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

Abstract

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.

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

“…Since the cytokine storm is a common junction of ample of hyper-inflammatory diseases, targeting the cytokine storm with EXO-CD24 is the key to a successful cure for all these indications. [ 30 , 32 , 36 – 42 ].…”

“…Our group has developed a unique platform of genetically engineered exosomes to over-express CD24, called EXO-CD24 [ 30 ].…”

Inhaled CD24-Enriched Exosomes (EXO-CD24) as a Novel Immune Modulator in Respiratory Disease

“…In this study, it was demonstrated that EXO-CD24 increased survival in an animal model of pulmonary sepsis and that it had positive effects in a model of ovalbumin type I-induced allergic asthma, as well as a model of bleomycin-induced pulmonary fibrosis. In addition to the evidence gathered in more than 180 ARDS patients treated with EXO-CD24, these standardized pre-clinical studies further highlight its potential [ 18 , 29 ]. In the LPS-induced ARDS mouse model, EXO-mCD24 was superior to dexamethasone, primarily by enabling the rapid reversion of the immune system back to normal activity, which allows for a more robust response to pathogen clearance.…”

“…A phase IIb (NCT04902183) dose finding study in 91 patients in Greece confirmed this safety profile and again supported the potential for therapeutic efficacy. Further, in a separate study, again, efficacy and safety were also confirmed in 12 patients with severe ARDS [29]. An international, multi-center, randomized, quadri-blind clinical study of EXO-CD24 versus a placebo has recently opened for recruitment (NCT05947747).…”

“…EXO-CD24 are exosomes genetically enriched with the CD24 glycoprotein [ 28 ]. EXO-CD24 was designed as a targeted therapy for hyperactive immune systems in the context of ARDS induced by COVID-19 [ 18 , 29 ].…”