PNPLA3 Expression Modulators via Antisense Oligonucleotides

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Solution Overview

Problem

Current treatments for non-alcoholic fatty liver disease (NAFLD) and related conditions, such as non-alcoholic steatohepatitis (NASH), are inadequate in effectively reducing PNPLA3 expression and activity, leading to ongoing liver damage and disease progression.

Innovation Solution

Development of compounds and compositions that specifically target and inhibit PNPLA3 mRNA and protein expression, using antisense oligonucleotides and other modified oligonucleotides to reduce liver damage, steatosis, and inflammation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for NAFLD and NASH are used, then liver disease management is maintained, but PNPLA3 expression and activity are not effectively reduced, leading to ongoing liver damage and disease progression

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidPNPLA3 expression and activity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts and targets the specific harmful component PNPLA3 for inhibition while leaving the rest of the liver system intact. Antisense oligonucleotides are designed to specifically bind to PNPLA3 mRNA, extracting the harmful effect of this specific gene product without affecting other liver functions.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the expression level parameter of PNPLA3 by introducing antisense oligonucleotides that reduce mRNA stability and translation. This parameter change (from normal to reduced expression) directly addresses the harmful effect of excessive PNPLA3 activity in NAFLD and NASH.

Inventive Principle:

Principle #35Parameter changes

2Ease of operation

If PNPLA3 expression is not inhibited, then current treatment protocols are maintained, but liver damage, steatosis, and inflammation continue to progress

Engineering Contradiction:

Improvesimplicity of treatment protocolVSAvoidliver damage, steatosis, and inflammation

Core Design Contradiction:

Ease of operationVSObject-affected harmful factors

Solution Approach 1:

The patent applies preliminary action by administering antisense oligonucleotides before significant liver damage occurs. The treatment prevents disease progression by inhibiting PNPLA3 expression early in the disease course, addressing harmful factors before they become irreversible.

Inventive Principle:

Principle #10Preliminary action

3Adaptability or versatility

If existing treatments are used, then treatment accessibility is maintained, but therapeutic potency is insufficient to effectively reduce PNPLA3 activity

Engineering Contradiction:

Improvetherapeutic valueVSAvoidPNPLA3 protein amount

Core Design Contradiction:

Adaptability or versatilityVSQuantity of substance

Solution Approach 1:

The patent introduces antisense oligonucleotides as an intermediary substance that mediates between the administered treatment and the target PNPLA3 mRNA. This intermediary mechanism provides superior therapeutic potency by directly interfering with mRNA translation, achieving greater reduction in PNPLA3 protein levels compared to existing treatments.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20240076675A1Modulators of pnpla3 expression

Publication Date: 2024.03.07 IONIS PHARMACEUTICALS INC

AI summary

The present embodiments provide methods, compounds, and compositions useful for inhibiting PNPLA3 expression, which may be useful for treating, preventing, or ameliorating a disease associated with PNPLA3.