Antisense Oligomer Targeting CYP3A5 mRNA for Renal Selective Inhibition

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Solution Overview

Problem

Current antihypertensive treatments are unable to specifically inhibit cytochrome P450 3A5 (CYP3A5) enzyme without affecting other cytochrome P450 enzymes, leading to undesirable side effects and uncontrolled hypertension in some patients, particularly in populations with darker skin colors, and renal transplant patients taking immunosuppressive drugs.

Innovation Solution

Administration of antisense oligomers that target and reduce the expression of CYP3A5 enzyme, specifically designed to bind to the AUG start site or G4 structures within the CYP3A5 mRNA, using phosphorodiamidate morpholino oligonucleotides or phosphorothioate 2′-O-methyl oligoribonucleotides, to decrease salt retention and hypertension.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If substrate inhibitors are used to inhibit CYP3A5, then CYP3A5 enzyme activity is reduced, but other cytochrome P450 enzymes are also inhibited causing undesirable side effects

Engineering Contradiction:

ImproveCYP3A5 inhibition efficacyVSAvoidside effects from non-specific inhibition

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention divides the inhibition approach into two separate mechanisms: antisense oligomers that specifically target CYP3A5 mRNA for degradation, and substrate inhibitors that block the active site. The antisense component provides gene-specific inhibition without affecting other P450 enzymes, while the substrate inhibitor component can be used at lower doses with reduced off-target effects.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention introduces antisense oligomers as an intermediary that specifically binds to CYP3A5 mRNA to prevent translation. This intermediary approach allows selective reduction of CYP3A5 protein synthesis without directly competing with substrate inhibitors for the enzyme active site, thereby avoiding non-specific inhibition of other P450 enzymes.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If CYP3A5 is inhibited to treat hypertension, then blood pressure control is improved, but reactive metabolite formation and kidney damage may occur

Engineering Contradiction:

Improvehypertension controlVSAvoidreactive metabolite formation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The invention applies preliminary action by using antisense oligomers to prevent CYP3A5 protein synthesis before the enzyme can generate harmful reactive metabolites. By blocking mRNA translation at the genetic level, the approach eliminates the source of reactive oxygen species and hydroxyl radicals that would otherwise be produced during CYP3A5 catalytic activity.

Inventive Principle:

Principle #10Preliminary action

3Adaptability or versatility

If broad-spectrum CYP3A inhibitors are used, then multiple CYP3A enzymes are inhibited, but specificity for CYP3A5 is lost

Engineering Contradiction:

Improvebroad CYP3A inhibitionVSAvoidCYP3A5 specificity

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

The invention applies local quality by designing antisense oligomers with sequences specifically complementary to CYP3A5 mRNA regions that differ from other CYP3A isoforms. This localized sequence specificity ensures that only CYP3A5 mRNA is targeted for degradation, while CYP3A4 and other P450 enzymes remain unaffected.

Inventive Principle:

Principle #3Local quality

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 antisense oligomers effectively reduce CYP3A5 production, thereby lowering blood pressure with reduced side effects and specific targeting to the kidney, improving hypertension control and preventing organ transplant rejection.

Implementation Method 1

antisense oligomers that target and reduce the expression of CYP3A5 enzyme, specifically designed to bind to the AUG start site or G4 structures within the CYP3A5 mRNA

Methodology Applied

Scientific EffectAntisense oligomer binding:

Data Source

PatentUS10538769B2Renal selective inhibition of cytochrome P450 3A5

Publication Date: 2020.01.21 THE STATE OF OREGON ACTING BY & THROUGH THE OREGON STATE BOARD OF HIGHER EDUCATION ON BEHALF OF OREGON STATE UNIV

AI summary

Compositions and methods for treating hypertension in a subject are provided, including administering an antisense oligomer effective to reduce expression of cytochrome P450 3A5 (CYP3A5) enzyme. The antisense oligomer includes phosphorodiamidate morpholino oligonucleotide (PMO), phosphorothioate 2′-O-methyl oligoribonucleotides (PSO), locked nucleic acid nucleotide, locked nucleic acid analog nucleotide, or another modified oligonucleotide backbone or nuclease-resistant backbone. The antisense oligomer is administered transdermally, subcutaneously, or orally, and optionally with a pharmaceutically acceptable carrier. In one embodiment, the antisense oligomer is an oligomer that is antisense to mRNAs that encode CYP3A5, for instance targeted at the AUG start site of the mRNAs that encode CYP3A5 or at a G4 structure within CYP3A5.