Angelman is a genetic disorder caused by mutations in the\u00a0UBE3A gene, which encodes a protein of the same name. Everyone inherits two copies of the\u00a0UBE3A\u00a0gene, one from each biological parent \u2014 but in certain brain cells, only the copy inherited from the biological mother is active. Angelman syndrome develops when this maternal copy has a mutation leading to low functional UBE3A protein levels in those brain cells.<\/p>\n
One potential strategy to treat Angelman would be to turn on the paternally inherited copy of the UBE3A\u00a0gene in brain cells. Theoretically, this could provide functional UBE3A protein in key brain regions to effectively address the underlying cause of Angelman. Rugonersen is designed to do just that: It\u2019s designed to reduce levels of UBE3A-ATS, an RNA molecule that normally acts to silence the paternal copy of the UBE3A gene in cells.<\/p>\n
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Tests in cells, mice, primates show promise<\/p>\n
Rugonersen belongs to a class of genetic medicines called antisense oligonucleotides. Researchers, in search of an antisense oligonucleotide that can target UBE3A-ATS to increase UBE3A protein levels, conducted a screen of many such molecules in nerve cells derived from Angelman patients, and identified rugonersen as a potential Angelman treatment.<\/p>\n
They first conducted tests in nerve cells in dishes, then in mouse models of Angelman, and finally in nonhuman primates. In all these models, rugonersen consistently led to an increase in UBE3A protein levels as designed, and safety data didn\u2019t indicate any unacceptable risks.<\/p>\n
\u201cRugonersen produced a long-lasting reduction of UBE3A-ATS in monkey brains, concomitant with upregulation of paternal UBE3A\u201d protein, the researchers wrote.<\/p>\n
The discovery and preclinical development of rugonersen were funded by Roche, which subsequently launched a Phase 1 clinical trial (NCT04428281)<\/a> that tested the therapy in dozens of children with Angelman syndrome. Although safety data from the study were generally positive, efficacy markers fell short of what Roche had determined would be necessary to justify investing in further development, and in 2023 the company said it would no longer pursue rugonersen development<\/a>.<\/p>\n Yet the study\u2019s authors said the Phase 1 trial \u201crevealed signals of clinical improvement in core AS symptom domains beyond expectation from natural history data.\u201d<\/p>\n