What is Angelman syndrome?
Angelman syndrome is a rare disease caused by mutations in a gene called UBE3A. The mutations mean that the protein ubiquitin-protein ligase E3A is not made in certain brain regions, leading to the symptoms of the disease.
Humans usually have two copies of every gene — one inherited from each parent. However, for some genes, only the copy from one parent is used to make protein. In the case of UBE3A, the maternal copy is used to make protein and is the one affected by mutations in Angleman syndrome. Every cell also has an inactive copy of the paternal copy of the UBE3A gene, so some therapies are targeted at “turning on” the inactive paternal copy of the gene to replace the function of the mutated copy of the UBE3A gene.
How does indotecan work?
Indotecan contains a small molecule that inhibits a protein called topoisomerase 1 (Top1). Top1 controls and changes DNA structure during the process of making a temporary copy of a gene, a process called transcription. This temporary copy, called messenger RNA (mRNA) is then used as a template by the protein-making machinery of the cell.
Top1 also is necessary for the process of DNA replication in cells; when cells divide, they need to replicate their DNA so that both of the new cells have a copy of the genome. In cancer, where cell division is uncontrolled, inhibiting Top1 may be an effective treatment to slow tumor growth.
Indotecan in clinical trials
Researchers at the University of North Carolina demonstrated, in cell culture and mouse models of Angelman syndrome, that indotecan was able to un-silence the paternal copy of UBE3A. The results of their study were published in the journal Molecular Autism. The researchers think this occurs because the silencing machinery that turns off the paternal copy of UBE3A is inhibited, and they propose that indotecan could be a potential treatment for Angelman syndrome.
As yet, no clinical trials for indotecan in Angelman syndrome have been started. However, the safety and tolerability of the treatment were examined in a Phase 1 clinical trial (NCT01794104) in cancer patients with malignant solid tumors or lymphoma (a type of blood cancer). A total of 21 participants were involved in the study. Patients received indotecan every day for five days, or once per week. The first patient in each group was monitored; if no adverse reactions occurred, the next patient received a higher dosage of the treatment.
The results of the study were published in Cancer Chemotherapy and Pharmacology. The researchers established a maximum safe dosage of 60 mg/m2 per day for five days (the dosage is presented in units of treatment to body surface area), or 90 mg/m2 once per week.
Last updated: Oct. 20, 2019
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