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Heart Rhythm Jun 2024Cardiac tachyarrhythmia presents a significant health care challenge, causing notable morbidity and mortality. Conventional treatments have limitations and potential... (Meta-Analysis)
Meta-Analysis
Cardiac tachyarrhythmia presents a significant health care challenge, causing notable morbidity and mortality. Conventional treatments have limitations and potential risks, resulting in an elevated disease burden. Adeno-associated virus (AAV)-mediated gene therapy holds promise as a potential future treatment option. Therefore, we aimed to provide a measured overview of the latest developments in this rapidly growing field. PubMed and Embase databases were searched up to January 2024. Studies that employed AAV as a vector for delivery of therapeutic agents to treat cardiac tachyarrhythmia were included. Of the 26 studies included, 20 published in the last 5 years. There were 22 novel molecular targets identified. More than 80% of the included studies employed small-animal models or used AAV9. In atrial fibrillation preclinical studies, AAV-mediated gene therapy reduced atrial fibrillation inducibility by 81% (odds ratio, 0.19 [0.08-0.45]; P < .01). Similarly, for acquired and inherited ventricular arrhythmia, animal models receiving gene therapy had less inducible ventricular arrhythmia (odds ratio, 0.06 [0.03-0.11]; P < .01). This review highlights the rapid progress of AAV-mediated gene therapy for cardiac tachyarrhythmia. Although these investigations are currently in the early stages of clinical application, they present promising prospects for gene therapy. (PROSPERO registry: CRD42023479448).
Topics: Animals; Humans; Dependovirus; Genetic Therapy; Genetic Vectors; Tachycardia
PubMed: 38336191
DOI: 10.1016/j.hrthm.2024.02.001 -
Translational Vision Science &... Nov 2023This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV). (Meta-Analysis)
Meta-Analysis
PURPOSE
This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV).
METHODS
MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1.
RESULTS
Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%).
CONCLUSIONS
AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up.
TRANSLATIONAL RELEVANCE
This systematic review will help to inform and guide future clinical trials.
Topics: Humans; Retinal Degeneration; Dependovirus; Macular Degeneration; Retinitis Pigmentosa; Genetic Therapy
PubMed: 37982768
DOI: 10.1167/tvst.12.11.24 -
Journal of Translational Medicine Oct 2023Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a long-term disabling illness without a medically explained cause. Recently during COVID-19 pandemic, many... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a long-term disabling illness without a medically explained cause. Recently during COVID-19 pandemic, many studies have confirmed the symptoms similar to ME/CFS in the recovered individuals. To investigate the virus-related etiopathogenesis of ME/CFS, we conducted a systematic assessment of viral infection frequency in ME/CFS patients.
METHODS
We conducted a comprehensive search of PubMed and the Cochrane Library from their inception through December 31, 2022, using selection criteria of viral infection prevalence in ME/CFS patients and controls. Subsequently, we performed a meta-analysis to assess the extent of viral infections' contribution to ME/CFS by comparing the odds ratio between ME/CFS patients and controls (healthy and/or diseased).
RESULTS
Finally, 64 studies met our eligibility criteria regarding 18 species of viruses, including a total of 4971 ME/CFS patients and 9221 control subjects. The participants included healthy subjects and individuals with one of 10 diseases, such as multiple sclerosis or fibromyalgia. Two DNA viruses (human herpes virus (HHV)-7 and parvovirus B19, including their co-infection) and 3 RNA viruses (borna disease virus (BDV), enterovirus and coxsackie B virus) showed odds ratios greater than 2.0 compared with healthy and/or diseased subjects. Specifically, BDV exceeded the cutoff with an odds ratio of ≥ 3.47 (indicating a "moderate association" by Cohen's d test) compared to both healthy and diseased controls.
CONCLUSION
This study comprehensively evaluated the risk of viral infections associated with ME/CFS, and identified BDV. These results provide valuable reference data for future studies investigating the role of viruses in the causation of ME/CFS.
Topics: Humans; Encephalitis; Fatigue Syndrome, Chronic; Fibromyalgia; Virus Diseases
PubMed: 37898798
DOI: 10.1186/s12967-023-04635-0 -
BMC Infectious Diseases Apr 2023Viral reactivations and co-infections have been reported among COVID-19 patients. However, studies on the clinical outcomes of different viral reactivations and...
