For the First Time, Gene Therapy Delivered Straight to the Lungs

MIT bioengineers advance a technique to deliver nucleic-acid-based treatment to the lung by a noninvasive aerosol inhalation.

by Kayt Sukel
February 25, 2019

Massachusetts Institute of Technology biomedical engineers have, for the first time, delivered gene therapy agents directly to the lung with a nebulizer. This represents a giant first step in treating potentially fatal diseases like cystic fibrosis and alpha-1 antitrypsin deficiency.

These diseases are caused by insufficient numbers or lack of a single protein. Researchers hope to use genetic therapies to instruct lung cells to produce those proteins, but first they need to find a way to get genetic material into the lungs.

The MIT group focuses on using messenger ribonucleic acid (mRNA) to deliver instructions to lung cells. mRNA acts as a cellular courier, carrying the genetic code required for cells to manufacture specific proteins.

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Suman Bose, Ph.D., a post-doctoral fellow in Robert Langer’s laboratory at MIT, said getting RNA molecules into the lungs is particularly tricky. Langer is a pioneering bioengineer and a widely cited researchers who has spun off more than 40 companies.

Past research by Langer’s group has shown that different types of ribonucleic acid, like small interfering ribonucleic acids (siRNA), can offer biopharmaceutical benefit for a variety of diseases when encapsulated in liposomes and delivered intravenously to the bloodstream.

“When you inject it into the blood, it goes pretty much everywhere in the body—except the lungs,” he said. “There’s only one direct way into the lungs and that’s to inhale something. And it’s better because the molecules go where they are needed and you don’t have to worry about toxicity or off-target effects.”

Treatments for conditions like asthma and chronic obstructive pulmonary disease rely on inhalers or nebulizers to deliver therapeutics via powdered particles or aerosols, respectively. Liposomes, however, are too large for either approach, and would shear and fall apart during delivery, Bose said.

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To find another way forward, Asha Patel, a former post-doctoral fellow at MIT who is now an assistant professor at Imperial College London, created a new type of biodegradable polymer particle called a hyperbranched poly(beta-amino ester). It has a treelike structure consisting of multiple branches. When synthesized in a solution of mRNA, the branches entangle mRNA payloads to form a 150-nanometer-diameter particle.

Patel then mixes these positively charged particles with negatively charged nucleic acids, which are able to travel through cell walls. The two systems bind through electrostatic interaction. The resulting particles remained stable when suspended in water droplets and when delivered through a nebulizer.

“The material helps to protect the RNA during nebulization,” she said. “It also promotes its uptake into cells where it can be translated into protein.”

While the exact mechanism for cell uptake requires further study, the combination of the particles’ positive charge and surface chemistry likely assist, Patel said.

When she and her colleagues tested the new material in mice using mRNA that codes for luciferase, a bioluminescent protein, they found the animals’ epithelial cells along the lining of the lungs with the bioluminescent protein within 24 hours. What’s more, they were able maintain bioluminescence over time with repeated doses.

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The technique requires significant work before Bose can translate it into clinical use. While poly(beta-amino esters) are relatively simple to synthesize at lab scale, it will require additional studies to scale up and purify the material, as well as to assess toxicity and test potential therapeutic mRNA on models of lung disease.

Still, Bose is optimistic about the potential of this approach for future biopharmaceutical development.

“There is no genetic modification here,” Bose said. “You are not changing the genetic structure. You are just delivering the mRNA that tells cells how to make a missing protein.

“This is the first demonstration that you can create a polymer that can be nebulized and hit the lung directly with mRNA,” she added. “While there is a lot of optimization that needs to be done, there are so many applications that can be opened up to treat lung diseases, or even lung cancers, in the future. It’s very exciting.”

Kayt Sukel is an independent writer who focuses on technology.

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