Peripheral neuron phenotypes of familial dysautonomia are rescued by AAV-mediated gene therapy.

Immune responses in the mammalian inner ear and their implications for AAV-mediated inner ear gene therapy

Gene therapy for hemophilia: a step closer to reality.

Gene Therapy Strategies to Restore ER Proteostasis in Disease.

Rare pediatric neurogenetic diseases always have early onset, no specific therapy, high mortality, and pose a severe risk to the health and survival of children. Adeno-associated virus (AAV)-mediated gene therapy, a type of disease-modifying therapy, provides a new option for the treatment of rare pediatric neurogenetic diseases and represents a significant advancement in the field. Currently, the US Food and Drug Administration (FDA) and the European Medicines Association (EMA) have approved AAV-mediated gene therapy medications for treating spinal muscular atrophy, aromatic L-amino acid decarboxylase deficiency, and Duchenne muscular dystrophy. Numerous preclinical and clinical trial research findings from recent years indicate that AAV-mediated gene therapy has a promising future in treating genetic disorders. The quick approval process for rare diseases medications may bring hope for the treatment of children with rare neurogenetic diseases. AAV-mediated gene therapy is an emerging technology with certain risks and challenges. It is necessary to establish a standardized regulatory system and a sound long-term follow-up system to evaluate the efficacy and safety of gene therapy.

Familial dysautonomia (FD) is a rare genetic, neurodevelopmental and neurodegenerative disorder, where a homozygous mutation in the ELP1 gene is responsible for defects and symptoms found in 99% of patients (1). FD symptoms mainly affect the peripheral nervous system (PNS) (2), including the autonomic and sensory nervous systems (ANS, SNS) (3). The ANS regulates unconscious physiological responses and maintains body homeostasis, such as heart rate, blood pressure, gland secretion, and breathing, which are vital for bodily function. The SNS is the key mediator that processes and relays sensory information from the internal and external environment to the brain, including limb position, temperature, and pain.

Emerging therapeutic potential of adeno-associated virus-mediated gene therapy in liver fibrosis

Significant progress in understanding the molecular basis of retinal disorders has led to the development of gene therapies for treatment of these diseases. Adeno-associated virus (AAV) is a useful vector for the treatment of retinal diseases due to its low toxicity and immunogenicity, ability to transducer both dividing and non-dividing cells, and stable transgene expression. A variety of animal studies and clinical trials have proved the safety and effectivity of retinal AAV-mediated gene therapy. AAV-mediated gene therapy, such as anti-angiogenic proteins, neurotrophic factors, anti-apoptosis factors were studied in animal disease models, and the results were satisfactory. However, the main drawback of AAV vectors is its relatively small packaging capacity, which needs further improvement.

Gene therapy has revolutionized the field of medicine, offering new hope for those with common and rare diseases. For nearly three decades, adeno-associated virus (AAV) has shown significant therapeutic benefits in multiple clinical trials, mainly due to its unique replication defects and non-pathogenicity in humans. In the field of cardiovascular disease (CVD), compared with non-viral vectors, lentiviruses, poxviruses, and adenovirus vectors, AAV possesses several advantages, including high security, low immunogenicity, sustainable and stable exogenous gene expression etc., which makes AAV one of the most promising candidates for the treatment of many genetic disorders and hereditary diseases. In this review, we evaluate the current information on the immune responses, transport pathways, and mechanisms of action associated with AAV-based CVD gene therapies and further explore potential optimization strategies to improve the efficiency of AAV transduction for the improved safety and efficiency of CVD treatment. In conclusion, AAV-mediated gene therapy has great potential for development in the cardiovascular system.

Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited neurodegenerative lysosomal storage disease (LSD) caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1). Studies in Ppt1(-/-) mice demonstrate that glial activation is central to the pathogenesis of INCL. Astrocyte activation precedes neuronal loss, while cytokine upregulation associated with microglial reactivity occurs before and concurrent with neurodegeneration. Therefore, we hypothesized that cytokine cascades associated with neuroinflammation are important therapeutic targets for the treatment of INCL. MW01-2-151SRM (MW151) is a blood-brain barrier penetrant, small-molecule anti-neuroinflammatory that attenuates glial cytokine upregulation in models of neuroinflammation such as traumatic brain injury, Alzheimer's disease, and kainic acid toxicity. Thus, we used MW151, alone and in combination with CNS-directed, AAV-mediated gene therapy, as a possible treatment for INCL. MW151 alone decreased seizure susceptibility. When combined with AAV-mediated gene therapy, treated INCL mice had increased life spans, improved motor performance, and eradication of seizures. Combination-treated INCL mice also had decreased brain atrophy, astrocytosis, and microglial activation, as well as intermediary effects on cytokine upregulation. These data suggest that MW151 can attenuate seizure susceptibility but is most effective when used in conjunction with a therapy that targets the primary genetic defect.

Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (ELP1) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical foundational data for translation to FD patients.

NG.I.4 - AAV-mediated gene therapy in central nervous system of dystrophin-Dp71 deficient mouse

Mitigation of cerebellar neuropathy in globoid cell leukodystrophy mice by AAV-mediated gene therapy

New approaches to gene and cell therapy for hemophilia

Gene therapy is an opportunity for haemophilia patients to receive a one-time treatment and have lasting factor levels for years or decades instead of dependence on repeated administration within short intervals and on sustained supply of drug. Great strides have been made in the development of gene therapy for haemophilia in the last decade. Adeno-associated virus (AAV) vector-mediated gene transfer in haemophilia A and B has entered the phase III trial stage. Gene transfer by lentiviral vector or gene editing technologies using factor VIII (FVIII) or IX (FIX) genes are now entering clinical evaluation. It is expected that the first FVIII and FIX gene therapy products will soon be approved and distributed in major markets. Global access to gene therapy is a critical goal. This review presents new and ongoing efforts towards this goal in countries other than North America and Europe. In Japan, researchers, regulators and funders have established a promising gene therapy development platform for multiple diseases including haemophilia. Decades of scientific and clinical research in haemophilia gene therapy in China have led to a recently registered clinical trial of AAV-mediated gene therapy for haemophilia B. Other countries are in earlier phases of building gene therapy programmes or participate in international trials. A phase 2 feasibility trial of AAV-mediated FIX gene therapy in low- and middle-income countries aims to demonstrate that gene therapy could become available in resource-constrained socio-economic settings. The different strategies for establishing gene therapy provide opportunities for closing the global gap in haemophilia care.

Background and ObjectiveThe adeno-associated virus (AAV) is a member of the Parvoviridae family and has emerged as one of the most popular and promising approaches for gene therapy due to its low toxicity, low immunogenicity, and excellent safety after optimization. Advances in gene therapy methods have allowed novel treatments such as using AAV to knock out or repair target genes. AAV-mediated gene therapy has been used in numerous tumor studies, including lymphatic metastasis of prostate cancer, liver cancer, and renal cell carcinoma in mice. Ovarian cancer is an extremely aggressive malignancy which is prone to recurrence, and AAV vector-based gene therapy may be a potential treatment strategy.MethodsHerein, we reviewed the current research to provide an update on the role of AAV-mediated gene therapy in tumor research, especially in ovarian cancer. To find recent developments in pertinent research, we examined the PubMed database.Key Content and FindingsAAV vectors may produce steady and effective gene expression without becoming harmful, making it a viable gene delivery technique. AAV-based gene therapy products have been widely used in preclinical research and some have achieved marketing approval.ConclusionsDue to its affinity for various organs, reliable integration, and long-lasting expression, certain AAV serotypes have been widely used in gene therapy. However, there are also some challenges. Extensive research on the role of AAV in disease and gene therapy has shown great potential. Herein, we examined the literature to better understand the function of the AAV in tumor research, particularly in ovarian cancer research.