Systematic review, meta-analysis, and future scope of lentivirus-mediated gene therapy
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ABSTRACT: Gene therapy has emerged as a promising therapeutic option for many inherited and acquired diseases. Lentivirus-mediated gene transfer is a powerful technique to deliver therapeutic genes into target cells and offers several advantages over other gene delivery methods. This systematic review explores the mechanistic intricacies of lentivirus-based vectors and provides the current status on their safety and efficacy in therapeutic applications underpinned by meta-analysis of clinical trials reported from across the globe. Our findings elucidate that gene therapy using lentiviruses has been extended to various diseases spanning from immunodeficiencies and hemoglobinopathies to specific malignancies and lysosomal storage diseases. Although the meta-analysis indicates a positive trend with respect to safety, the results pertaining to efficacy were not significant, highlighting the importance of continued investigation and cautious interpretation of the results. The findings from this study underscore the imperative for advancing research in vector development followed by preclinical and clinical assessments, to elevate the potential of lentiviral gene therapy as a potential therapeutic modality in the future.
Project description:Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy.
Project description:BackgroundOsteosarcopenia, a combination of osteopenia/osteoporosis and sarcopenia, is a common condition among older adults. While numerous studies and meta-analyses have been conducted on the treatment of osteoporosis, the pharmacological treatment of osteosarcopenia still lacks evidence. Denosumab, a human monoclonal antibody, has shown encouraging results for the treatment of osteosarcopenia. Our systematic review and meta-analysis aimed to investigate the potential dual role of denosumab as an anti-resorptive agent and for other beneficial muscle-related effects in patients with osteosarcopenia, and to evaluate whether denosumab can be a treatment of choice compared to bisphosphonate.MethodsRelevant literature was collated from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Google Scholar databases. The primary outcome was denosumab's effect on lumbar spine bone mineral density (LS BMD), handgrip strength, and gait speed change. The secondary outcome was the effect of denosumab on appendicular lean mass (ALM). The outcomes were presented as mean difference (MD). A random effects model was used in the analysis to represent the population. The risk of bias was assessed using funnel plots.ResultsOut of the 3,074 studies found, four full-text studies met the inclusion criteria, including 264 and 244 participants in the intervention and control groups, respectively. Regarding a primary outcome, our meta-analysis showed that denosumab showed no significant differences in LS BMD and gait speed changes compared to other agents-MD=0.37, 95% confidence interval (CI), -0.35 to 0.79; p=0.09 and MD=0.11; 95% CI, -0.18 to 0.40; p=0.46, respectively. Denosumab had a significant effect on handgrip strength change compared to standard agents-MD=5.16; 95% CI, 1.38 to 18.94; p=0.007, based on the random effects model.ConclusionsDenosumab was better than bisphosphonate and placebo in improving muscle strength (handgrip strength). Therefore, denosumab may be favored in individuals with osteosarcopenia to improve muscular performance and reduce fall risk.
Project description:Due to the limited therapeutic options after ischemic stroke, gene therapy has emerged as a promising choice, especially with recent advances in viral vector delivery systems. Therefore, we aimed to provide the current state of the art of lentivirus (LV) and adeno-associated virus (AAV) mediated gene interventions in preclinical ischemic stroke models. A systematic analysis including qualitative and quantitative syntheses of studies published until December 2020 was performed. Most of the 87 selected publications used adult male rodents and the preferred stroke model was transient middle cerebral artery occlusion. LV and AAV vectors were equally used for transgene delivery, however loads of AAVs were higher than LVs. Serotypes having broad cell tropism, the use of constitutive promoters, and virus delivery before the stroke induction via stereotaxic injection in the cortex and striatum were preferred in the analyzed studies. The meta-analysis based on infarct volume as the primary outcome confirmed the efficacy of the preclinical interventions. The quality assessment exposed publication bias and setbacks in regard to risks of bias and study relevance. The translational potential could increase by using specific cell targeting, post-stroke interventions, non-invasive systematic delivery, and use of large animals.
Project description:The safety and efficacy of lentivirus-mediated gene therapy was recently demonstrated in five male patients with Fabry disease-a rare X-linked lysosomal storage disorder caused by GLA gene mutations that result in multiple end-organ complications. To evaluate the risks of clonal dominance and leukemogenesis, which have been reported in multiple gene therapy trials, we conducted a comprehensive DNA insertion site analysis of peripheral blood samples from the five patients in our gene therapy trial. We found that patients had a polyclonal integration site spectrum and did not find evidence of a dominant clone in any patient. Although we identified vector integrations near proto-oncogenes, these had low percentages of contributions to the overall pool of integrations and did not persist over time. Overall, we show that our trial of lentivirus-mediated gene therapy for Fabry disease did not lead to hematopoietic clonal dominance and likely did not elevate the risk of leukemogenic transformation.
