Molecular Level Computer Simulation Provides Insights for Successful Gene Therapy

Molecular-level computer simulations of dendrimer/DNA complexes in the presence of a model cell membrane provide insights that directly pertain to critical issues arising in emerging gene delivery therapeutic applications. This work “Dendrimers as synthetic gene vectors: Cell membrane attachment” appeared in the Journal of Chemical Physics.

Key Finding: Dendrimers should be able to work effectively for gene therapy and cancer drug delivery. Dendrimers are known to be safer than virus delivery of genes and drugs but to this point have been less effective. This work shows how to increase effectiveness.

Science Daily has coverage. A group of researchers at the University of California, Berkeley and Los Alamos National Laboratory have completed the first comprehensive, molecular-level numerical study of gene therapy. Their work should help scientists design new experimental gene therapies and possibly solve some of the problems associated with this promising technique.

“There are several barriers to gene delivery,” says Nikolaos Voulgarakis of Berkeley, the lead author on the new paper. “The genetic material must be protected during transit to a cell, it must pass into a cell, it must survive the cell’s defense mechanisms, and it must enter into the cell’s guarded nucleus.”

If all of these barriers can be overcome, gene therapy would be a valuable technique with profound clinical implications. It has the potential to correct a number of human diseases that result from specific genes in a person’s DNA makeup not functioning properly — or at all. Gene therapy would provide a mechanism to replace these specific genes, swapping out the bad for the good. If doctors could safely do this, they could treat or even cure diseases like cystic fibrosis, certain types of cancer, sickle cell anemia, and a number of rare genetic disorders.

Dendrimers seem to offer many advantages over viruses. They may be much less toxic, and they may offer other advantages in terms of cost, ease of production, and the ability to transport very long genes. If they can be designed to efficiently — and safely — shuttle genes into human cells, then they may be a more practical solution to gene therapy than viruses.

So far, laboratory experiments with different types of dendrimers have shown that they can insert genes into cells, but only with very low efficiency. Hoping to discover the key to improving this efficiency, Voulgarakis and his colleagues simulated the detailed, atomic-level physical process of dendrimers entering cells. They varied parameters like the dendrimer size and the length of the DNA they carry. Modeling these parameters on a computer is a fast, inexpensive approach for testing different ideas and optimizing the delivery vehicle.

What they uncovered were the key factors that determine the success of dendrimers as gene delivery vehicles — things like the charges of the dendrimers and their target cell membranes, the length of DNA, and the concentration of surrounding salt. Their work has illuminated some of the molecular-level details that should help clinicians design the most appropriate gene vectors.

“Our study indicates that, over a broad range of biological conditions, the dendrimer/nucleic acid package will be stable enough to remain on the surface of the cell until translocation,” says Voulgarakis.

Dendrimers are also used clinically for delivering cancer drugs to tumors, and for helping to image the human body. In the future, Voulgarakis and his colleagues plan to study the possibility of using dendrimers as drug delivery vehicles.

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