Department of Dermatology Associate Scientist Deeba Syed, MBBS, PhD, recently confirmed the validity of early tests for a revolutionary anti-cancer mechanism developed by Aseem Ansari’s lab in the Department of Biochemistry.
The molecule synthesized by the Ansari Lab targets the genetic condition Friedrich’s Ataxia, which disrupts production of the critical protein frataxin by replicating signals within the genetic codes used to transcribe and produce the protein.
Syed explained the problem in lay terms:
“In a normal situation, RNA polymerase—the enzyme that transcribes proteins—‘walks’ on the gene, picks up the genetic code, and transcribes the code to produce the protein. In diseased genes, some of the signals in the code are repeated, sort of tripping the polymerase and preventing it from walking on it.” The molecule developed by the Ansari Lab is designed to bind itself to the gene and “pull the RNA polymerase forward so it keeps walking on the gene in spite of any repetition.”
The Ansari Lab conducted cell culture experiments on their synthetic molecule in both established cell lines and in cell lines derived from a variety of patients with Friedrich’s Ataxia. They found that it worked, increasing the expression of the protein in the diseased variants.
“The next step was to confirm the phenomenon in animals, which is when they approached us.”
Syed developed a mouse model of the disorder by injecting both diseased and normal cells bearing a luciferase reporter (a bioluminescent compound commonly used to measure the size of tumors in cancer research) into immunosuppressed mice. The compound was then injected into these animals and several types of readouts were used to gauge its efficacy.
“We were able to show in an unambiguous manner that the compound can increase transcription of the gene. We are currently designing subsequent experiments to complement these early studies in other transgenic mouse models of the disease.” After further confirmation, the Ansari Lab can begin developing a clinical deployment for the molecule.
Once implemented, it could have wide ranging effects. Though the molecule was specifically developed and tested to work against Friedrich’s Ataxia, the mechanism that makes it effective “could act on a diverse array of diseases caused by different stages of transcriptional dysfunction,” according to the article in Science announcing the discovery.
In other words, Ansari’s synthetic molecule could lead to effective therapy for a great number of genetic disorders and the patients affected by them.
Deeba Syed is a scientist in the lab of Professor Hasan Mukhtar. She was assisted in this project by a visiting fellow in the Mukhtar Lab, Durdana Waseem of Quaid-i-Azam University in Pakistan.
Readers with a subscription to Science Magazine can read the article here: http://science.sciencemag.org/content/358/6370/1617
The article on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29192133