This clinical trial aims to evaluate the safety and effectiveness of umbilical cordmesenchymal stem cell (UCMSC)-derived extracellular vesicle nebulization inhalationtherapy for the treatment of chronic cough after COVID-19 infection. The main objectiveis to assess whether UCMSC-derived exosome nebulization inhalation therapy alleviateschronic cough after COVID-19.Participants will be asked to complete a questionnaire to help researchers evaluate theircough severity and to record their scores before nebulization inhalation of UCMSC-derivedexosomes. Participants will receive either continuous nebulized inhalation ofUCMSC-derived exosomes for 5 days, twice daily, or no treatment. Researchers will comparethe experimental and control groups to evaluate the safety and efficacy of UCMSC-derivedexosomes for the treatment of chronic cough after COVID-19 infection.
1. Background 1.1 Post-COVID-19 Syndrome, also known as Long Covid, is still causing
great trouble to the public despite China having successfully passed the first wave
of infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
for over three years, which has resulted in over 5 million deaths globally.
Long Covid is a multiple-system disease that includes a variety of severe symptoms
that persist after infection with COVID-19, such as (1) heart-related symptoms:
chest pain, palpitations; (2) respiratory symptoms: cough, shortness of breath, loss
of taste or smell; (3) pancreatic symptoms: diabetes, pancreatic injury; (4) immune
system: autoimmunity, mast cell activation syndrome MCAS; (5) neurological symptoms:
cognitive impairment (brain fog), fatigue, sleep disorders, memory loss, tinnitus;
(6) vascular symptoms: fatigue, coagulation disorders, deep vein thrombosis,
endothelial dysfunction, microvascular disease, stroke; (7) reproductive symptoms:
erectile dysfunction, menstrual disorders, etc., which severely affect the patient's
daily life. Long Covid can occur in people of all ages, and the likelihood of
developing it is closely related to the severity of acute COVID-19 infection. The
main high-risk factors that can trigger Long Covid include (1) type II diabetes, (2)
high viral load during COVID-19 infection, (3) previous infection with EB virus, and
(4) excessive specific autoantibodies. Treatment strategies for COVID-19 mainly
involve using antiviral drugs to block the replication cycle of the virus and
various methods to suppress host inflammation to improve symptoms. Currently, the
conventional immunotherapy methods used in clinics mainly involve the use of
hormones, monoclonal antibody drugs, etc., but they are mainly targeted at more
severe inflammatory reactions and suffer from low bioavailability, high cost, and
significant side effects, making them unsuitable for the treatment of long COVID.
Therefore, developing new immune-regulating methods with low side effects and costs
would be significant for the treatment of long COVID.
1.2 Mesenchymal stem cells (MSCs) MSCs have been shown to have comprehensive and
powerful immune-regulatory and regenerative functions. MSCs can counteract cell
death related to the pathogenesis of chronic obstructive pulmonary disease (COPD),
idiopathic pulmonary fibrosis, asthma, ARDS, and pulmonary hypertension, and promote
cell regeneration. Exosomes are one of the key paracrine effectors secreted by MSCs,
and they are considered powerful candidates for alternative treatment of various
diseases because their biological material is like that of progenitor cells, and
they have the ability to maintain healing properties. Under physiological and
pathological conditions, exosomes play a critical role in intercellular
communication by transporting various biomolecules (such as miRNA and proteins) into
target cells.
1.3 the mechanism of MSC-derived exosomes MSC-derived exosomes inherit
immunosuppressive properties from their source cells. MSC-EVs may use multiple
mechanisms to balance the function of the immune system. One key mechanism is
reprogramming and changing the phenotype of various immune cells.
In multiple models, MSC-exosomes have therapeutic properties similar to MSCs and are
easier to prepare, store, and transport to the bedside, while avoiding some
limitations of cell therapy, such as the risk of pulmonary embolism and tumor
formation. Exosomes secreted by MSCs can regulate immunity through an interaction
with immune cells and inhibit inflammatory reactions through cytokines. Numerous
studies have shown that exosomes secreted by MSCs can be used to treat
immunodeficiency, inflammation, ARDS, and other lung diseases, so exosomes secreted
by MSCs may also be effective in treating COVID-19 infections and pneumonia. The
conventional method of stem cell therapy is an intravenous injection, and exosomes
are one of the main active components secreted by stem cells with a size of 30-150
nm. After nebulization, exosomes can directly reach the bronchioles and alveoli,
which is conducive to maximizing drug absorption.
1.4 Clinical cases of MSC-derived exosomes therapy China has also actively launched
relevant clinical studies. A clinical study at Wuxi Fifth People's Hospital in
Jiangsu Province confirmed that nebulized umbilical cord mesenchymal stem
cell-derived exosomes are safe and feasible for treating COVID-19 pneumonia.
