Editorial: "Auditory and vestibular science: challenges and progress in gene therapy for hearing loss".

Hearing loss is a global health concern affecting hundreds of millions of individuals, with current interventions like hearing aids and cochlear implants offering only functional improvements rather than addressing the root causes. Gene therapy holds promise for restoring hearing by correcting underlying molecular defects, but its success hinges on the safe and effective delivery of therapeutic genes to the delicate cells of the cochlea. Nanotechnology has emerged as a transformative solution, providing non-viral carriers such as nanoparticles that can protect genetic material, target specific inner ear cells, and promote regeneration with minimal invasiveness. This review explores the integration of nanotechnology with gene therapy for hearing loss from three perspectives: (1) the biological mechanisms underlying hearing loss and gene therapy, (2) technological innovations in nanoparticle design and delivery systems, and (3) clinical applications and challenges. By examining recent advancements and preclinical studies, this review highlights the potential of nanotechnology-enhanced gene therapy to revolutionize the treatment of hearing loss while addressing key barriers to clinical translation.

Editorial: Gene therapy for hearing loss: from mechanism to clinic.

Gene Therapy for Hearing Loss on the Horizon

CHAPTER 15 - Cancer gene therapies progress in pre and postgenomics era

Gene therapy is the use of genetic material for therapeutic purposes. It is still mostly an investigational treatment that involves the introduction of recombinant nucleic acids into an individual’s cells to prevent, cure or alleviate disease. From the beginning, gene therapy had a rocky course, but due to breakthrough successes during the last few years, gene therapy is now on its way to progressing from an exploratory therapy to an approved treatment. Most commonly, DNA is introduced into cells or tissues by means of the socalled “vectors”. From the very early beginnings of gene therapy until now, the choice of vector was and still remains one of the most crucial points to consider when planning a gene therapy treatment. To date, viruses that are genetically modified to be safe for the patient are the most frequently used type of vector in gene therapy clinical trials worldwide. Once the genetic material has successfully been introduced into the target cell, the cellular machinery is used to express the transferred gene and to produce the encoded protein and consequently cure or alleviate the patient’s disease. Due to major scientific advances during the last decades and the progress of gene therapy from the bench to the bedside, three critical aspects have emerged for all gene transfer approaches which are also fundamental to further develop this novel and highly sophisticated therapy1,2:

Background: Current gene-based strategies for treatment of erectile dysfunction (ED) are based on the nitric oxide (NO)/cGMP system; although growth factors, calcium sensitization, and potassium channel expression have been studied. Initial investigations of stem-cell-based therapy have attracted attention. Results of the first gene transfer clinical trial for treatment of ED with maxi-K channels are positive. Moreover, there is progress in gene and stem-cell therapy for the treatment of cardiovascular (CV) diseases. Objective: To improve understanding of gene and stem-cell therapy for CV disease, with emphasis on ED. Methods: Review of current literature. Results/conclusion: Treatment and prevention of ED can be improved by the application of CVD gene/cell-based therapy. New discoveries based on gene- and cell-based therapy will lead to new advances in the treatment of ED.

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated enzyme-CAS holds great promise for treating many uncured human diseases and illnesses by precisely correcting harmful point mutations and disrupting disease-causing genes. The recent Food and Drug Association (FDA) approval of the first CRISPR-based gene therapy for sickle cell anemia marks the beginning of a new era in gene editing. However, delivering CRISPR specifically into diseased cells in vivo is a significant challenge and an area of intense research. The identification of new CRISPR/Cas variants, particularly ultra-compact CAS systems with robust gene editing activities, paves the way for the low-capacity delivery vectors to be used in gene therapies. CRISPR/Cas technology has evolved beyond editing DNA to cover a wide spectrum of functionalities, including RNA targeting, disease diagnosis, transcriptional/epigenetic regulation, chromatin imaging, high-throughput screening, and new disease modeling. CRISPR/Cas can be used to engineer B-cells to produce potent antibodies for more effective vaccines and enhance CAR T-cells for the more precise and efficient targeting of tumor cells. However, CRISPR/Cas technology has challenges, including off-target effects, toxicity, immune responses, and inadequate tissue-specific delivery. Overcoming these challenges necessitates the development of a more effective and specific CRISPR/Cas delivery system. This entails strategically utilizing specific gRNAs in conjunction with robust CRISPR/Cas variants to mitigate off-target effects. This review seeks to delve into the intricacies of the CRISPR/Cas mechanism, explore progress in gene therapies, evaluate gene delivery systems, highlight limitations, outline necessary precautions, and scrutinize the ethical considerations associated with its application.

