A View from Emily Singer
Biomedical News in Brief
Mimicking autism, new drugs for skin cancer, and a promising treatment for muscular dystrophy.
Mimicking autism in mice
By deleting a single gene in mice, researchers have created a strain of animals that show two key characteristics of autism; abnormal social interactions and repetitive behavior. The gene, called Shank3, codes for a protein found in the connections between neurons and has previously been implicated in human genetic studies of autism.
“We now have a very robust model with a known cause for autistic-like behaviors. We can figure out the neural circuits responsible for these behaviors, which could lead to novel targets for treatment,” said senior author Guoping Feng, professor of brain and cognitive sciences and member of the McGovern Institute for Brain Research at MIT, in a press release from the university.
According to the release;
Even though only a small percentage of autistic patients have mutations in Shank3, Feng believes that many other cases may be caused by disruptions of other synaptic proteins. He is now doing a study, with researchers from the Broad Institute, to determine whether mutations in a group of other synaptic genes are associated with autism in human patients.
If that turns out to be the case, it should be possible to develop treatments that restore synaptic function, regardless of which particular synaptic protein is defective in the individual patient, Feng says.
The research was published online in Nature earlier this month.
Zebrafish point to new combination treatments for cancer
Using zebrafish designed to mimic melanoma, an aggressive skin cancer, researchers from Children’s Hospital Boston identified a potential new drug combination—an existing arthritis drug and a compound currently in clinical trials for cancer—stopped tumor growth in mice.
The engineered fish carry mutations in a gene called BRAF, which has previously linked to melanoma. Researchers exposed the animals to 2000 chemicals in search of those that would prevent formation of abnormal cells, called neural crest cells, which are linked to later risk of cancer.
According to a press release from the hospital;
[Leonard Zon, director of the hospital’s Stem Cell Program] and his colleagues found that a compound that interfered with dihydroorotate dehydrogenase (DHODH), an enzyme involved in neural crest cell development, showed promise.
The team turned to leflunomide, a DHODH-inhibitor approved to treat forms of arthritis. In the zebrafish model, leflunomide knocked down expression of a number of genes overexpressed in both melanomas and neural crest cells, while in rats it prevented neural crest stem cells from renewing themselves. Leflunomide also stopped the growth of cultured cells from human melanomas and caused regression of human tumors transplanted into nude mice.
According to Zon, “We realized that a combined blockade of DHODH and BRAF would cooperate to suppress melanoma growth by targeting both the fate and the growth of melanoma precursors.” The researchers then tested in mice a combination of leflunomide and a BRAF inhibitor developed by Plexxikon, which is in late-stage clinical trials. Together, the combination of drugs led to an almost complete abolition of tumor growth; 40 percent of the mice experienced a near complete tumor regression.
“The combination of the two drugs was more effective than either drug alone, and allowed us to use lower doses of each,” said Zon, who has begun to plan a clinical trial of the combination treatment. “It will be interesting to put them into the clinic together.”
The research was published today in the journal Nature.
A promising treatment for muscular dystrophy
An experimental drug shows promise in treating a specific form of muscular dystrophy, an inherited muscle wasting diseases that strikes in childhood and causes severe disability. The drug, called an antisense oligonucleotide, is made up of a short strand of nucleic acids, the building blocks of RNA and DNA. The molecule is designed to eliminate the abnormal part of the protein in a subset of children with a specific mutation in the gene for dystrophin. It is being developed by Prosensa, a Dutch biopharmaceutical company and pharmaceutical giant GlaxoSmithKline and is now in late-stage clinical trials.
According to a piece from WebMd;
When the body is decoding the dystrophin gene, the drug causes the mRNA that is “reading” the gene to skip over the mutated exon 51. The result is a dystrophin protein that isn’t exactly normal, but which works well enough. Muscular dystrophy patients who have naturally occurring dystrophin like this have a much milder form of the disease known as Decker’s muscular dystrophy.
In their study, van Deutekom and colleagues enrolled 12 DMD patients at an average age of 9 years. In the first phase of the study, they gave increasing doses of the drug to sets of three patients. There were no serious safety issues, and patients given higher doses showed evidence of making functional dystrophin.
This led to a second phase in which all 12 patients received weekly abdominal injections of PRO051 at the highest dose tested.
“We noticed a modest improvement, which is quite remarkable for patients with this disease, in the distance they can walk in six minutes,” van Deutekom says. “The dystrophin probably accumulated over time in their muscles and led to the observed improvement.”
The research was published in the New England Journal of Medicine.