Viral vector platforms within the gene therapy landscape

Throughout its 40-year history, the field of gene therapy has been marked by many transitions. It has seen great strides in combating human disease, has given hope to patients and families with limited treatment options, but has also been subject to many setbacks. Treatment of patients with this class of investigational drugs has resulted in severe adverse effects and, even in rare cases, death. At the heart of this dichotomous field are the viral-based vectors, the delivery vehicles that have allowed researchers and clinicians to develop powerful drug platforms, and have radically changed the face of medicine. Within the past 5 years, the gene therapy field has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes. These modalities range from vector-based cancer therapies, to treating monogenic diseases with life-altering outcomes. At present, the three key vector strategies are based on adenoviruses, adeno-associated viruses, and lentiviruses. They have led the way in preclinical and clinical successes in the past two decades. However, despite these successes, many challenges still limit these approaches from attaining their full potential. To review the viral vector-based gene therapy landscape, we focus on these three highly regarded vector platforms and describe mechanisms of action and their roles in treating human disease

A Persistence Detector for Metabolic Network Rewiring in an Animal

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a persistence detector in a type 1, coherent feed-forward loop with an AND-logic gate to delay shunt activation upon propionate accumulation and to avoid spurious shunt activation in response to a non-sustained pulse of propionate. Together, our findings identify a persistence detector in an animal, which transcriptionally rewires propionate metabolism to maintain homeostasis

High Seroprevalence of anti-SARS-CoV-2 antibodies among Ethiopian healthcare workers [preprint]

Background COVID-19 pandemic has a devastating impact on the economies and health care system of sub-Saharan Africa. Healthcare workers (HWs), the main actors of the health system, are at higher-risk because of their occupation. Serology-based estimates of SARS-CoV-2 infection among HWs represent a measure of HWs’ exposure to the virus and a guide to the prevalence of SARS-CoV-2 in the community. This information is currently lacking in Ethiopia and other African countries. This study aimed to develop an in-house antibody testing assay, assess the prevalence of SARS-CoV-2 antibodies among Ethiopian high-risk frontline HWs. Methods and findings A cross-sectional seroprevalence study was conducted among HWs in five public hospitals located in different geographic regions of Ethiopia. Socio-demographic and clinical data were collected using questionnaire-based interviews. From consenting HWs, blood samples were collected between December 2020 and February 2021, the period between the two peaks of COVID-19 in Ethiopia. The collected sera were tested using an in-house immunoglobin G (IgG) enzyme-linked immunosorbent assay (ELISA) for SARS-CoV-2 specific antibodies on sera collected from HWs. Of 1,997 HWs who provided a blood sample, demographic and clinical data, 50.5% were female, 74.0% had no symptoms compatible with COVID-19, and 29.0% had history of contact with suspected or confirmed patient with SARS-CoV-2 infection. The overall seroprevalence was 39.6%. The lowest (24.5%) and the highest (48.0%) seroprevalence rates were found in Hiwot Fana Specialized Hospital in Harar and ALERT Hospital in Addis Ababa, respectively. Of the 821 seropositive HWs, 224(27.3%) had history of symptoms consistent with COVID-19. A history of close contact with suspected/confirmed COVID-19 cases was strongly associated with seropositivity (Adjusted odds Ratio (AOR) =1.4, 95% CI 1.1-1.8; p=0.015). Conclusion High SARS-CoV-2 seroprevalence levels were observed in the five Ethiopian hospitals. These findings highlight the significant burden of asymptomatic infection in Ethiopia, and may reflect the scale of transmission in the general population