Nanotech could be answer to gene therapy delivery

Problems with delivery systems for genes - often based on the use of viral vectors - have already caused researchers to pull gene therapy projects. An inhaled adenoviral vector-delivered gene therapy led to the death of a US patient after it caused an inflammatory response in the lungs.

And in 2003 a number of trials were halted after French researchers reported a higher than expected number of cases of leukaemia among children being treated for the fatal 'baby-in-a-bubble' syndrome, severe combined immunodeficiency (X-SCID) using a retroviral gene therapy. This led the US Food and Drug Administration (FDA) to issue a moratorium on the conduct of all gene therapy trials using retroviruses.

Now, scientists at the Lankenau Institute for Medical Research and Massachusetts Institute of Technology (MIT) have performed preclinical proof-of- principle studies showing how nanotechnology can be used as a non-viral approach to enhance gene therapy for cancer.

The nanotechnology-based approach used by the researchers has minimal toxic side effects to normal cells.

the MIT group identified a polymer termed C32 that the Lankenau group demonstrated was capable of delivering genes to cancer cells more efficiently and with less toxicity than other polymers that have been tested in the field to date. C32 works by condensing the DNA in a gene and allowing the resulting nanoparticles that are formed to enter cells through a process called endocytosis. Therapeutic genes delivered to cells in this manner are able to drive cellular production of a gene-encoded protein through normal processes.

The researchers used the polymer to deliver a genetically modified diphtheria toxin gene that would be produced only in prostate cells. When this was injected into the prostate tumours in animals, tumour growth was suppressed or reversed (in 40 per cent of cases), relative to untreated tumors.

Dr Janet Sawicki, one of the investigators at Lankenau, said that the study showed that the C32 nanoparticles deliver DNA very efficiently to tumor cells, "C32 delivered DNA intratumorally around four-fold better than one of the best commercially available reagents, jetPEI (polyethyleneimine), and 26-fold better than naked DNA,"​ she said. Moreover, it was also very inefficient at delivering its genetic payload to healthy muscle cells. This feature may help safeguard the healthy tissue surrounding tumours, offering a significant improvement over currently available therapies, which tend to damage the healthy tissue near the cancer.

The results of the study were reported as a cover article in a recent issue of the Proceedings of the National Academy of Sciences.

In future work, the Lankenau and MIT researchers aim to expand their work to test whether this nanotechnology can be adapted for a non-radioactive type of brachytherapy, a practice that has grown in popularity to treat localised prostate cancer. They also aim to explore whether nanoparticles can be delivered intravenously to attack metastatic tumour cells, which are found throughout the body in advanced stages of cancer.