Rare Daily Staff

Scientists at Cincinnati Children’s and the University of Cincinnati reports helping mice with a genetic mutation identical to one in humans that causes a fatal newborn lung disease, survive longer by using nanoparticles to deliver a gene into the lungs to stimulate blood vessel growth.

The disease alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is caused by genetic variations that prevent proper blood vessel formation in the lungs. Within days or weeks after birth, infants turn blue from lack of oxygen while blood pressure spikes within their lungs. The few who survive do so by receiving extremely rare infant-sized lung transplants. Worldwide, medical experts have documented about 200 cases, but an unknown number of infants may have died without the condition ever being diagnosed, according to the National Organization for Rare Disorders.

ACDMPV has been linked to the FOXF1 gene. The gene STAT3 is a key downstream target of FOXF1, and its delivery can correct the vascular deficiency in ACDMPV mice according to the study published online in the journal Circulation.

Without treatment, about 70 percent of mice born with ACDMPV die within 28 days of birth. The new treatment reduced that mortality rate to 35 percent. If these results can be matched in human studies in the years to come, the co-authors said this success could boost the pace of development for other nanoparticle-based therapies for a wide range of conditions.

“Nanoparticle carriers have shown minimal toxicity and have accelerated the development of novel therapies for human cancers, diabetes, and chronic inflammatory disorders. We have developed a unique nanoparticle delivery system that can deliver genes capable of stimulating micro-vessel growth in the newborn lung,” said study senior author Vlad Kalinichenko, a member of the Center for Lung Regenerative Medicine and the Perinatal Institute at Cincinnati Children’s. “This study shows that a single injection of the nanoparticles with the STAT3 gene vector was sufficient to increase alveolar capillary density, prevent excessively high blood pressures, and dramatically improve survival.”

The therapy works by delivering an engineered nanoparticle made of several polymers, fatty acids and a bit of cholesterol that carries the non-integrating STAT3 gene, which in turn prompts blood vessel growth in the lung tissue.

Unlike gene replacement therapies that can make permanent changes to the body, this nanoparticle approach involves materials that do not stay in the body longer than seven days. Nevertheless, in the mice studied, a single treatment early after birth was enough to divert an entire stream of later-developing problems that occur with ACDMPV.

With more blood vessels in place, the rapidly growing newborn lungs formed in a closer-to-normal fashion, without setting off dangerous molecular remodeling signals that can cause permanent malformations and death from lung failure.

Much more work must be completed before the nanoparticles can be tried in human newborns with ACDMPV, including safety tests and determining whether repeated treatments would be needed.

Photo: Vlad Kalinichenko, a member of the Center for Lung Regenerative Medicine and the Perinatal Institute at Cincinnati Children’s

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