Researchers at Ruijin Hospital and Jin Yin-tan Hospital jointly conducted nebulized
exosome therapy for COVID-19 using exosomes derived from human allogeneic adipose
mesenchymal stem cells (HAMSCs-Exos). Recently, the inhaled anti-COVID-19 drug
Exo-CD24, a combination of exosomes and CD24 protein, has shown promising results in
phase I clinical trial led by Israeli medical center expert Nadir Arber. Out of 30
critically ill volunteers in the trial, 29 were cured after five days of treatment.
Although Exo-CD24 has yet to pass phase III testing, it has already demonstrated
enormous potential for the future. The US FDA has approved Direct Biologics to start
a phase I/II trial to evaluate ExoFlo™ for treating COVID-19. This marks the first
time that extracellular vesicles (EVS) have been approved by the US FDA for treating
the disease.
2. Research Purpose The aim of this study is to evaluate the safety and effectiveness
of umbilical cord mesenchymal stem cell exosome nebulization inhalation for treating
chronic cough in patients after COVID-19 infection through a non-randomized
controlled clinical trial.
3. Study Design The study design is a prospective, non-randomized, concurrent
controlled trial. Based on the routine treatment regimen for COVID-19 infection
according to clinical guidelines, umbilical cord mesenchymal stem cell exosome
nebulization inhalation will be used in the experimental group to treat chronic
cough in patients after COVID-19 infection. The experimental group (n=40) and
control group (n=40) will be compared with patients who did not receive exosome
nebulization inhalation therapy during the same period. The safety and effectiveness
of umbilical cord mesenchymal stem cell exosome nebulization inhalation for treating
chronic cough in patients after COVID-19 infection will be evaluated through cough
severity score surveys, symptom improvement time, and adverse event occurrence.
3.1 Study Population A total of 80 participants will be enrolled in the study, with a
ratio of 1:1 for the experimental group (n=40) and the control group (n=40). The study
population will consist of COVID-19-infected patients who meet the selection criteria and
are treated in the COVID-19 rehabilitation outpatient clinic at the Shenzhen Hospital of
Southern Medical University.
3.2 Grouping (1) Experimental group: Nebulization inhalation of umbilical cord
mesenchymal stem cell exosome preparation; specification: 5ml, exosome concentration in
preparation is 1*10^9 particles/ml.
(2) Control group: Patients during the same period who did not receive treatment with
stem cell exosomes.
Biological: MSC-derived exosomes
The total volume of MSC-derived exosomes is 5ml, and exosome concentration in preparation
is 1*10^9 particles/ml.
Inclusion Criteria:
- Trial participants voluntarily participate in this study and sign an informed
consent form.
- At the time of signing the informed consent form, the age of the subject should be
≥18 or ≤80 years old, with no gender restrictions.
- The subject has been diagnosed with COVID-19 (confirmed by positive nucleic acid or
antigen test) and has symptoms that have lasted for more than 4 weeks.
- Negative nucleic acid or antigen test at the time of screening.
- The subject has had continuous or intermittent coughing, or loss of taste/smell for
≥4 weeks, which did not occur before the onset of COVID-19 infection.
- No prior treatment with umbilical cord mesenchymal stem cell-derived extracellular
vesicles.
- The patient fully understands the purpose and requirements of this clinical study
and is willing to complete all trial procedures according to the study requirements.
Exclusion Criteria:
- Age ≤18 or ≥80 years old.
- Acute COVID-19 patients.
- Suspected or confirmed to have severe, active bacterial, fungal, or other infections
that may pose a risk when intervention measures are taken, as determined by the
researcher.
- Patients with a history of diagnosed bronchial asthma, cough variant asthma, or
chronic cough; patients with other pulmonary diseases such as chronic obstructive
pulmonary disease, bronchiectasis, tuberculosis, lung cancer, etc.
- Any of the following during the screening period: 1) ALT or AST > 3 times the upper
limit of normal; 2) eGFR <60 mL/min.
- Patients with a history of severe allergies.
- Patients with uncontrolled severe cardiovascular, cerebrovascular, liver, kidney,
endocrine, blood system diseases, and mental illness.
- Patients with active immunosuppression, immunodeficiency, and use of
immunosuppressive drugs.
- Pregnant and lactating women.
- Other factors that the researcher deems unsuitable for participation in the study
based on clinical considerations.
Huazhong University of Science and Technology Union Shenzhen Hospital
Shenzhen, Guangdong, China
Investigator: Jihui Du, PhD
Contact: 8613510083963
jihuidu@email.szu.edu.cn
Jihui Du, PhD
8613510083963
jihuidu@email.szu.edu.cn
Jihui Du, PhD, Principal Investigator
Huazhong University of Science and Technology Union Shenzhen Hospital