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| Status |
Public on Aug 07, 2022 |
| Title |
Identification and Characterization of a MAPT-targeting Locked Nucleic Acid Antisense Oligonucleotide Therapeutic for Tauopathies III |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of Tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic acid-modified antisense oligonucleotides (LNA-ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3’UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well-tolerated and produced a robust, long lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post-injection and corresponded with tau protein reduction in the CSF. Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.
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| Overall design |
RNA-seq for hiPSC-derived neurons (SA001; NIH Registration Number 0085; Cellectis, Sweden) differentiated for 42 days
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| Contributor(s) |
Easton A, Jensen ML, Wang C, Hagedorn PH, Li Y, Weed M, Meredith JE, Guss V, Jones K, Gill M, Krause C, Brown JM, Hunihan L, Fernandes A, Lu Y, Polino J, Bookbinder M, Cadelina G, Benitex Y, Sane R, Morrison J, Drexler D, Mercer SE, Bon C, Pandya NJ, Jagasia R, Yang TO, Distler T, Grüninger F, Meldgaard M, Terrigno M, Macor JE, Albright CF, Loy J, Hoeg AM, Olson RE, Cacace AM |
| Citation(s) |
36090761 |
| Submission date |
Jul 25, 2022 |
| Last update date |
Nov 06, 2022 |
| Contact name |
Amy Easton |
| Organization name |
Genentech, Inc
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| Department |
Department of Neuroscience
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| Street address |
1 DNA Way
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| City |
South San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94080 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (1) |
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| Relations |
| BioProject |
PRJNA862193 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE209747_RAW.tar |
4.7 Gb |
(http)(custom) |
TAR (of BAI, BAM) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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