September 24, 2017 |
Cancer Drug Shows Potential for Angelman and Prader-Willi Syndromes
August 6, 2013  | 

Sacramento, CA — UC Davis researchers have identified how and where in the genome a cancer chemotherapy agent acts on and ‘un-silences’ the epigenetically silenced gene that causes Angelman syndrome.

The agent, Topotecan, is a topoisomerase inhibitor, part of a class of drugs that in earlier research has been found to un-silence the Angelman gene, suggesting that it might be therapeutic for the condition, which affects approximately 1 in 25,000, or approximately 150,000 people worldwide. But how it acts has not been known.

Topotecan is primarily used to treat metastatic cancers, including ovarian cancer, cervical cancer and small-cell lung cancer, by preventing cells from dividing and causing their death.

The research, published online yesterday in Proceedings of the National Academy of Sciences (PNAS), found that the drug stabilizes the formation of strands of RNA that create RNA-DNA hybrids called ‘R-loops,’ in the Ube3a region of the gene15q11-q13. The gene is implicated in other neurodevelopmental disorders, including autism. About 1 percent of cases of autism are linked to duplications in 15q11-q13 or “Dup15q,” children that over-express Ube3a.

The research was conducted using molecular genetic approaches in neural cells from a genetically engineered mouse model and in cell lines containing inserted mouse and human genetic sequences.

“Now we have a molecular mechanism for a proposed drug for a disease, so we can understand how it works and begin to tweak it to develop therapies,” said lead study author Weston Powell, a third-year medical student in the Physician Scientist Training Program in the UC Davis School of Medicine. Continue>

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