Molecular Mailman Improves Delivery of Gene Therapy

Researchers discover new molecular linker that orients targeting antibodies to help nucleic-acid filled particles reach target cells via AABME

by Melissae Fellet
February 26, 2018

A new method, currently used on mice, efficiently assembles nanoparticle packages of nucleic acids for gene therapy. Antibodies coating the particles act as a molecular mailman that identifies and delivers the package to a receptor on the surface of diseased cells. The new process used to assemble the particles includes a molecular linker that orients antibodies for optimum cell recognition and package delivery.

In gene therapy, researchers want to send short strands of RNA to diseased cells to deactivate genes. The messages in the RNA strands induce cancer cells to kill themselves or immune cells to produce fewer inflammation molecules. But directing packaged nucleic acids to specific cells is challenging.

Researchers typically connect targeting antibodies to the surface of the nucleic acid packages using chemical reactions that form physical bonds between the antibody and the package’s lipid membrane. Since these reactions can occur at many different places on an antibody some attached antibodies may be pointed so that their binding site is most accessible to cells, while others may have buried binding sites.

Dan Peer, managing director of the Center for Translational Medicine at Tel Aviv University, and his colleagues wanted to join antibodies to lipid nanoparticles so that their binding sites were best oriented to recognize target cells.

A recent paper in Nature Nanotechnology described how they designed a short peptide linker with a lipid-decorated portion at one end to slip into the membrane of a nanoparticle package. The other end of the linker attracts the base of a subclass of mouse IgG antibodies, making the binding sites at the tips of the antibodies accessible to cells.

Next, the researchers incorporated the antibody attachment linker into nanoparticle packages for gene therapy delivery. They synthesized lipid nanoparticles containing short interfering RNA (siRNA) that deactivated genes involved in the production of inflammation molecules. 

Over one week, the researchers injected three doses of nanoparticle packages into mice with inflamed colons. Mice treated with nanoparticles carrying the anti-inflammatory siRNA had fewer physical symptoms of colitis than control mice. They also had three times less TNFα, an inflammatory protein, in their large intestine than mice treated with control nanoparticles. The TNFα levels in treated mice were even lower than in an uninflamed gut.

The antibody linker helps ensure the nucleic acid cargo only reaches the desired cells, Peer says. When targeted antibodies are randomly oriented on the surface of a nanoparticle package, immune cells generally searching for antibody-covered material swallow and destroy the nanoparticles. But with the linker pointing antibodies in the direction of target cells, the gene packages only reach and enter their targets.

The linker also addresses several issues involved with commercializing gene therapy, Peer says. The linker standardizes the antibody attachment process, making it easier for researchers to prepare nanoparticles consistently functionalized with the same number of antibodies.

The linker can also easily be modified to attract other subclasses of IgG antibodies. “This gives us endless options for targeting,” Peer says. There are thousands of IgG antibodies known to recognize cell surface receptors.

Finally, the specific attraction between the linker and target antibody means researchers consume less antibody during nanoparticle production, which could help reduce future production costs.

In 2015, Peer and colleagues chemically attached antibodies to nanoparticle packages directed to cancer cells in mouse bone marrow. When they prepared the particles used the same components, along with the new linker to attach the antibodies, the researchers used 250 times less antibody during the attachment step, Peer says.

Melissae Fellet is an independent writer.

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