BACKGROUND
Viral reactivations and co-infections have been reported among COVID-19 patients. However, studies on the clinical outcomes of different viral reactivations and co-infections are currently in limit. Thus, the primary purpose of this review is to perform an overarching investigation on the cases of latent virus reactivation and co-infection in COVID-19 patients to build collective evidence contributing to improving patient health. The aim of the study was to conduct a literature review to compare the patient characteristics and outcomes of reactivations and co-infections of different viruses.
METHODS
Our population of interest included confirmed COVID-19 patients who were diagnosed with a viral infection either concurrently or following their COVID-19 diagnosis. We extracted the relevant literature through a systematic search using the key terms in the online databases including the EMBASE, MEDLINE, Latin American Caribbean Health Sciences Literature (LILACS), from inception onwards up to June 2022. The authors independently extracted data from eligible studies and assessed the risk of bias using the Consensus-based Clinical Case Reporting (CARE) guidelines and the Newcastle-Ottawa Scale (NOS). Main patient characteristics, frequency of each manifestation, and diagnostic criteria used in studies were summarized in tables.
RESULTS
In total, 53 articles were included in this review. We identified 40 reactivation studies, 8 coinfection studies, and 5 studies where concomitant infection in COVID-19 patients was not distinguished as either reactivation or coinfection. Data were extracted for 12 viruses including IAV, IBV, EBV, CMV, VZV, HHV-1, HHV-2, HHV-6, HHV-7, HHV-8, HBV, and Parvovirus B19. EBV, HHV-1, and CMV were most frequently observed within the reactivation cohort, whereas IAV and EBV within the coinfection cohort. In both reactivation and coinfection groups, patients reported cardiovascular disease, diabetes, and immunosuppression as comorbidities, acute kidney injury as complication, and lymphopenia and elevated D-dimer and CRP levels from blood tests. Common pharmaceutical interventions in two groups included steroids and antivirals.
CONCLUSION
Overall, these findings expand our knowledge on the characteristics of COVID-19 patients with viral reactivations and co-infections. Our experience with current review indicates a need for further investigations on virus reactivation and coinfection among COVID-19 patients.
Topics: Humans; Coinfection; COVID-19 Testing; COVID-19; Virus Diseases; Cytomegalovirus Infections
PubMed: 37101275
DOI: 10.1186/s12879-023-08117-y -
Frontiers in Immunology 2022Recombinant Adeno-associated virus (rAAV) is one of the main delivery vectors for gene therapy. To assess immunogenicity, toxicity, and features of AAV gene therapy in... (Meta-Analysis)
Meta-Analysis
Recombinant Adeno-associated virus (rAAV) is one of the main delivery vectors for gene therapy. To assess immunogenicity, toxicity, and features of AAV gene therapy in clinical settings, a meta-analysis of 255 clinical trials was performed. A total of 7,289 patients are planned to be dosed. AAV2 was the most dominantly used serotype (29.8%, n=72), and 8.3% (n=20) of trials used engineered capsids. 38.7% (n=91) of trials employed neutralizing antibody assays for patient enrollment, while 15.3% (n=36) used ELISA-based total antibody assays. However, there was high variability in the eligibility criteria with cut-off tiers ranging from 1:1 to 1:1,600. To address potential immunogenicity, 46.3% (n=118) of trials applied immunosuppressants (prophylactic or reactive), while 32.7% (n=18) of CNS and 37.5% (n=24) of ocular-directed trials employed immunosuppressants, possibly due to the immune-privileged status of CNS and retina. There were a total of 11 patient deaths across 8 trials, and 18 out of 30 clinical holds were due to toxicity findings in clinical studies. 30.6% (n=78) of trials had treatment-emergent serious adverse events (TESAEs), with hepatotoxicity and thrombotic microangiopathy (systemic delivery) and neurotoxicity (CNS delivery) being the most prominent. Additionally, the durability of gene therapy may be impacted by two distinct decline mechanisms: 1) rapid decline presumably due to immune responses; or 2) gradual decline due to vector dilution. The durability varied significantly depending on disease indication, dose, serotypes, and patient individuals. Most CNS (90.0%) and muscle trials (73.3%) achieved durable transgene expression, while only 43.6% of ocular trials had sustained clinical outcomes. The rAAV production system can affect rAAV quality and thus immunogenicity and toxicity. Out of 186 trials that have disclosed production system information, 63.0% (n=126) of trials used the transient transfection of the HEK293/HEK293T system, while 18.0% (n=36) applied the baculovirus/Sf9 (rBac/Sf9) system. There were no significant differences in TESAEs and durability between AAV generated by rBac/Sf9 and HEK293/HEK293T systems. In summary, rAAV immunogenicity and toxicity poses significant challenges for clinical development of rAAV gene therapies, and it warrants collaborative efforts to standardize monitoring/measurement methods, design novel strategies to overcome immune responses, and openly share relevant information.
