Pulsed Low-Dose RANKL Therapy for Atherosclerosis and Bone Loss

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Solution Overview

Problem

Current treatments for atherosclerosis and osteoporosis-related bone loss are inadequate, as they either fail to directly address bone loss or come with severe safety issues and high costs, and existing therapies do not effectively reduce inflammation or promote bone formation.

Innovation Solution

Administering a low-dose RANKL at pulsed intervals to induce FoxP3+ CD8 T-cells (TcREG), which suppress osteoclast activity and promote bone formation, thereby reducing atherosclerotic lesions and osteoporosis symptoms.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If anti-inflammatory agents (NSAIDs, steroids, biologics) are used to treat inflammation and bone loss, then inflammation is reduced, but severe safety issues and adverse reactions occur

Engineering Contradiction:

ImproveinflammationVSAvoidsafety

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent introduces regulatory T cells (Tregs) as intermediary cells that mediate between the immune system and bone tissue. Tregs are activated by RANKL to suppress osteoclast activity and reduce inflammation simultaneously, avoiding the direct harmful effects of NSAIDs and steroids while achieving both anti-inflammatory and bone-protective effects

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent converts the harmful effect of RANKL (which normally promotes osteoclast activity and bone loss) into a beneficial effect by using low-dose RANKL to activate Tregs. The activated Tregs then suppress osteoclasts and reduce inflammation, transforming RANKL from a bone-destructive agent into a therapeutic tool that protects bone and reduces inflammation

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

2Quantity of substance

If bisphosphonates are used to prevent bone loss, then bone mass is maintained, but osteonecrosis of the jaw and increased fracture risk occur

Engineering Contradiction:

Improvebone massVSAvoidosteonecrosis and fracture risk

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

Instead of directly inhibiting osteoclasts as bisphosphonates do, the patent inverts the approach by using low-dose RANKL to activate Tregs, which then indirectly suppress osteoclasts. This indirect suppression maintains bone mass while avoiding the direct toxic effects of bisphosphonates on bone tissue and jaw necrosis

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent enables the immune system to self-regulate bone metabolism through Treg activation. The activated Tregs naturally suppress osteoclast activity and promote bone formation without requiring continuous external drug intervention, reducing the risk of severe side effects associated with long-term bisphosphonate use

Inventive Principle:

Principle #25Self-service

3Quantity of substance

If Denosumab is used to block RANKL, then bone loss is reduced, but infection risk increases due to off-target effects

Engineering Contradiction:

Improvebone massVSAvoidinfection risk

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by using low-dose RANKL specifically at the bone interface to activate Tregs, rather than systemically blocking RANKL with Denosumab. This localized approach achieves bone protection while avoiding the widespread immune suppression and infection risk associated with systemic RANKL blockade

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent changes the dosage parameter of RANKL from high-dose blockade (Denosumab) to low-dose activation. This parameter change transforms RANKL's effect from suppressing bone formation to activating Tregs for bone protection, avoiding the infection risk while maintaining bone mass

Inventive Principle:

Principle #35Parameter changes

4Quantity of substance

If pulsed low-dose RANKL is administered, then Tregs are activated and bone mass increases, but precise dosing control is required

Engineering Contradiction:

Improvebone massVSAvoiddosing control

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The patent employs periodic action by administering RANKL in pulsed intervals rather than continuously. This periodic administration allows Treg activation and bone formation while preventing osteoclast overactivation, achieving bone mass increase with manageable dosing complexity through scheduled pulses

Inventive Principle:

Principle #19Periodic action

Data Source

PatentUS10328123B2Pulsed introduction of low-dose RANKL as a therapy for atherosclerosis

Publication Date: 2019.06.25 SAINT LOUIS UNIV

AI summary

Systems and methods for inhibiting atherosclerosis using FoxP3+ CD8 T-cells (TcREG). Osteoclasts are induced to produce FoxP3+ CD8 T-cells (TcREG) through introduction of a low-dose of a RANK agonist suck as RANKL. The RANKL was found to best work when provided in accordance with a schedule resulting in a pulsed administration.