturbation of ER homeostasis activates signaling sensors within its lumen, the unfolded protein response (UPR) that orchestrates ER stress and is extensively studied. Increased ER stress markers are reported in diabetic complications in addition to lncRNA that acts as an upstream marker inducing ER stress response. This review focuses on the mechanisms of lncRNA that regulate ER stress markers, especially during the progression of diabetic complications. Through this systemic review, we showcase the dysfunctional lncRNAs that act as a leading cause of ER stress response to the progression of diabetic complications.

Viral vectors have been proven useful in a broad spectrum of gene therapy applications due to their possibility to accommodate foreign genetic material for both local and systemic delivery. The wide range of viral vectors has enabled gene therapy applications for both acute and chronic diseases. Cancer gene therapy has been addressed by the delivery of viral vectors expressing anti-tumor, toxic, and suicide genes for the destruction of tumors. Delivery of immunostimulatory genes such as cytokines and chemokines has also been applied for cancer therapy. Moreover, oncolytic viruses specifically replicating in and killing tumor cells have been used as such for tumor eradication or in combination with tumor killing or immunostimulatory genes. In a broad meaning, vaccines against infectious diseases and various cancers can be considered gene therapy, which has been highly successful, not the least for the development of effective COVID-19 vaccines. Viral vector-based gene therapy has also demonstrated encouraging and promising results for chronic diseases such as severe combined immunodeficiency (SCID), muscular dystrophy, and hemophilia. Preclinical gene therapy studies in animal models have demonstrated proof-of-concept for a wide range of disease indications. Clinical evaluation of drugs and vaccines in humans has showed high safety levels, good tolerance, and therapeutic efficacy. Several gene therapy drugs such as the adenovirus-based drug Gendicine® for non-small-cell lung cancer, the reovirus-based drug Reolysin® for ovarian cancer, lentivirus-based treatment of SCID-X1 disease, and the rhabdovirus-based vaccine Ervebo against Ebola virus disease, and adenovirus-based vaccines against COVID-19 have been developed.

Gene therapy has proven to be extremely beneficial in the management of a wide range of genetic disorders for which there are currently no or few effective treatments. Gene transfer vectors are very significant in the field of gene therapy. It is possible to attach a non-viral attachment vector to the donor cell chromosome instead of integrating it, eliminating the negative consequences of both viral and integrated vectors. It is a safe and optimal express vector for gene therapy because it does not cause any adverse effects. However, the modest cloning rate, low expression, and low clone number make it unsuitable for use in gene therapy. Since the first generation of non-viral attachment episomal vectors was constructed, various steps have been taken to regulate their expression and stability, such as truncating the MAR element, lowering the amount of CpG motifs, choosing appropriate promoters and utilizing regulatory elements. This increases the transfection effectiveness of the non-viral attachment vector while also causing it to express at a high level and maintain a high level of stability. A vector is a genetic construct commonly employed in gene therapy to treat various systemic disorders. This article examines the progress made in the development of various optimization tactics for nonviral attachment vectors and the future applications of these vectors in gene therapy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to death by progressive paralysis and respiratory failure within 2-4 years of onset. About 90-95% of ALS cases are sporadic (sALS), and 5-10% are inherited through family (fALS). Though the mechanisms of the disease are still poorly understood, so far, approximately 40 genes have been reported as ALS causative genes. The mutations in some crucial genes, like SOD1, C9ORF72, FUS, and TDP-43, are majorly associated with ALS, resulting in ROS-associated oxidative stress, excitotoxicity, protein aggregation, altered RNA processing, axonal and vesicular trafficking dysregulation, and mitochondrial dysfunction. Recent studies show that dysfunctional cellular pathways get restored as a result of the repair of a single pathway in ALS. In this review article, our aim is to identify putative targets for therapeutic development and the importance of a single suppressor to reduce multiple symptoms by focusing on important mutations and the phenotypic suppressors of dysfunctional cellular pathways in crucial genes as reported by other studies.