Neuromuscular diseases (NMDs) are a group of rare disorders characterized by significant genetic and clinical complexity. Advances in genomics have revolutionized both the diagnosis and treatment of NMDs. While fewer than 30 NMDs had known genetic causes before the 1990s, more than 600 have now been identified, largely due to the adoption of next-generation sequencing (NGS) technologies such as whole-exome sequencing (WES) and whole-genome sequencing (WGS). These technologies have enabled more precise and earlier diagnoses, although the genetic complexity of many NMDs continues to pose challenges. Gene therapy has been a transformative breakthrough in the treatment of NMDs. In spinal muscular atrophy (SMA), therapies like nusinersen, onasemnogene abeparvovec, and risdiplam have dramatically improved patient outcomes. Similarly, Duchenne muscular dystrophy (DMD) has seen significant progress, most notably with the FDA approval of delandistrogene moxeparvovec, the first micro-dystrophin gene therapy. Despite these advancements, challenges remain, including the rarity of many NMDs, genetic heterogeneity, and the high costs associated with genomic technologies and therapies. Continued progress in gene therapy, RNA-based therapeutics, and personalized medicine holds promise for further breakthroughs in the management of these debilitating diseases.

Coronary artery bypass grafting(CABG) is a safe and highly effective method for treatment of ischemic heart disease. The autologous saphenous vein grafts are the most common types of conduits used in CABG. But the restenosis of vein grafts which result from thrombosis, neointimal hyperplasia and atherosclerosis has severely affected the venous grafts patency, and effective pharmacological interventions for vein grafts failure have not emerged. The advances in molecular biology offers novel approaches for the management of vein graft restenosis, and gene therapy is the hot spot currently. This article reviews the progress in gene therapy for vein grafts restenosis, regarding therapeutic target gene, methods of gene delivery and gene vector. Key words: Coronary artery bypass graft; Vein graft; Restenosis; Gene vector

The rapid progress in gene therapy has expanded our ability to alter genetic structure, necessitating the development of methods for detecting the activity of new vectors. The central concept of a reporter gene is simple: it is a defined nucleotide sequence, which when introduced into a biological system, yields a readily measurable phenotype on expression. This provides a convenient parameter that is correlated to the molecular events associated with genetic expression. In this study we demonstrate that Pseudomonas exotoxin A (PE) can serve as a sensitive reporter gene to detect gene expression in single cells of mouse lung on cationic liposome delivery of PE-encoding DNA in vivo. Furthermore, we show that PE expression can be detected as early as 2 hr after systemic gene delivery in lungs of recipient mice. We compared PE with the widely used beta-galactosidase gene for this purpose. PE induces apoptosis that can be detected by TdT end labeling of DNA fragments (TUNEL assay) Since few expressed PE molecules are necessary to trigger the apoptosis cascade, the minimal amount of PE-encoding plasmid DNA needed for detection of apoptotic cells after systemic delivery was 0.1 microg per animal compared with at least 1 microg for the beta-galactosidase-encoding plasmid DNA. The maximum number of apoptotic cells detected in lungs was about 15-20 times higher than the maximum number of beta-galactosidase-positive cells. Specificity of apoptosis due to PE expression on delivery of the PE-encoding plasmid was shown by prevention of the apoptotic cascade by the caspase inhibitor Z-VAD-fmk.

