Molecular Therapy: Nucleic Acids (Sep 2022)
Identification and characterization of a MAPT-targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies
- Amy Easton,
- Marianne L. Jensen,
- Congwei Wang,
- Peter H. Hagedorn,
- Yuwen Li,
- Michael Weed,
- Jere E. Meredith,
- Valerie Guss,
- Kelli Jones,
- Martin Gill,
- Carol Krause,
- Jeffrey M. Brown,
- Lisa Hunihan,
- Joanne Natale,
- Alda Fernandes,
- Yifeng Lu,
- Joe Polino,
- Mark Bookbinder,
- Greg Cadelina,
- Yulia Benitex,
- Ramola Sane,
- John Morrison,
- Dieter Drexler,
- Stephen E. Mercer,
- Charlotte Bon,
- Nikhil J. Pandya,
- Ravi Jagasia,
- Tai-Hsien Ou Yang,
- Tania Distler,
- Fiona Grüninger,
- Michael Meldgaard,
- Marco Terrigno,
- John E. Macor,
- Charles F. Albright,
- James Loy,
- Anja M. Hoeg,
- Richard E. Olson,
- Angela M. Cacace
Affiliations
- Amy Easton
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA; Corresponding author Amy Easton, 1 DNA Way, South San Francisco, CA 94080, USA.
- Marianne L. Jensen
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Copenhagen, Hørsholm DK 2970, Denmark
- Congwei Wang
- Roche Pharma Research and Early Development, Neuroscience and Rare Disease Discovery and Translational Area, Roche Innovation Center Basel, 4070 Basel, Switzerland
- Peter H. Hagedorn
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Copenhagen, Hørsholm DK 2970, Denmark
- Yuwen Li
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Michael Weed
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Jere E. Meredith
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Valerie Guss
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Kelli Jones
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Martin Gill
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Carol Krause
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Jeffrey M. Brown
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Lisa Hunihan
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Joanne Natale
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Alda Fernandes
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Yifeng Lu
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Joe Polino
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Mark Bookbinder
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Greg Cadelina
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Yulia Benitex
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Ramola Sane
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- John Morrison
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Dieter Drexler
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Stephen E. Mercer
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Charlotte Bon
- Roche Pharma Research and Early Development, Neuroscience and Rare Disease Discovery and Translational Area, Roche Innovation Center Basel, 4070 Basel, Switzerland
- Nikhil J. Pandya
- Roche Pharma Research and Early Development, Neuroscience and Rare Disease Discovery and Translational Area, Roche Innovation Center Basel, 4070 Basel, Switzerland
- Ravi Jagasia
- Roche Pharma Research and Early Development, Neuroscience and Rare Disease Discovery and Translational Area, Roche Innovation Center Basel, 4070 Basel, Switzerland
- Tai-Hsien Ou Yang
- Roche Pharma Research and Early Development, pREDi Data Science, Roche Innovation Center New York, Little Falls, NJ 07424, USA
- Tania Distler
- Roche Pharma Research and Early Development, Neuroscience and Rare Disease Discovery and Translational Area, Roche Innovation Center Basel, 4070 Basel, Switzerland
- Fiona Grüninger
- Roche Pharma Research and Early Development, Neuroscience and Rare Disease Discovery and Translational Area, Roche Innovation Center Basel, 4070 Basel, Switzerland
- Michael Meldgaard
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Copenhagen, Hørsholm DK 2970, Denmark
- Marco Terrigno
- Roche Pharma Research and Early Development, Neuroscience and Rare Disease Discovery and Translational Area, Roche Innovation Center Basel, 4070 Basel, Switzerland
- John E. Macor
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Charles F. Albright
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- James Loy
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Anja M. Hoeg
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Copenhagen, Hørsholm DK 2970, Denmark
- Richard E. Olson
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Angela M. Cacace
- Bristol Myers Squibb Research and Development, Cambridge, MA 02142, USA
- Journal volume & issue
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Vol. 29
pp. 625 – 642
Abstract
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 (LNA)-modified antisense oligonucleotides (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 cerebrospinal fluid (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.
