Skip to main content
Premium Trial:

Request an Annual Quote

Fruit Fly Assay Screens for Therapies for Disparate Disorders

Premium

A University of Arizona investigator was granted an unspecified amount of funding this week from the Autism Speaks foundation to continue developing a Drosophila neuron-based assay for autism research and drug discovery.

The same screen can also be used to identify potential therapies for gliomas, according to the researcher.

The assay is being developed by Linda Restifo, a professor of neurobiology, cell biology, and neurology at the UA College of Medicine and the Arizona Research Laboratory division of neurobiology. It screens for fascin, which is believed to be important in brain development, Restifo told CBA News this week.

A lack of fascin results in neurons with a "curly" shape, and is associated with impaired cognitive functioning in children with autism or mental retardation. Conversely, fascin expression in carcinoma and glioma cells in adults is associated with increased tumor aggression and metastases.

Restifo explained that by using different fascin mutations in fruit flies, the researchers could control the amount of fascin in the neurons.

"The severity of the curliness is inversely proportional to how much fascin [the neurons] have," she said. "You can think of that in terms of the actual amount of protein or the amount of protein function."

Said Restifo, "I had gotten some money from the National Institutes of Health to try this drug screen on the curly, fascin-deficient neurons. As we were getting geared up to start that screen, I was doing my usual monthly literature searches on fascin, and what I realized was that the bulk of the publications were coming from cancer biology."

She added that an increasing number of research papers were saying that in the different kinds of carcinomas, the more aggressive tumors had higher levels of fascin, and that patients with high levels of fascin in their tumors had worse clinical outcomes.

Restifo said that although the investigators’ original goal was to try to cure fascin-deficient neurons, they then asked, "What if we redesigned the drug screen so that we were also looking for things that would make the curliness worse by blocking the little bit of fascin present in the mutant neurons?"

That would give the investigators the ability to screen for compounds that compensate for the loss of fascin, in the context of developmental brain disorders in children, and they could also screen for drugs that block fascin expression or function, which would be useful for treating adults with carcinomas and gliomas.

Super Fly

Restifo and her lab are using this fruit fly-based system to screen compounds chosen from a library of about 1,000, most of which are already approved by the Food and Drug Administration for other indications.

The neurons are dissected out under a microscope from the brain of a fruit fly at the maggot stage. Each group of cells is treated with a single drug. The cells are cultured for three days and then observed under the microscope for morphological changes.

Restifo declined to specify which compounds were used in the screen until the data are published. She did say however, that all of compounds in the library are listed on the NINDS web site, and they cover "the whole gamut of chemical drug types and the medical indications that they are used for. You would see lots of things that you recognize as over-the-counter or prescription drugs."

[ pagebreak ]

Restifo did mention that her lab identified "several dozen drugs that either normalized the curliness or made the curliness worse."

Tim Tully, chief scientific officer of CNS drug developer Dart Neuroscience and a former colleague of Restifo’s, told CBA News that "above and beyond what Linda is talking about, my lab at Cold Spring Harbor, in collaboration with other researchers, has in fact produced evidence that genes involved in four different forms of mental retardation in humans are specifically involved in long-term memory formation in the fly model, and that drugs made against genes in long-term memory can ameliorate the symptoms in a mouse of one form of mental retardation."

Tully went to say this implies that there are probably going to be many types of mental retardation in humans that are occurring because the biochemistry of memory formation is dysfunctional. Consequently, because it’s a biochemical defect, "we should be able to find to find small molecule drugs that could be used to treat those conditions," he said.

"The discovery is that we do not think that all forms of mental retardation will necessarily be developmental disabilities" about which doctors can do nothing, Tully added.

Tully also said he believes that the day will come when a pharmaceutical or a biotech company will get a drug approved from this kind of work that has an application treating some type of mental retardation. "I think it would spark a radical change in the way that we think about mental retardation," he said.

Into Mammalian Models

The immediate next step in this work is to move testing into mammalian models, said Restifo. "I have always viewed the fruit fly model as a stepping stone," she said. The researchers must validate their data by studying either mouse models of developmental brain disorders or testing the drugs that they think will be effective against gliomas and carcinomas in human tumor cells.

"I have lots of grant applications pending to try and push this work into mammalian validation studies," Restifo said. She estimated she would have a more definite timeline for this phase of the research within the next few months because many of the grant applications were submitted in the fall.

Commercialization of this assay is something that "I think about a lot, but I think that timing will be really key," Restifo said. Little VC money is currently available. So, "I think we should stay in the academic arena for now until we have done a few more proof-of-concept studies, and wait for the right opportunity, both scientifically and economically, to move it out of the university arena," said Restifo.

She did say that the assay can be used to identify new compounds "if it can be automated to shift towards higher throughput." It is currently a medium-throughput assay.

"I have some ideas with some very innovative collaborators, and we might be able to automate the actual set up of the neuronal culture. We have a grant application at the NIH that is pending to do that as well," she said.

"I am kind of on the fence about whether or not we should wait to do more cross-species validation studies" prior to submitting a manuscript for publication, said Restifo.

There are also some very tricky intellectual property issues, she said. "If we cannot protect the IP, nobody is going want to invest in it. If I let the cat out of the bag, so to speak, about what drugs [were used in the screen], then it will make the IP protection virtually impossible."

Restifo continued by saying that, in speaking with technology transfer experts, she had not yet been able to "figure a way out of this," except to actually do some studies in mice. "I am hoping that we can do some of those key experiments later this year, and publish on the basis of that," she said.

The Scan

Shape of Them All

According to BBC News, researchers have developed a protein structure database that includes much of the human proteome.

For Flu and More

The Wall Street Journal reports that several vaccine developers are working on mRNA-based vaccines for influenza.

To Boost Women

China's Ministry of Science and Technology aims to boost the number of female researchers through a new policy, reports the South China Morning Post.

Science Papers Describe Approach to Predict Chemotherapeutic Response, Role of Transcriptional Noise

In Science this week: neural network to predict chemotherapeutic response in cancer patients, and more.