Epidermolysis bullosa (EB) is the overarching term for a set of rare inherited skin fragility disorders that result from mutations in at least 20 different genes. Currently, there is no cure for any of the EB subtypes associated with various mutations. Existing therapies primarily focus on alleviating pain and promoting early wound healing to prevent potential complications. Consequently, there is an urgent need for innovative therapeutic approaches. The objective of this research was to assess the efficacy of various topical treatments in patients with EB with the goal of achieving wound healing. A secondary objective was to analyse the efficacy of topical treatments for symptom reduction. A literature search was conducted using scientific databases, including The Cochrane Library, Medline (Pubmed), Web of Science, CINHAL, Embase, and Scopus. The protocol review was registered in PROSPERO (ID: 418790), and inclusion and exclusion criteria were applied, resulting in the selection of 23 articles. Enhanced healing times were observed compared with the control group. No conclusive data have been observed on pain management, infection, pruritus episodes, and cure rates over time. Additionally, evidence indicates significant progress in gene therapies (B-VEC), as well as cell and protein therapies. The dressing group, Oleogel S-10, allantoin and diacerein 1%, were the most represented, followed by fibroblast utilisation. In addition, emerging treatments that improve the patient’s innate immunity, such as calcipotriol, are gaining attention. However, more trials are needed to reduce the prevalence of blistering and improve the quality of life of individuals with epidermolysis bullosa.

This book is a completely revised new edition of the definitive reference on disorders of hemoglobin. Authored by world-renowned experts, the book focuses on basic science aspects and clinical features of hemoglobinopathies, covering diagnosis, treatment, and future applications of current research. While the second edition continues to address the important molecular, cellular, and genetic components, coverage of clinical issues has been significantly expanded, and there is more practical emphasis on diagnosis and management throughout. The book opens with a review of the scientific underpinnings. Pathophysiology of common hemoglobin disorders is discussed next in an entirely new section devoted to vascular biology, the erythrocyte membrane, nitric oxide biology, and hemolysis. Four sections deal with α and β thalassemia, sickle cell disease, and related conditions, followed by special topics. The second edition concludes with current and developing approaches to treatment, incorporating new agents for iron chelation, methods to induce fetal hemoglobin production, novel treatment approaches, stem cell transplantation, and progress in gene therapy.

Asthma is a complex and chronic inflammatory condition that continues to pose major challenges in clinical practice due to its varied symptoms and inconsistent responses to standard treatments. In recent years, advances in novel drug delivery systems have opened up new possibilities for emerging more targeted, effective, and patient-compliant therapies. While traditional treatments such as inhaled corticosteroids and long-acting beta agonists remain the backbone of asthma management, their limitations have spurred the development of innovative delivery methods and new therapeutic targets. Biologic therapies, particularly monoclonal antibodies, have emerged as promising options for patients with severe asthma, offering greater precision and fewer systemic side effects. Liposome-based drug delivery, polymer-based drug delivery, dendrimer-based drug delivery, and noisome-based drug delivery have shown significant potential by enhancing drug stability, improving bioavailability, and enabling targeted delivery to the lungs. Additionally, this review article also covers the use of small molecule inhibitors, including those targeting Janus kinase, tyrosine kinase, and phosphodiesterase pathways, which are being explored for difficult-to-treat asthma cases. This review also delves into the latest progress in gene therapy and RNA-based treatments, as well as discusses about clinical trials and their outcomes. These novel approaches highlight a shift towards more personalised and effective asthma care, with the potential to significantly improve patient outcomes.

In recent years, with the development of gene editing technology, the site-specific genome can be modified. The curability of genetic disease may be achieved by the use of gene editing techniques. As the simplicity, high specificity and economical efficiency, much attention has been paid to the CRISPR/Cas9 system, which was been widely used in research of molecular biology and other fields of life science. In this review, the mechanism for CR1SPR/Cas9 system and the progress of gene therapy, such as for hemophilia, betathalassaemia and chronic myeloid leukemia were summarized briefly.

The concept and application of ethical principles in the context of medical research is changing rapidly. This is especially true for fast moving fields such as gene therapy, a relatively new but rapidly maturing field offering opportunities to influence health at a fundamental level, which may become a cornerstone of medicine. By 2004, over 700 gene therapy clinical protocols had been initiated worldwide, and two highly publicized gene therapy-related side effects have helped to shape recent ethical debate. These events have influenced not only clinical trial design but also public opinion and systems of independent oversight. Both the science of gene therapy and the regulatory environment are continually evolving. How well the field is able to respond to these challenges will determine the extent to which gene therapy will ultimately be integrated into medical practice.