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Genetic Linkage

New Roads to Drug Discovery for the New Year

In this age of expiring drug patents and stalled pipelines, I was pleasantly surprised to find in my morning batch of news releases four reports of promising, eclectic ways to fight diverse diseases. The efforts represent the entire trajectory in drug discovery, from the most basic research to a stage 3 clinical trial. Read on!

STRATEGY: Alter the insect vector
A genetically modified mosquito might sound like something from a science fiction film, but it is a powerful intervention in the horrific cycle that is malaria. George Dimopoulos and colleagues from the Johns Hopkins Malaria Research Institute altered a gene in the Anopheles mosquito in a way that ramps up its immune response against the parasite that causes malaria. The GM mosquitoes live as long as and lay as many eggs as their non-manipulated brethren. Perhaps with a few more tweaks they can take over, biting but not infecting.

STRATEGY: Awaken a dormant gene
Angelman syndrome is rare – 1 in 15,000 – and causes intellectual disability, developmental delay, seizures, uncontrollable movements, and inability to speak. It’s a disorder of genomic imprinting, occurring when the mother’s copy of a gene on chromosome 15 is absent, while the father’s is enshrouded in RNA, silenced. Benjamin Philpot and co-investigators at the University of North Carolina at Chapel Hill identified a class of approved anti-cancer drugs (topoisomerase inhibitors) that awaken the paternal gene. The drugs indeed turn on the gene for the missing protein in brain cells – in mice. Perhaps they will be useful against others of the 150+ diseases in humans that are the result of abnormal imprinting (the silencing of a gene from one gender only).

STRATEGY: Unveil a glitch hidden in the genome sequence
People who develop lung cancer but never smoked may have a gene fusion, finds a study from the Genomic Medicine Institute in Seoul. Jeong-Sun Seo and co-workers compared the genome sequences of a healthy cell and a lung cancer cell from a patient, seeking the differences. (NIH director Francis Collins took this approach for the cells of noted journalist Christopher Hitchens, who died on December 15 from esophageal cancer despite the use of the drug Gleevec, which his DNA suggested would work.)

When the usual oncogene and tumor suppressor suspects didn’t appear, the researchers considered RNA profiles. What were the cancer cells doing that the normal ones weren’t? And that’s when the gene fusion stood out – hidden in plain sight because it didn’t alter the DNA sequence. Instead, a piece of chromosome 10 flipped, juxtaposing the genes KIF5B and RET, the former harboring a section that boosted activity of the latter. The result: cancer. The gene fusion, which turned up in other patients, is now a drug target.

STRATEGY: Correct protein misfolding
In Fabry disease, a misfolded enzyme (alpha-galactosidase) causes its substrate to build up, clogging cells lining blood vessel interiors with fat, eventually harming the brain, heart, kidneys and skin. Enzyme replacement therapy can treat Fabry and a handful of other lysosomal storage diseases, but it’s costly and cumbersome, requiring infusion by a physician. An alternative, pharmacological chaperone therapy, is in phase 3 clinical trials and is a pill. Scott Garman and co-workers at the University of Massachusetts at Amherst attached two small “chaperone” molecules to the errant enzyme, guiding it to fold properly and function. The Fabry treatment may be a model for other disorders of protein folding, which include such rare diseases as Pompe, Gaucher, and Huntington’s diseases, and such common ones as Parkinson’s and Alzheimer’s diseases.

CODA: Biomedical research in general and drug discovery in particular are part of a vast continuum of experimental efforts, with the “breakthroughs” reaching the public the tiniest tip of the iceberg. Investigators do not just “find a cure,” like one falls out of the sky or pops up under a Petri dish. Recognizing or inventing what becomes a so-called breakthrough rests on understanding the science behind an illness – then manipulating the situation.
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