Current Issue : October-December Volume : 2024 Issue Number : 4 Articles : 5 Articles
Chronic pain is common in our population, and most of these patients are inadequately treated, making the development of safer analgesics a high priority. Knee osteoarthritis (OA) is a primary cause of chronic pain and disability worldwide, and lower extremity OA is a major contributor to loss of qualityadjusted life-years. In this study we tested the hypothesis that a novel JDNI8 replication-defective herpes simplex-1 viral vector (rdHSV) incorporating a modified carbonic anhydrase-8 transgene (CA8*) produces analgesia and treats monoiodoacetate-induced (MIA) chronic knee pain due to OA. We observed transduction of lumbar DRG sensory neurons with these viral constructs (vHCA8*) (~40% of advillin-positive cells and ~ 50% of TrkA-positive cells colocalized with V5-positive cells) using the intra-articular (IA) knee joint (KJ) route of administration. vHCA8* inhibited chronic mechanical OA knee pain induced by MIA was dose- and time-dependent. Mechanical thresholds returned to Baseline by D17 after IA KJ vHCA8* treatment, and exceeded Baseline (analgesia) through D65, whereas negative controls failed to reach Baseline responses. Weightbearing and automated voluntary wheel running were improved by vHCA8*, but not negative controls. Kv7 voltage-gated potassium channel-specific inhibitor XE-991 reversed vHCA8*-induced analgesia. Using IHC, IA KJ of vHCA8* activated DRG Kv7 channels via dephosphorylation, but negative controls failed to impact Kv7 channels. XE-991 stimulated Kv7.2–7.5 and Kv7.3 phosphorylation using western blotting of differentiated SH-SY5Y cells, which was inhibited by vHCA8* but not by negative controls. The observed prolonged dose-dependent therapeutic effects of IA KJ administration of vHCA8* on MIA-induced chronic KJ pain due to OA is consistent with the specific activation of Kv7 channels in small DRG sensory neurons. Together, these data demonstrate for the first-time local IA KJ administration of vHCA8* produces opioid-independent analgesia in this MIA-induced OA chronic pain model, supporting further therapeutic development....
Alport syndrome is a hereditary disease caused by mutations in the genes encoding the alpha 3, alpha 4, and alpha 5 chains of type IV collagen. It is characterized by hematuria, proteinuria, progressive renal dysfunction, hearing loss, and ocular abnormalities. The main network of type IV collagen in the glomerular basement membrane is composed of α3α4α5 heterotrimer. Mutations in these genes can lead to the replacement of this network by an immature network composed of the α1α1α2 heterotrimer. Unfortunately, this immature network is unable to provide normal physical support, resulting in hematuria, proteinuria, and progressive renal dysfunction. Current treatment options for Alport syndrome include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which aim to alleviate glomerular filtration pressure, reduce renal injury, and delay the progression of renal dysfunction. However, the effectiveness of these treatments is limited, highlighting the need for novel therapeutic strategies and medications to improve patient outcomes. Gene therapy, which involves the use of genetic material to prevent or treat diseases, holds promise for the treatment of Alport syndrome. This approach may involve the insertion or deletion of whole genes or gene fragments to restore or disrupt gene function or the editing of endogenous genes to correct genetic mutations and restore functional protein synthesis. Recombinant adeno-associated virus (rAAV) vectors have shown significant progress in kidney gene therapy, with several gene therapy drugs based on these vectors reaching clinical application. Despite the challenges posed by the structural characteristics of the kidney, the development of kidney gene therapy using rAAV vectors is making continuous progress. This article provides a review of the current achievements in gene therapy for Alport syndrome and discusses future research directions in this field....
Right dominant arrhythmogenic cardiomyopathy, commonly known as Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), represents a formidable challenge in cardiovascular medicine, as conventional therapies are commonly ineffective in impeding disease progression and the development of end-stage heart failure. Recombinant adeno-associated virus (AAV)-mediated gene therapy presents a promising avenue for targeted therapeutic interventions, potentially revolutionising treatment approaches for ARVC patients. Encouraging results from preclinical studies have sparked optimism about the possibility of curing specific subtypes of ARVC in the near future. This narrative review delves into the dynamic landscape of genetic therapy for ARVC, elucidating its underlying mechanisms and developmental stages, and providing updates on forthcoming trials. Additionally, it examines the hurdles and complexities impeding the successful translation of ARVC genetic therapies into clinical practice. Despite notable scientific advancements, the journey towards implementing genetic therapies for ARVC patients in real-world clinical settings is still in its early phases....
Background: We performed gene therapy for critical limb ischemia in thromboangiitis obliterans (TAO) by the intramuscular administration of plasmids of the vascular endothelial growth factor gene (VEGF 165) with or without bone marrow-derived stem cells. Methods: The 21 patients were randomly assigned to three groups: A—with dual therapy, cells and plasmid; B—plasmid only; and C—control group, where patients received intramuscular injections of saline. Serum VEGF levels, the ankle–brachial index (ABI), transcutaneous oxygen pressure (TcPO2), and the rest pain measured by the visual analog scale (VAS) were determined sequentially before treatment, and then 1 and 3 months after treatment. Results: In the treatment groups, serum VEGF levels increased by 4 weeks and returned to baseline values after 3 months. ABI after 12 weeks increased by an average of 0.18 in group A, and 0.09 in group B and group C. TcPO2 increased by an average of 17.3 mmHg in group A, 14.1 mmHg in group B, and 10.7 mmHg in group C. The largest pain decrease was observed in group A and averaged 5.43 less pain intensity. Conclusions: Gene therapy using the VEGF plasmid along with or without bone marrow-derived mononuclear cells administered intramuscularly into an ischemic limb in TAO is a safe and effective therapy....
Chronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate receptor-1 (ITPR1) via subsequent decrease in ER calcium release and reduction of cytoplasmic free calcium, essential to the regulation of neuronal excitability. This study tested the hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vectors (rdHSV) carrying a CA8 transgene (vHCA8) reduce primary afferent neuronal excitability. Whole-cell current clamp recordings in small DRG neurons showed that vHCA8 transduction caused prolongation of their afterhyperpolarization (AHP), an essential regulator of neuronal excitability. This AHP prolongation was completely reversed by the specific Kv7 channel inhibitor XE-991. Voltage clamp recordings indicate an effect via Kv7 channels in vHCA8-infected small DRG neurons. These data demonstrate for the first time that vHCA8 produces Kv7 channel activation, which decreases neuronal excitability in nociceptors. This suppression of excitability may translate in vivo as non-opioid dependent behavioral- or clinical analgesia, if proven behaviorally and clinically....
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