Clinical translation of nanomedicines: Challenges, opportunities, and keys

Humoral Innate Immunity and Acute-Phase Proteins

Abstract Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential. 

/pdf/autoantibodies-against-chemokines-post-sars-cov-2-infection-1ediuv9w.pdf

Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course

Background Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid. Methods: This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14. Result: The median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m2 (IQR 27 to 34); 51% had a BMI >30kg/m2. Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385). Conclusions: There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial. Trial registration: NCT04510194; IND 152439

Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up

Predictions for a near end of the pandemic by the World Health Organization should be interpreted with caution. Current evidence indicates that the efficacy of a fourth dose of classical mRNA vaccines (BT162b2 or mRNA-1273) is low and short-lived in preventing SARS-CoV-2 infection in its predominant variant (Omicron). However, its efficacy is high against severe symptomatic infection, hospitalization and death. The new vaccines being introduced are bivalent and active against the Omicron variants. Potential new vaccines to be introduced in the coming year include a vaccine based on a recombinant protein that emulates the receptor binding domain of the Spike protein under development by the Spanish company Hipra, as well as vaccines for nasal or oral administration. Available information suggests that vaccines against COVID-19 can be administered in association with influenza vaccination without particular complications. New drugs against COVID-19, both anti-viral and anti-inflammatory, are under investigation, but this does not seem to be the case with monoclonal antibodies. The indication to use masks in some circumstances will be maintained next year in view of the accumulation of scientific data on their efficacy. Finally, the long COVID or Post-COVID syndrome may continue to affect a very high proportion of patients who have had the disease, requiring combined diagnostic and therapeutic resources.

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Insights for COVID-19 in 2023

Post-acute sequelae of SARS-CoV-2 (PASC), also known as Post-Covid Syndrome, and colloquially as Long Covid, has been defined as a constellation of signs and symptoms which persist for weeks or months after the initial SARS-CoV-2 infection. PASC affects a wide range of diverse organs and systems, with manifestations involving lungs, brain, the cardiovascular system and other organs such as kidney and the neuromuscular system. The pathogenesis of PASC is complex and multifactorial. Evidence suggests that seeding and persistence of SARS-CoV-2 in different organs, reactivation, and response to unrelated viruses such as EBV, autoimmunity, and uncontrolled inflammation are major drivers of PASC. The relative importance of pathogenetic pathways may differ in different tissue and organ contexts. Evidence suggests that vaccination, in addition to protecting against disease, reduces PASC after breakthrough infection although its actual impact remains to be defined. PASC represents a formidable challenge for health care systems and dissecting pathogenetic mechanisms may pave the way to targeted preventive and therapeutic approaches. 

/pdf/long-covid-where-we-stand-and-challenges-ahead-90x0e1rq.pdf

Long Covid: where we stand and challenges ahead

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptfgr) are implicated as a TGFβ1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER −SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated IER -Sftpc I73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER -Sftpc I73T mice crossed to a Ptgfr null (FPr−/−) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. IER -Sftpc I73T /FPr−/− mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an “inflammatory/transitional” cell state in a PGF2α/ FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.

/pdf/disruption-of-prostaglandin-f2a-receptor-signaling-26y0s46b.pdf

Disruption of Prostaglandin F2α Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis

Prostaglandin F2α Signaling, a Novel Modulator of Adventitial Fibroblasts in a Preclinical Mouse Model of Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition resulting in progressive loss of lung function culminating in death or need for transplantation. Despite approved treatment options (nintedanib; pirfenidone), unmet need persists for well-tolerated and effective IPF therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPR are implicated as a TGFβ1 independent mediator of IPF. To assess the role of PGF2α/ FPR signaling in IPF, we leveraged our published murine PF model (IER-SftpcI73T) expressing an inducible disease associated missense mutation in the SFTPC gene (I73T). Tamoxifen treatment of IER-SftpcI73T mice results in an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling. For this study, IER-SftpcI73T mice were crossed to a FPR null (FPR−/−) line and given 2 sequential doses of tamoxifen by intraperitoneal or oral routes. FPR deletion resulted in both attenuated weight loss and gene dosage dependent rescue of mortality compared to FPR+/+ cohorts. At day 28, lungs from surviving IER-SftpcI73T/FPR−/− mice showed 40-60% reductions in fibrotic endpoints including soluble collagen content (Sircol), fibrillar collagen deposition (picrosirius red), and collagen gene expression. Administration of nintedanib to IER-SftpcI73T/FPR−/− was not additive for any endpoint. Collectively, findings in&nbsp;IER-SftpcI73T/FPR−/− mice provide added equipoise for a role for PGF2α signaling in IPF and establish a benchmark effect size for this pathway in mitigating fibrotic lung disease.

G. Fitzgerald

Papers

Long Covid: where we stand and challenges ahead

Disruption of Prostaglandin F2α Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis

Prostaglandin F2α Signaling, a Novel Modulator of Adventitial Fibroblasts in a Preclinical Mouse Model of Idiopathic Pulmonary Fibrosis

Disruption of prostaglandin F2α receptor signaling attenuates fibrotic remodeling in a preclinical murine model of idiopathic pulmonary fibrosis