The safety and potential efficacy of exosomes overexpressing CD24 (EXO-CD24) in mild-moderate COVID-19 related ARDS.

INTRODUCTION: EXO-CD24 are exosomes genetically manipulated to over-express Cluster of Differentiation (CD) 24. It consists of two breakthrough technologies: CD24, the drug, as a novel immunomodulator that is smarter than steroids without any side effects, and exosomes as the ideal natural drug carrier. METHODS: A randomized, single blind, dose-finding phase IIb trial in hospitalized patients with mild to moderate Coronavirus disease 2019 (COVID-19) related Acute Respiratory Distress Syndrome (ARDS) was carried out in two medical centers in Athens. Patients received either 109 or 1010 exosome particles of EXO-CD24, daily, for five consecutive days and monitored for 28 days. Efficacy was assessed at day 7 among 91 patients who underwent randomization. The outcome was also compared in a post-hoc analysis with an income control group (n = 202) that fit the inclusion and exclusion criteria. RESULTS: The mean age was 49.4 (± 13.2) years and 74.4% were male. By day 7, 83.7% showed improved respiratory signs and 64% had better oxygen saturation (SpO2) (p < 0.05). There were significant reductions in all inflammatory markers, most notably in C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, fibrinogen and an array of cytokines. Conversely, levels of the anti-inflammatory cytokine Interleukin-10 (IL-10) were increased (p < 0.05). Of all the documented adverse events, none were considered treatment related. No drug-drug interactions were noted. Two patients succumbed to COVID-19. Post-hoc analysis revealed that EXO-CD24 patients exhibited greater improvements in clinical and laboratory outcomes compared to an observational income control group. CONCLUSIONS: EXO-CD24 presents a promising therapeutic approach for hyper-inflammatory state and in particular ARDS. Its unique combination of exosomes, as a drug carrier, and CD24, as an immunomodulator, coupled with inhalation administration, warrants further investigation in a larger, international, randomized, quadri-blind trial against a placebo.

Inhaled Exosomes Genetically Manipulated to Overexpress CD24 (EXO-CD24) as a Compassionate Use in Severe ARDS Patients.

RATIONALE: Acute respiratory distress syndrome (ARDS) is a major global health concern with a significant unmet need. EXO-CD24 is delivered via inhalation-reduced cytokines and chemokine secretion and lung injury in ARDS and improved survival in mice models of ARDS, influenza, and sepsis. OBJECTIVES: This clinical paper aims to evaluate the potential of EXO-CD24, a novel immunomodulatory treatment, in the compassionate care of critically ill, intubated patients with post-infection-induced acute respiratory distress syndrome (ARDS). METHODS: Eleven critically ill patients diagnosed with post-infection ARDS (10 with COVID-19 and one with an adenovirus-associated infection) were administered EXO-CD24 in four medical centers across Israel. The patients had multiple co-morbidities, including cancer, hypertension, diabetes, and ischemic heart disease, and met the criteria for severe ARDS according to the Berlin classification. EXO-CD24 was administered via inhalation, and adverse events related to its use were carefully monitored. MEASUREMENTS AND MAIN RESULTS: The administration of EXO-CD24 did not result in any recorded adverse events. The median hospitalization duration was 11.5 days, and the overall mortality rate was 36%. Notably, patients treated at the Tel Aviv Medical Center (TASMC) showed a lower mortality rate of 12.5%. The WBC and CRP levels decreased in comparison to baseline levels at hospitalization, and rapid responses occurred even in patients with kidney transplants who were off the ventilator within a few days and discharged shortly thereafter. The production of cytokines and chemokines was significantly suppressed in all patients, including those who died. Among the patients at TASMC, four had kidney transplants and were on immunosuppressive drugs, and all of them fully recovered and were discharged from the hospital. CONCLUSIONS: EXO-CD24 holds promise as a potential therapeutic agent for all stages of ARDS, even in severe intubated cases. Importantly, EXO-CD24 demonstrated a favorable safety profile without any apparent side effects with promising efficacy. Furthermore, the potential of EXO-CD24 as a platform for addressing hyper-inflammatory states warrants exploration. Further research and larger-scale clinical trials are warranted to validate these preliminary findings.

Oral and Dental Considerations of Combat-Induced Post Traumatic Stress Disorder (PTSD)-A Cross-Sectional Study.

Objective: This study compared dental, periodontal, oral, and joint/muscle tenderness among Israeli combat-induced post-traumatic stress disorder (Ci-PTSD) war veterans to non-PTSD patients. Study design: This retrospective three-arm study compared oral and facial manifestations between 100 Israeli veterans with Ci- PTSD (study group) and 103 non-PTSD periodontal patients (Control group). The study group was further divided into two subgroups of individuals who received psychiatric medications (40 patients) or did not (60 patients). All patients underwent complete dental, oral, and periodontal examinations, including assessing signs of parafunction. Results: All PTSD patients had poor oral hygiene. The plaque index (PI) was higher in the PTSD group compared to the control group (0.72 ± 0.28 vs. 0.45 ± 0.29, respectively, p < 0.001). The decayed, missing, and filled teeth score (DMFt) was higher in the PTSD population than in the controls (19.97 ± 8.07 vs. 13.05 ± 6.23 p < 0.05). Severe periodontal disease was more common among the PTSD subgroup taking medications (med -group) (62.5%) compared to the nonmedicated group (non-med group) (30.0%) and the controls (27.2%) (p = 0.001). Heavy smoking was more prevalent in the medicated PTSD patients than in other groups. Conclusions: The present study shows higher morbidities in combat-induced PTSD patients, including oral, dental, and periodontal manifestations, especially in medicated patients.