Angelman's syndrome is a neuro-genetic disorder characterized by severe developmental delays, seizures, speech impairments and physical impairments. It is an epigenetic disease and other treatments focus on symptoms. It is caused by a deletion or mutation of the maternal allele for the
ubiquitinproteinligase E3A.[11]UBE3A is expressed in most body tissues. However, in neurons only the maternal copy of the gene is expressed. UBE3A is located on
chromosome 15 and the paternal copy for the gene is genetically imprinted and is silenced by an
antisense RNA transcript. The maternal copy control center of the gene is methylated, suppressing transcription in the antisense direction while the paternal copy control center is unmethylated.[12]
Treatment involves unsilencing the paternal allele allowing the normal paternal UBE3A allele to be transcribed. UBE3A, in normal function, adds ubiquitin chains to proteins to target unnecessary or damaged proteins for degradation by the
proteasome.[13]
16 topoisomerase inhibitors unsilence paternal UBE3A. Topoisomerases are enzymes that regulate the unwinding of DNA.[14] Of these 16 inhibitors, topotecan was found to induce the strongest upregulation of UBE3A.[15] The enzymes bind to the DNA and cut the phosphate backbone, allowing the DNA to be unwound. Topotecan unsilences the paternal UBE2A allele by reducing the transcription of an antisense transcript. Topotecan inhibits topoisomerase I restoring UBE3A levels to wild-type range in cultured mince neurons.[16]
Transgenic mice with a fluorescently tagged UBE3A were used to test the effectiveness of unsilencing the paternal copy.[12] When tested on mice in vivo, topotecan affected the
hippocampus,
striatum and
cerebral cortex but not the
cerebellum unless a higher dose was administered (21.6 micrograms/hour for five days). The study suggested that the topoisomerase inhibitors have the potential to produce a normally functioning UBE3A protein. Most symptoms due to Angelman's syndrome are traditionally treated by
speech therapy,
physical therapy and
occupational therapy.
Anti-seizure medication is often prescribed as seizures are a common symptom of Angelman's syndrome.[17] These treatments target only symptoms.
This drug has been administered to cancer patients. It was well tolerated when administered to pediatric and adult patients.
Mechanism of action
Topotecan is a semi-synthetic derivative of
camptothecin. Camptothecin is a natural product extracted from the bark of the tree
Camptotheca acuminata. Topoisomerase-I is a nuclear enzyme that relieves torsional strain in
DNA by opening single strand breaks.[18] Once topoisomerase-I creates a single strand break, the DNA can rotate in front of the advancing replication fork. In physiological environments, topotecan is in equilibrium with its inactive carboxylate form.[19] Topotecan's active lactone form
intercalates between DNA bases in the topoisomerase-I cleavage complex.[20] The binding of topotecan in the cleavage complex prevents topoisomerase-I from religating the nicked DNA strand after relieving the strain.[20] This intercalation therefore traps the topoisomerase-I in the cleavage complex bound to the DNA.[20] When the replication-fork collides with the trapped topoisomerase-I, DNA damage occurs.[20] The unbroken DNA strand breaks and mammalian cells cannot efficiently repair these double strand breaks.[21] The accumulation of trapped topoisomerase-I complexes is a known response to apoptotic stimuli.[22] This disruption prevents DNA replication and ultimately leads to cell death. This process leads to breaks in the DNA strand resulting in
apoptosis. Administration of topotecan down-regulates its target, topoisomerase-I; therefore, it is dosed to maximize efficacy and minimize related toxicity.[19] Topotecan is often given in combination with
paclitaxel as first line treatment for extensive-stage
small-cell lung cancer.[19]
Side effects
Myelosuppression, specifically neutropenia, leukopenia, anemia, and thrombocytopenia
Diarrhea, nausea, vomiting, stomatitis, and constipation
^Léger F, Loos WJ, Bugat R, Mathijssen RH, Goffinet M, Verweij J, et al. (December 2004). "Mechanism-based models for topotecan-induced neutropenia". Clinical Pharmacology and Therapeutics. 76 (6): 567–78.
doi:
10.1016/j.clpt.2004.08.008.
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^Gelderblom H, Loos WJ, Sissung TM, Burger H, Nooter K, Soepenberg O, et al. (July 2004). "Effect of ABCG2 genotype and mRNA expression on the bioavailability of topotecan". Journal of Clinical Oncology. 22 (14 suppl): 2015.
doi:
10.1200/jco.2004.22.90140.2015.
PMID28015603.
^Haglof K (2006). "Recent developments in the clinical activity of topoisomerase-1 inhibitors". Update on Cancer Therapeutics. 1 (2): 117–145.
doi:
10.1016/j.uct.2006.05.010.
^Bertrand R, Solary E, O'Connor P, Kohn KW, Pommier Y (April 1994). "Induction of a common pathway of apoptosis by staurosporine". Experimental Cell Research. 211 (2): 314–21.
doi:
10.1006/excr.1994.1093.
PMID8143779.
^DNA Topoisomerases and Cancer, Yves Pommier Editor, Humana Press 2012
Sources
Dagli AI, Mueller J, Williams CA (1993-01-01). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.).
Angelman Syndrome. University of Washington, Seattle.
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