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Today we report on unpublished findings that Benjamin Philpot presented 20 March at the New York Academy of Sciences. A compound his lab is investigating to treat Angelman syndrome can turn on a deficient gene associated with the disorder for a year or more — and perhaps permanently — in mice.
In addition to the chemical’s long-lasting effect, its specificity is surprising. The drug — a topoisomerase inhibitor called topotecan, currently used to treat some cancers — seems to only affect expression of the Angelman syndrome-linked gene, UBE3A.
UBE3A is an imprinted gene, meaning that one copy, in this case the paternal copy, is silenced. Individuals with Angelman syndrome have mutations in the maternal copy, leading to complete loss of function of the gene. Unsilencing the healthy paternal copy could make up for that deficiency.
Topoisomerase inhibitors such as topotecan interfere with the enzymes necessary for DNA replication. How exactly topotecan unsilences UBE3A remains unclear. But because such genes can be turned on and off by chemical changes independent of the DNA sequence — a process known as epigenetics — scientists have assumed that any drugs that change imprinted genes would affect many other genes across the board.
If instead these chemicals can target individual genes, it’s good news for other disorders linked to imprinted genes, such as Prader-Willi syndrome. Indeed, some imprinted genes have been linked to autism, including GABRB3, SHANK2 and APBA2.
What do you think?
- What molecular mechanisms might explain the specificity of topotecan?
- Despite the promising results, topotecan’s inability to permeate the blood–brain barrier remains a major hurdle in becoming an effective treatment. What novel delivery method might get such compounds into the brain?
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