Scientists at universities and pharmaceutical companies alike in the next several years may be working in a transformed research environment, one in which ideas may more quickly and cheaply be translated into effective therapies to treat a wide array of life-robbing illnesses.
Instead of targeting offending proteins in disease with small-molecule drugs – the standard way to develop new pharmaceuticals today – the hope is to interfere with a different type of molecule, already famous in some guises, called a nucleic acid.
Through the Human Genome Project launched two decades ago, scientists produced a Rosetta stone for getting a handle on all our deoxyribonucleic acid, or DNA. DNA is the stuff of genes, of course. Genes encode and direct the production of proteins, which in turn give us form and enable us to function.
Using this key for what a healthy human’s genes ought to look like, researchers now have made huge strides in figuring out which genetic abnormalities play important roles in disease.
In cancer, for instance, the DNA mutations that drive out-of-control tumor growth typically are those that cause genes to be switched on abnormally. This leads to abnormal biochemical signaling by proteins. Many of these proteins now are targets for new drug development by major pharmaceutical companies.
But DNA is not the only nucleic acid of interest. Another type of nucleic acid, called RNA, promises to put academic scientists on the cutting edge of drug development. It’s these research scientists at universities who are most likely to make the groundbreaking discoveries that lead to whole new classes of drugs. Yet even lab scientists who work at major academic medical centers – alongside physician-colleagues who lead clinical trials – have traditionally found it prohibitively time-consuming and expensive to translate their discoveries into useful therapies.
Fortunately, that situation now may be changing, thanks to the Nobel Prize-winning discovery of RNA interference. RNA interference is a process whereby small RNA molecules govern the activity of specific genes. There is a class of molecules called short inhibitory RNAs, or siRNAs, which can be made in the laboratory and “tuned” to interfere with and inactivate almost any gene. Researchers already can reliably accomplish this in the lab. Soon, it may also prove possible to inhibit disease-causing genes in humans.
The same UCSF researchers who took the early lead in developing biotechnologies that now are widely used to track genes and genetic abnormalities in disease – including expression profiling, fluorescence in situ hybridization (FISH) and comparative genomic hybridization – now have formed a new, multi-university consortium. They have reached out to other exceptionally talented scientists at several leading cancer research centers to advance cancer drug development based on siRNA.
The siRNA therapeutics consortium includes laboratory and clinical researchers from UCSF, UC Berkeley, UC San Diego and MD Anderson Cancer Center, and is led by Joe Gray, PhD, and Frank McCormick, PhD, at UCSF and Steve Martin, PhD, at UC Berkeley. The consortium includes experts in cancer target identification, experts in basic siRNA research and experts in drug delivery.
The common genetic abnormalities that arise in cancers now are increasingly well known. However, the functions of these abnormal genes in many cases are still not understood. SiRNA may not yet be a treatment – although a few siRNA drugs have entered clinical trials. But in recent years, siRNA already has become an established research tool. Researchers use siRNA to knock down genes and discover their functions. They are using siRNA to find out which abnormal genes in cancer really are critical for tumors to survive, grow and spread.
siRNA as New Type of Cancer Treatment
But McCormick and Gray are particularly excited about siRNA’s potential as a new type of cancer treatment.
Traditionally, drug companies have tried to make small molecules to target the proteins encoded by critical genes in cancer. However, many proteins are not “druggable” in this way. Furthermore, demonstrating that proteins are worth targeting and testing small-molecule drugs preclinically take many years, sometimes a decade or more, and are very costly.
With siRNA, researchers are looking upstream in the biochemical chain of events within a tumor cell that triggers out-of-control and potentially deadly behavior. Instead of only targeting already formed protein molecules, researchers can switch off the genes that control production of these cancer-promoting proteins. SiRNA now is being investigated as a drug strategy to inactivate genes that otherwise would contribute to abnormal protein production and tumor growth.
If siRNA realizes its potential for cutting preclinical drug identification and development costs, drug companies may become more willing to pursue truly innovative drug strategies. Companies may spend less time and money developing and marketing “me-too” drugs, which with minimal molecular modifications have approximately the same pharmacological effects as competitors’ drugs.
How does siRNA work, and what makes it so different? To target a particular gene via siRNA, researchers actually target its messenger RNA, an intermediary in protein production made by transcribing the gene’s DNA sequence. Scientists need only consider a finite list of small, well-defined siRNA sequences to match the messenger RNA.
Instead of screening tens of thousands or even millions of molecules to identify potential drug candidates, as is traditionally done to identify small molecules with which to target a protein, the researchers might make and test tens to hundreds of siRNAs. It requires comparatively little time to conduct the initial evaluation of siRNA molecules in an academic laboratory and to determine which siRNAs will interfere the best.
Similar Approach Should Work in Many Diseases
“Theoretically, once you have figured out how to manufacture and deliver an siRNA to target one gene, then you have an approach that can be used for any gene,” Gray says.
Coming up with an siRNA that targets a single gene can be done in an individual scientist’s academic laboratory. By contrast, finding a small molecule drug candidate to target the protein itself typically requires the resources of pharmaceutical companies.
However, there is still more to be done before settling on a manufacturing technique for siRNA therapies. And it remains a significant challenge to find ways to deliver siRNA to tumor cells in patients.
Again, UCSF and consortium researchers are combining their talents to marry innovative ideas for getting the siRNAs to tumor cells within the body. UCSF researchers led by John Park, MD, and James Marks, MD, PhD, have for many years been working to develop a vehicle for delivering siRNA and other drugs to targeted cells.
Their approach is to encapsulate siRNA within microscopic fat sacs called liposomes. Some versions of liposomes already are used for commercial drug delivery. Park is an expert on liposome delivery, and Marks is one of the world’s experts in targeting antibodies to specific markers on cells – including molecules that may be uniquely displayed on cancer cells.
“We’re not there yet, but it’s quite promising,” Gray says. “I think the UCSF-led consortium is at the forefront of research in this area. Successful development of a strategy to deliver siRNAs to humans will put drug development in the hands of university researchers. This will be incredibly enabling for translating research into better treatment.”
Lab image by Kaz Tsuruta