Identification and characterization of a MAPT-targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies

Easton, Amy; Jensen, Marianne L.; Wang, Congwei; Hagedorn, Peter; Li, Yuwen; Weed, Michael R.; Meredith, Jere E.; Guss, Valerie; Jones, Kelli; Gill, Martin R.; Krause, Carol; Brown, Jeffrey M.; Hunihan, Lisa; Natale, JoAnne E.; Fernandes, Alda; Lu, Yifeng; Polino, Joe; Bookbinder, Mark; Cadelina, Gregory; Benitex, Yulia; Sane, Ramola; Morrison, J. S.; Drexler, Dieter M.; Mercer, Stephen E.; Bon, Charlotte; Pandya, Nikhil J.; Jagasia, Ravi; Yang, Tai-Hsien Ou; Distler, Tania; Grüninger, Fiona; Meldgaard, Michael; Terrigno, Marco; Macor, John E.; Albright, Charles F.; Loy, James; Hoeg, Anja M.; Olson, R. E.; Cacace, Angela

doi:10.1016/j.omtn.2022.07.027

Cited by 12 publications

(14 citation statements)

References 60 publications

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“…As the last step in the optimization process, we created compounds building on the ideal properties identified so far. To generate potentially clinically meaningful compounds, we decided to work with an ASO targeting the MAPT gene . Specifically, two aspects were considered at this stage: first, replacing the one-step conjugation reaction by a two-step approach, with the aim to avoiding the high amounts of ASO substrate needed to drive the enzymatic KTG reaction.…”

Section: Discussionmentioning

confidence: 99%

“…49 In their study, two consecutive intrathecal injections of a MAPTtargeting ASO led to an 80% knockdown of tau transcript and tau protein in different brain regions of cynomolgus monkeys. 49 Overall, we demonstrate how a diligent approach to conjugate architecture can enable the creation of antibody-ASO conjugates with optimal PK characteristics. We believe that this four-step approach of (1) smart choice of conjugation technology, (2) careful optimization of the processes to produce conjugates, (3) generation of broad knowledge on the impact of basic design choices, and (4) adoption of the linker and linking technology to the payload of interest will help to accelerate the field of antibody-based delivery of oligonucleotides to the CNS.…”

Section: ■ Introductionmentioning

confidence: 98%

“…To develop the approach with a clinically relevant target, we used a locked nucleic acid (LNA)-ASO targeting the tau gene (microtubule-associated protein tau, MAPT) in neurons as a tool compound. Tauopathies are a group of neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD), , that originate from hyperphosphorylated, oligomerized tau forms or tangles, with differentiated pathological tau phenotypes .…”

Section: Introductionmentioning

confidence: 99%

“…Tauopathies are a group of neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD), , that originate from hyperphosphorylated, oligomerized tau forms or tangles, with differentiated pathological tau phenotypes . The application space of drugs targeting one type of misfolded tau protein is therefore limited; hence, targeting tau on the mRNA level with MAPT-directed ASOs is of great interest. , For example, Easton et al showed that LNA-ASOs can reach high levels of target reduction in the CNS space . In their study, two consecutive intrathecal injections of a MAPT-targeting ASO led to an 80% knockdown of tau transcript and tau protein in different brain regions of cynomolgus monkeys …”

Section: Introductionmentioning

confidence: 99%

“…The application space of drugs targeting one type of misfolded tau protein is therefore limited; hence, targeting tau on the mRNA level with MAPT-directed ASOs is of great interest. , For example, Easton et al showed that LNA-ASOs can reach high levels of target reduction in the CNS space . In their study, two consecutive intrathecal injections of a MAPT-targeting ASO led to an 80% knockdown of tau transcript and tau protein in different brain regions of cynomolgus monkeys …”

Section: Introductionmentioning

confidence: 99%

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Diligent Design Enables Antibody-ASO Conjugates with Optimal Pharmacokinetic Properties

Sela,

Mansø,

Siegel

et al. 2023

Bioconjugate Chem.

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Antisense-oligonucleotides (ASOs) are a promising drug modality for the treatment of neurological disorders, but the currently established route of administration via intrathecal delivery is a major limitation to its broader clinical application. An attractive alternative is the conjugation of the ASO to an antibody that facilitates access to the central nervous system (CNS) after peripheral application and target engagement at the blood–brain barrier, followed by transcytosis. Here, we show that the diligent conjugate design of Brainshuttle-ASO conjugates is the key to generating promising delivery vehicles and thereby establishing design principles to create optimized molecules with drug-like properties. An innovative site-specific transglutaminase-based conjugation technology was chosen and optimized in a stepwise process to identify the best-suited conjugation site, tags, reaction conditions, and linker design. The overall conjugation performance was found to be specifically governed by the choice of buffer conditions and the structure of the linker. The combination of the peptide tags YRYRQ and RYESK was chosen, showing high conjugation fidelity. Elaborate conjugate analysis revealed that one leading differentiating factor was hydrophobicity. The increase of hydrophobicity by the ASO payload could be mitigated by the appropriate choice of conjugation site and the heavy chain position 297 proved to be the most optimal. Evaluating the properties of the linker suggested a short bicyclo[6.1.0]nonyne (BCN) unit as best suited with regards to conjugation performance and potency. Promising in vitro activity and in vivo pharmacokinetic behavior of optimized Brainshuttle-ASO conjugates, based on a microtubule-associated protein tau (MAPT) targeting oligonucleotide, suggest that such designs have the potential to serve as a blueprint for peripherally delivered ASO-based drugs for the CNS in the future.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Diligent Design Enables Antibody-ASO Conjugates with Optimal Pharmacokinetic Properties

Sela,

Mansø,

Siegel

et al. 2023

Bioconjugate Chem.

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Novel avenues of tau research

Sexton,

Bitan,

Bowles

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONThe pace of innovation has accelerated in virtually every area of tau research in just the past few years.METHODSIn February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co‐organized and co‐sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation.RESULTSRepresenting academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research.DISCUSSIONThe virtual meeting provided an opportunity to foster cross‐sector collaboration and partnerships as well as a forum for updating colleagues on research‐advancing tools and programs that are steadily moving the field forward.

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TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models

Dominguez,

Laufer,

Ghosh

et al. 2023

iScience

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Identification and characterization of a MAPT-targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies

Cited by 12 publications

References 60 publications

Diligent Design Enables Antibody-ASO Conjugates with Optimal Pharmacokinetic Properties

Diligent Design Enables Antibody-ASO Conjugates with Optimal Pharmacokinetic Properties

Novel avenues of tau research

TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models

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