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Chitin-Derived AVR-48 Prevents Experimental Bronchopulmonary Dysplasia (BPD) and BPD-Associated Pulmonary
Pragnya Das1,2, Suchismita Acharya3,4, Varsha M Prahaladan1,2
1Department of Pediatrics, Division of Neonatology, Cooper University Hospital, Camden, NJ 08103, USA.
Insights
AVR-48, a chitin derivative, shows promise in preventing and reversing experimental bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) in mice. This novel therapy improved lung structure and reduced inflammation, offering a potential treatment for this common prematurity complication.
Area of Science:
- Neonatology
- Pulmonology
- Pharmacology
Background:
- Bronchopulmonary dysplasia (BPD) is a major complication of prematurity, leading to significant healthcare costs and long-term respiratory issues.
- BPD can cause pulmonary hypertension (PH), a serious condition contributing to neonatal mortality and morbidity.
- Current treatment options for BPD and associated PH are limited, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To evaluate the safety and efficacy of AVR-48, a chitin derivative, as a prophylactic therapy for experimental BPD in a mouse model.
- To assess the impact of AVR-48 on lung structure, inflammation, and pulmonary hypertension in neonatal mice.
Main Methods:
- Newborn mice received intranasal, intraperitoneal, or intravenous doses of AVR-48 on postnatal days 2 and 4.
- Outcomes were assessed by analyzing broncho-alveolar lavage fluid for inflammatory cells, lung tissue for alveolarization, and Fulton's Index for PH.
- Pharmacokinetic and toxicity studies were conducted in neonatal mice and rat pups to determine drug bioavailability and safety.
Main Results:
- AVR-48 treatment improved alveolar simplification, reduced inflammatory cells in BALF, and decreased the Fulton's Index, indicating reduced PH.
- The therapy increased angiogenesis and cell proliferation while decreasing lung inflammation and cell death.
- AVR-48 demonstrated safety, with a determined no-observed-adverse-effect level (NOAEL) of 100 mg/kg in rat pups via IV dosing.
Conclusions:
- AVR-48 effectively reversed the cardiopulmonary phenotype of experimental BPD and BPD-PH in mice.
- The drug is safe, well-tolerated, and shows potential as a future therapeutic candidate for BPD and associated PH.
- AVR-48's ability to improve lung function and reduce inflammation offers a promising new avenue for managing complications of prematurity.
Abstract:
Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and a key contributor to the large health care burden associated with prematurity, longer hospital stays, higher hospital costs, and frequent re-hospitalizations of affected patients through the first year of life and increased resource utilization throughout childhood. This disease is associated with abnormal pulmonary function that may lead to BPD-associated pulmonary hypertension (PH), a major contributor to neonatal mortality and morbidity. In the absence of any definitive treatment options, this life-threatening disease is associated with high resource utilization during and after neonatal intensive care unit (NICU) stay. The goal of this study was to test the safety and efficacy of a small molecule derivative of chitin, AVR-48, as prophylactic therapy for preventing experimental BPD in a mouse model. Two doses of AVR-48 were delivered either intranasally (0.11 mg/kg), intraperitoneally (10 mg/kg), or intravenously (IV) (10 mg/kg) to newborn mouse pups on postnatal day (P)2 and P4. The outcomes were assessed by measuring total inflammatory cells in the broncho-alveolar lavage fluid (BALF), chord length, septal thickness, and radial alveolar counts of the alveoli, Fulton's Index (for PH), cell proliferation and cell death by immunostaining, and markers of inflammation by Western blotting and ELISA. The bioavailability and safety of the drug were assessed by pharmacokinetic and toxicity studies in both neonatal mice and rat pups (P3-P5). Following AVR-48 treatment, alveolar simplification was improved, as evident from chord length, septal thickness, and radial alveolar counts; total inflammatory cells were decreased in the BALF; Fulton's Index was decreased and lung inflammation and cell death were decreased, while angiogenesis and cell proliferation were increased. AVR-48 was found to be safe and the no-observed-adverse-effect level (NOAEL) in rat pups was determined to be 100 mg/kg when delivered via IV dosing with a 20-fold safety margin. With no reported toxicity and with a shorter half-life, AVR-48 is able to reverse the worsening cardiopulmonary phenotype of experimental BPD and BPD-PH, compared to controls, thus positioning it as a future drug candidate.