Project description:The effectiveness of T cell-mediated rejection (TCMR) therapy for achieving histological remission remains undefined in patients on modern immunosuppression. We systematically identified, critically appraised, and summarized the incidence and histological outcomes after TCMR treatment in patients on tacrolimus (Tac) and mycophenolic acid (MPA). English-language publications were searched in MEDLINE (Ovid), Embase (Ovid), Cochrane Central (Ovid), CINAHL (EBSCO), and Clinicaltrials.gov (NLM) up to January 2021. Study quality was assessed with the National Institutes of Health Study Quality Tool. We pooled results using an inverse variance, random-effects model and report the binomial proportions with associated 95% confidence intervals (95% CI). Statistical heterogeneity was explored using the I2 statistic. From 2875 screened citations, we included 12 studies (1255 participants). Fifty-eight percent were good/high quality while the rest were moderate quality. Thirty-nine percent of patients (95% CI 0.26-0.53, I2 77%) had persistent ≥Banff Borderline TCMR 2-9 months after anti-rejection therapy. Pulse steroids and augmented maintenance immunosuppression were mainstays of therapy, but considerable practice heterogeneity was present. A high proportion of biopsy-proven rejection exists after treatment emphasizing the importance of histology to characterize remission. Anti-rejection therapy is foundational to transplant management but well-designed clinical trials in patients on Tac/MPA immunosuppression are lacking to define the optimal therapeutic approach.
Project description:Purpose: This study aims to analyse the efficacy of different treatment methods for acute basilar artery occlusion, with an emphasis placed on evaluating the latest treatment methods. Method: A systematic review and meta-analysis was performed to analyse the current data on the therapies available for treating acute basilar artery occlusion. Results: A total of 102 articles were included. The weighted pooled rate of mortality was 43.16% (95% CI 38.35-48.03%) in the intravenous thrombolysis group, 45.56% (95% CI 39.88-51.28) in the intra-arterial thrombolysis group, and 31.40% (95% CI 28.31-34.56%) for the endovascular thrombectomy group. The weighted pooled rate of Modified Ranking Score (mRS) 0-2 at 3 months was 31.40 (95% CI 28.31-34.56%) in the IVT group, 28.29% (95% CI 23.16-33.69%) in the IAT group, and 35.22% (95% CI 32.39-38.09%) for the EVT group. Meta-analyses were also done for the secondary outcomes of recanalization and symptomatic haemorrhage. There was no difference between stent retriever and thrombo-aspiration thrombectomy on subgroup analysis in both clinical outcome and safety profile. Limitations: The included studies were observational in nature. There was significant heterogeneity in some of the outcomes. Conclusions: Superior outcomes and better recanalization rates for acute basilar occlusion were seen with patients managed with endovascular thrombectomy when compared with either intravenous and/or intraarterial thrombolysis. No superiority of stent-retrievers over thrombo-aspiration thrombectomy was seen.
Project description:We employed fibrin hydrogel as a bioactive matrix for lentivirus mediated gene transfer. Fibrin-mediated gene transfer was highly efficient and exhibited strong dependence on fibrinogen concentration. Efficient gene transfer was achieved with fibrinogen concentration between 3.75 and 7.5mg/ml. Lower fibrinogen concentrations resulted in diffusion of virus out of the gel while higher concentrations led to ineffective fibrin degradation by target cells. Addition of fibrinolytic inhibitors decreased gene transfer in a dose-dependent manner suggesting that fibrin degradation by target cells may be necessary for successful gene delivery. Under these conditions transduction may be limited only to cells interacting with the matrix thereby providing a method for spatially-localized gene delivery. Indeed, when lentivirus-containing fibrin microgels were spotted in an array format gene transfer was confined to virus-containing fibrin spots with minimal cross-contamination between neighboring sites. Collectively, our data suggest that fibrin may provide an effective matrix for spatially-localized gene delivery with potential applications in high-throughput lentiviral microarrays and in regenerative medicine.
Project description:Primary outcome(s): The primary endpoint was long-term survival including overall survival (OS) and recurrence/relapse-free survival (RFS).
Project description:Bernard-Soulier syndrome (BSS) is an inherited bleeding disorder caused by a defect in the platelet glycoprotein (GP) Ib-IX-V complex. The main treatment for BSS is platelet transfusion but it is often limited to severe bleeding episodes or surgical interventions due to the risk of alloimmunization. We have previously reported successful expression of human GPIbα (hGPIbα) in human megakaryocytes using a lentiviral vector (LV) encoding human GP1BA under control of the platelet-specific integrin αIIb promoter (2bIbα). In this study, we examined the efficacy of this strategy for the gene therapy of BSS using GPIbα(null) as a murine model of BSS. GPIbα(null) hematopoietic stem cells (HSC) transduced with 2bIbα LV were transplanted into lethally irradiated GPIbα(null) littermates. Therapeutic levels of hGPIbα expression were achieved that corrected the tail bleeding time and improved the macrothrombocytopenia. Sequential bone marrow (BM) transplants showed sustained expression of hGPIbα with similar phenotypic correction. Antibody response to hGPIbα was documented in 1 of 17 total recipient mice but was tolerated without any further treatment. These results demonstrate that lentivirus-mediated gene transfer can provide sustained phenotypic correction of murine BSS, indicating that this approach may be a promising strategy for gene therapy of BSS patients.