Topics: Humans; Dependovirus; HEK293 Cells; Genetic Vectors; Genetic Therapy; Immunosuppressive Agents
PubMed: 36389770
DOI: 10.3389/fimmu.2022.1001263 -
Asia-Pacific Journal of Ophthalmology...Genetic eye diseases, representing a wide spectrum of simple and complex conditions, are one of the leading causes of visual loss in children and working adults, and...
Genetic eye diseases, representing a wide spectrum of simple and complex conditions, are one of the leading causes of visual loss in children and working adults, and progress in the field has led to changes in disease investigation, diagnosis, and management. The past 15 years have seen the emergence of novel therapies for these previously untreatable conditions to the extent that we now have a licensed therapy for one form of genetic eye disease and many more in clinical trial. This is a systematic review of published and ongoing clinical trials of gene therapies for monogenic eye diseases. Databases of clinical trials and the published literature were searched for interventional studies of gene therapies for eye diseases. Standard methodological procedures were used to assess the relevance of search results. A total of 59 registered clinical trials are referenced, showing the significant level of interest in the potential for translation of these therapies from bench to bedside. The breadth of therapy design is encouraging, providing multiple possible therapeutic mechanisms. Some fundamental questions regarding gene therapy for genetic eye diseases remain, such as optimal dosing, the relative benefits of adeno-associated virus (AAV)-packaging and the potential for a significant inflammatory response to the therapy itself. As a result, despite the promise of the eye as a target, it has proven difficult to deliver clinically effective gene therapies to the eye. Despite setbacks, the licensing of Luxturna (voretigene neparvovec, Novartis) for the treatment of RPE65-mediated Leber congenital amaurosis (LCA) is a major advance in efforts to treat these rare, but devastating, causes of visual loss.
Topics: Adult; Child; Dependovirus; Eye Diseases; Genetic Therapy; Genetic Vectors; Humans; Leber Congenital Amaurosis; Mutation; cis-trans-Isomerases
PubMed: 36041151
DOI: 10.1097/APO.0000000000000545 -
Journal of Emergency Nursing Jul 2022Immunoglobulin A vasculitis is historically more commonly found in children after certain viral infections such as Epstein-Barr, varicella virus, and parvovirus B19....
INTRODUCTION
Immunoglobulin A vasculitis is historically more commonly found in children after certain viral infections such as Epstein-Barr, varicella virus, and parvovirus B19. COVID-19 has not been formally established in literature as a trigger for immunoglobulin A vasculitis. However, a main pathogenetic mechanism of COVID-19 is vascular damage, which makes it likely that vasculitis associated with COVID-19 (ie, COVID-19-mediated immunoglobulin A vasculitis) could be biologically plausible, with serious implications, especially for adults. The purpose of this review is to assist emergency nurses in gaining knowledge on the pathophysiology, symptoms, and treatment of COVID-19-mediated immunoglobulin A vasculitis.
METHODS
A systematic search for case reports of COVID-19-associated immunoglobulin A vasculitis was conducted in the PubMed and Scopus electronic databases. The search terms used were COVID-19, coronavirus 2019, SARS COVID-19, and IgA vasculitis, case reports. The following were the inclusion criteria: publication dates between December 1, 2019, and December 1, 2021; full-text article, clinical case studies, and letters to the editor available electronically in English. The following were exclusion criteria: a summary of reports and newspaper publications.
RESULTS
Only 13 clinical cases met the inclusion criteria. The median age of patients described in the case reports were 38.1 years. Of them, 3 children were less than 5 years old. Twelve patients were male. In 7 of 13 cases of immunoglobulin A vasculitis, renal involvement was found.
DISCUSSION
The analysis of published clinical cases showed that COVID-19-associated immunoglobulin A vasculitis affected mostly adults and was characterized by a more severe course because of renal involvement. COVID-19 may be a possible trigger for immunoglobulin A-related disorders. More research is needed to better understand the relationship between immunoglobulin A vasculitis and COVID-19.
