CRISPR-Cas9 and LASER ART for HIV Eradication

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Solution Overview

Problem

Current treatments for HIV infection, particularly in eradicating the virus from viral reservoirs, face limitations in achieving long-term undetectable viremia without antiretroviral therapy and in effectively targeting and removing integrated retroviral DNA.

Innovation Solution

A combination therapy using long-acting slow effective release antiretroviral therapy (LASER ART) and gene editing with CRISPR-Cas systems, specifically targeting HIV genomes in humanized mice, where antiretroviral agents like dolutegravir, lamivudine, and rilpivirine are nanoformulated for enhanced bioavailability and CRISPR-Cas9 is used to edit HIV genomes, excising proviral DNA fragments.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antiretroviral therapy is used, then viral replication is suppressed, but integrated retroviral DNA in reservoirs persists and virus rebounds after treatment cessation

Engineering Contradiction:

Improvelong-term viral suppressionVSAvoidpersistence of viral reservoirs

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The CRISPR-Cas9 gene editing system is designed to preemptively target and excise integrated proviral DNA from viral reservoirs before viral rebound can occur. The gRNA-Cas9 complex is delivered to infected cells and specifically binds to HIV genomic sequences, cutting the DNA at targeted locations to prevent reactivation of latent virus

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention extracts and removes the harmful integrated retroviral DNA from the host genome using CRISPR-Cas9 mediated gene editing. The system specifically targets and excises proviral sequences from viral reservoirs, physically removing the genetic material that enables viral persistence and rebound

Inventive Principle:

Principle #2Taking out (Extraction)

2Manufacturing precision

If CRISPR-Cas9 gene editing is used to target integrated HIV DNA, then proviral DNA excision is achieved, but delivery efficiency to infected cells remains a challenge

Engineering Contradiction:

Improvespecificity of HIV genome targetingVSAvoiddelivery system complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

Lipid nanoparticle vectors serve as intermediary carriers to deliver CRISPR-Cas9 components into infected cells. These nanoparticles encapsulate the gene editing machinery and facilitate cellular uptake, bridging the gap between extracellular delivery and intracellular action while protecting the fragile CRISPR components

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention optimizes multiple parameters of the delivery system including lipid nanoparticle composition, size, charge, and stability to enhance cellular uptake efficiency. By adjusting these physical and chemical parameters, the system achieves improved delivery to target cells while maintaining the specificity of CRISPR-Cas9 targeting

Inventive Principle:

Principle #35Parameter changes

3Reliability

If multiple antiretroviral agents are combined (LASER ART), then pharmacokinetic coverage is improved, but drug resistance and toxicity may develop

Engineering Contradiction:

Improvepharmacokinetic coverageVSAvoiddrug resistance and toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention merges conventional LASER ART with CRISPR-Cas9 gene editing to create a dual-action therapeutic approach. The combination leverages the immediate viral suppression effect of antiretrovirals while simultaneously deploying the curative potential of genome editing to eliminate reservoirs, achieving synergistic effects that overcome the limitations of either approach alone

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The CRISPR-Cas9 system performs preliminary action by excising integrated proviral DNA before antiretroviral pressure can select for resistant mutants. By removing the genetic template for viral replication upfront, the system prevents the development of drug resistance that typically arises during prolonged ART treatment

Inventive Principle:

Principle #10Preliminary action

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

This approach demonstrates the potential for HIV eradication in a significant percentage of infected animals, with restored CD4+ T cells and no viral rebound post-treatment, indicating successful sterilization of the virus and improved pharmacokinetic profiles of antiretroviral drugs.

Implementation Method 1

gene editing with CRISPR-Cas systems, specifically targeting HIV genomes in humanized mice, where antiretroviral agents like dolutegravir, lamivudine, and rilpivirine are nanoformulated for enhanced bioavailability and CRISPR-Cas9 is used to edit HIV genomes, excising proviral DNA fragments

Methodology Applied

Scientific EffectCRISPR-Cas9 gene editing:

Implementation Method 2

long-acting slow effective release antiretroviral therapy (called LASER ART)

Methodology Applied

Scientific EffectLong-acting slow effective release (LASER):

Implementation Method 3

antiretroviral agents like dolutegravir, lamivudine, and rilpivirine are nanoformulated for enhanced bioavailability

Methodology Applied

Scientific EffectNanoformulation: Nanoporous Material

Data Source

PatentUS20210060138A1CRISPR and LASER ART Eliminates HIV

Publication Date: 2021.03.04 BOARD OF RGT UNIV OF NEBRASKA

AI summary

Methods of eliminating a retrovirus from a subject utilize nanoformulated anti-retroviral compounds and gene editing agents. Compositions comprise at least one anti-retroviral compounds, at least one gene-editing agent, or combinations thereof.