New Lipid Molecule Holds Promise For Gene Therapy

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New Lipid Molecule Holds Promise For Gene Therapy

http://www.medicalnewstoday.com/medicalnews.php?newsid=40141

Scientists at the University of California, Santa Barbara have

created a new molecule that holds promise in fighting disease via

gene therapy. Inherited diseases, as well as many cancers and

cardiovascular diseases, may eventually be helped by this approach,

which delivers therapeutic genes directly to cells. These genes can

correct genetic defects, for example, or help the body's immune

system fight cancer cells.

For more than two decades, gene delivery has been accomplished by

using engineered viruses as a vehicle to get into diseased cells and

70 percent of clinical trials worldwide continue to use this method.

But, the viruses used for gene delivery occasionally evoke severe

immune responses, so scientists continue to search for non-viral

delivery vehicles.

Reporting in an article to appear in the March 29 print edition of

the Journal of the American Chemical Society (published on-line on

March 8), the authors describe the synthesis of the new lipid

molecule.

Lipid DNA complexes are attracting increasing attention as non-viral

DNA delivery vehicles. They have been described as one of

the " hottest new technologies " for gene therapy, accounting for

nearly 10 percent of ongoing clinical trials.

Lipids are molecules with two parts, a water-liking " headgroup " and

oily tails that assemble together to avoid water. Lipids, along with

carbohydrates and proteins, constitute the main structural material

of living cells.

The novel lipid molecule created at UC Santa Barbara has a tree-

shaped, nanoscale headgroup and displays unexpectedly superior DNA-

delivery properties. " It generates a honeycomb phase of lipid DNA

complexes, " said Cyrus R. Safinya, a professor of materials; of

molecular, cellular and developmental biology; and of physics at

UCSB. The new molecule was synthesized in Safinya's laboratory by

first author Kai K. Ewert, a synthetic chemist who is a project

scientist in the research group.

" We've been trying to get a lipid-based honeycomb lattice for a long

time, " said Ewert. The structure of lipid DNA complexes strongly

affects their ability to deliver DNA.

" Complexes containing sheets or tubes of lipids have been known since

Safinya's group found these structures in 1997 and 1998, but no one

had ever seen nanoscale cylinders such as the ones in our honeycomb

lattice, " Ewart said. The scientists proved the formation of this

novel structure with X-ray scattering experiments. Ewert designed and

synthesized the new lipid by manipulating the size, shape and charge

of a series of molecules. He explained that the new lipid molecule

has 16 positive charges in its tree-shaped headgroup, the largest

number by far in the field of gene delivery.

The process of delivering a gene of interest into the cell is known

as " transfection. " In the paper, the authors describe transfection

efficiency studies carried out in four cancer cell lines using the

new molecule. Two of these are mouse cell lines and two are human

cell lines. The honeycomb structure turned out to be highly

effective.

" Our new gene carrier shows superior transfection efficiency compared

to commercially available carriers, " said Ewert. " However, the most

surprising result was obtained with the mouse embryonic fibroblast

cells known as MEFs. These are empirically known to be extremely hard

to transfect. "

Safinya added: " Our data confirm that MEFs are generally hard to

transfect. And the new molecule is far superior for transfection of

these cells as compared to commercial lipids. "

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The other co-authors are Safinya's graduate students andra

Zidovska, Nate Bouxsein, Ayesha Ahmad (now a postdoctoral fellow at

the Genetic Therapies Center at Imperial College in London) and

(now a postdoctoral fellow at the Max Planck Institute

for Dynamics and Self-Organization in Goettingen, Germany).

The research was supported by the National Institute of General

Medical Sciences of the National Institutes of Health.

The synchrotron X-ray scattering experiments were performed at the

Stanford Synchrotron Radiation Laboratory, a facility supported by

the Department of Energy.