MAPT RNAi Conjugates for Blood-Brain Barrier Tau Silencing
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Solution Overview
Problem
Current therapeutic options for neurodegenerative diseases like Alzheimer's disease and tauopathies primarily focus on symptomatic relief rather than disease modification, and existing treatments face challenges such as blood-brain barrier penetration and off-target effects, limiting the development of effective tau-targeting therapies.
Innovation Solution
Development of chemically modified small interfering RNAs (siRNAs) that selectively inhibit microtubule-associated protein tau (MAPT) gene expression, combined with specific antigen binding proteins and lipid PK/PD modulators for targeted delivery to CNS cells, reducing MAPT protein levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used for neurodegenerative diseases, then symptomatic relief is achieved, but disease modification is not accomplished
Solution Approach 1:
The patent uses RNAi agents as intermediaries to deliver therapeutic effect. These agents specifically target and silence pathological tau gene expression, acting as a mediator between the administration route and the target cells in the CNS, enabling disease modification rather than just symptomatic relief
Solution Approach 2:
The patent employs chemical modifications to the RNAi agents (such as 2'-O-methyl modifications) to change the pharmacokinetic and pharmacodynamic parameters of the therapeutic molecule, improving its stability, brain penetration, and specificity while reducing off-target effects
2Reliability
If RNAi agents are delivered to target CNS cells, then MAPT gene expression inhibition is achieved, but blood-brain barrier penetration remains challenging
Solution Approach 1:
The patent uses antigen binding proteins and lipid PK/PD modulators as intermediaries to facilitate the transport of RNAi agents across the blood-brain barrier, enabling delivery to CNS cells without requiring complex delivery devices or procedures
Solution Approach 2:
The patent creates composite therapeutic molecules by combining RNAi agents with antigen binding proteins and lipid modulators, forming a composite material that possesses both the gene-silencing capability of RNAi and the blood-brain barrier penetration ability of the protein-lipid conjugate
3Productivity
If conventional therapies are administered, then treatment coverage is provided, but off-target effects occur
Solution Approach 1:
The patent applies local quality by designing RNAi agents with specific nucleotide sequences that are complementary only to the target MAPT mRNA, ensuring that the therapeutic effect is localized to the intended target and does not affect other genes or biological processes
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The MAPT RNAi agents provide highly potent and efficient inhibition of MAPT gene expression, offering therapeutic benefits for neurodegenerative diseases by decreasing MAPT protein levels and potentially modifying disease progression.
Implementation Method 1
The sense strand and the antisense strand are partially, substantially, or fully complementary to each other
Data Source
AI summary
Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a microtubule associated protein tau (MAPT) gene. The MAPT RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of a MAPT gene. The MAPT RNAi agents are conjugated to an antigen binding protein that may enable subcutaneous delivery of the RNAi agents by facilitating crossing of the blood brain barrier (BBB). Pharmaceutical compositions that include one or more MAPT RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described MAPT RNAi agents to central nervous system (CNS) tissue, in vivo, provides for inhibition of MAPT gene expression and a reduction in MAPT activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including Alzheimer's disease, Frontotemporal lobar degeneration dementia (FTLD), Progressive supranuclear palsy, and other tauopathies.