Topics: Adult; COVID-19; Child; Child, Preschool; Female; Humans; IgA Vasculitis; Immunoglobulin A; Male; Vasculitis
PubMed: 35691763
DOI: 10.1016/j.jen.2022.05.002 -
Translational Research : the Journal of... Oct 2022Adeno-associated viruses (AAVs) represent some of the most commonly employed vectors for targeted gene delivery and their extensive study has resulted in the approval of... (Review)
Review
Adeno-associated viruses (AAVs) represent some of the most commonly employed vectors for targeted gene delivery and their extensive study has resulted in the approval of multiple gene therapies to treat human diseases. The intranasal route of vector application in gene therapy offers several advantages over traditional ways of administration. In addition to targeting local tissue like the olfactory epithelium, it provides minimally invasive access to various organ systems, including the central nervous system and the respiratory tract. Through a systematic literature review, a total of 53 articles that investigated the intranasal application of AAVs were identified, included, and summarized in this manuscript. Within these studies, AAV-based gene therapy was mainly investigated for its application in various infectious, pulmonary, or neurologic and/or psychiatric diseases. This review gives a comprehensive overview of the current technological state of the art regarding the intranasal application of AAVs for gene transfer and discusses remaining hurdles, which still have to be resolved before this approach can effectively be implemented in the routine clinical setting.
Topics: Administration, Intranasal; Dependovirus; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans
PubMed: 35597541
DOI: 10.1016/j.trsl.2022.05.002 -
Frontiers in Pharmacology 2021Viruses cause various human diseases, some of which become pandemic outbreaks. This study synthesized evidence on antiviral medicinal plants in Africa which could... (Review)
Review
Viruses cause various human diseases, some of which become pandemic outbreaks. This study synthesized evidence on antiviral medicinal plants in Africa which could potentially be further studied for viral infections including Coronavirus disease 2019 (COVID-19) treatment. PUBMED, CINAHIL, Scopus, Google Scholar, and Google databases were searched through keywords; antiviral, plant, herb, and Africa were combined using "AND" and "OR". studies, studies, or clinical trials on botanical medicine used for the treatment of viruses in Africa were included. Thirty-six studies were included in the evidence synthesis. Three hundred and twenty-eight plants were screened for antiviral activities of which 127 showed noteworthy activities against 25 viral species. These, were Poliovirus (42 plants), HSV (34 plants), Coxsackievirus (16 plants), Rhinovirus (14plants), Influenza (12 plants), Astrovirus (11 plants), SARS-CoV-2 (10 plants), HIV (10 plants), Echovirus (8 plants), Parvovirus (6 plants), Semiliki forest virus (5 plants), Measles virus (5 plants), Hepatitis virus (3 plants), Canine distemper virus (3 plants), Zika virus (2 plants), Vesicular stomatitis virus T2 (2 plants). Feline herpesvirus (FHV-1), Enterovirus, Dengue virus, Ebola virus, Chikungunya virus, Yellow fever virus, Respiratory syncytial virus, Rift Valley fever virus, Human cytomegalovirus each showed sensitivities to one plant. The current study provided a list of African medicinal plants which demonstrated antiviral activities and could potentially be candidates for COVID-19 treatment. However, all studies were preliminary and screening. Further are required for plant-based management of viral diseases.
PubMed: 35002686
DOI: 10.3389/fphar.2021.682794 -
Asian Journal of Transfusion Science 2021Human parvovirus B19 (B19V) is one of the blood-borne viruses. The virus can be transmitted to susceptible individuals by blood or blood products. The virus is not... (Review)
Review
BACKGROUND
Human parvovirus B19 (B19V) is one of the blood-borne viruses. The virus can be transmitted to susceptible individuals by blood or blood products. The virus is not associated with significant disease in general population, while people with underlying problems such as immunodeficiency can cause anemia and arthritis. The current systematic review and meta-analysis aimed to estimate the overall prevalence of B19V DNA, anti-B19V IgG, and anti-B19V IgM antibodies in blood donors worldwide.
METHODS
A systematic search was carried out in online databases for relevant studies from inception until March 30, 2019. Study selection was performed based on predesigned eligibility criteria. The proportion of B19V DNA, anti-B19V IgG, and anti-B19V IgM antibodies were pooled using the inverse variance method. All statistical analyses were performed using the R version 3.5.3, package "meta."
RESULTS
According to the random-effects model, the pool prevalence of B19V DNA, anti-B19V IgM, and anti-B19V IgG among blood donors was calculated to be 0.4% (95% confidence interval [CI] =0.3%-0.6%), 2.2% (95% CI = 1.3%-3.7%), and 50.1% (95% CI = 43.1%-57.1%), respectively.
CONCLUSION
For the transmission of B19V through blood, the presence of the virus genome is required, and the present study showed that the prevalence of the virus genome in blood donors is <1%. Therefore, there is no need to screen donated blood for B19V infection.
PubMed: 34908757
DOI: 10.4103/ajts.ajts_185_20