CCR5-Knockout Stem Cells for HIV Latent Reservoir Elimination
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Solution Overview
Problem
Current treatments for HIV are ineffective against latent HIV reservoirs in stem cells, as conventional therapies struggle to eradicate the virus due to its dormancy and ability to replicate upon cell differentiation, leading to potential relapse after cessation of antiviral therapy.
Innovation Solution
Genetically modifying autologous mesenchymal stem cells to knockout the CCR5 gene using CRISPR/Cas9, making them resistant to HIV infection and replication, and reintroducing these cells to replace patient's immune cells, thereby preventing new latent reservoirs from forming.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antiviral therapy is used to treat HIV, then viral replication is suppressed during treatment, but latent HIV reservoirs in stem cells persist and can cause relapse after therapy cessation
Solution Approach 1:
The patent applies preliminary action by genetically modifying mesenchymal stem cells ex vivo before transplantation to knockout the CCR5 gene, which is the HIV co-receptor. This preliminary genetic modification ensures that the transplanted stem cells are pre-protected against HIV infection, preventing the formation of new latent reservoirs before they can establish infection in the patient's body.
Solution Approach 2:
The patent uses copying by creating genetically modified versions of the patient's own stem cells (autologous transplantation). The CCR5-knockout stem cells serve as modified copies that replace the original HIV-susceptible stem cells, providing a permanent genetic solution rather than temporary viral suppression.
2Object-affected harmful factors
If CCR5 gene knockout is performed on mesenchymal stem cells, then HIV resistance is achieved, but genetic modification complexity increases
Solution Approach 1:
The patent uses viral vectors as intermediaries to deliver the CCR5 knockout genetic material into mesenchymal stem cells. The viral vector serves as a mediator that facilitates the transfer of genetic information, simplifying the genetic modification process compared to direct gene editing methods while achieving the desired CCR5 knockout effect.
Solution Approach 2:
The patent replaces complex mechanical gene editing systems with biochemical methods using viral vectors and nucleic acid delivery. This substitution of mechanical systems with biochemical pathways simplifies the overall genetic modification process while maintaining effectiveness.
3Reliability
If autologous stem cell transplantation is performed, then immune rejection is avoided, but the risk of reintroducing occult malignant cells remains
Solution Approach 1:
The patent applies taking out by extracting and removing potentially malignant or damaged stem cells from the patient's original bone marrow, and replacing them with genetically modified healthy stem cells grown in controlled laboratory conditions. This extraction and replacement process eliminates malignant cells while maintaining immune compatibility.
Solution Approach 2:
The patent performs preliminary screening and purification of stem cells during the ex vivo expansion and genetic modification process, allowing for the detection and removal of malignant cells before transplantation. This preliminary quality control step prevents malignant cell reintroduction while maintaining the benefits of autologous transplantation.
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 modified stem cells can populate the body, replace HIV-susceptible immune cells, and potentially cure HIV by preventing viral entry and replication, as demonstrated by initial patient successes.
Implementation Method 1
Genetically modifying autologous mesenchymal stem cells to knockout the CCR5 gene using CRISPR/Cas9
Data Source
AI summary
A method of curing (or at least treating) HIV, by obtaining small tissue mesenchymal stem cells (stMSC) from adipose tissue of a patient with HIV or from a syngeneic donor or an immuno-compatible donor, wherein said stMSC are i) 4-6 μm in diameter, ii) pluripotent, and iii) have CD11b−, CD34−, CD45−, CD 29, CD 49, Oct 4 and SSEA 4 surface markers when harvested. Preferred sources are autologous adipose tissue. Next those stMSCs are gene edited to provide CCR5− stMSCs and optionally amplified by growth in culture and/or by cell selection for gene edited stMSCs and then re-introducing into the patient. Preferably, the CCR5− stMSCs will re-populate the patient with stem cells that can no longer act as latent HIV reservoirs and can differentiate into immune cells that are HIV resistant. If desired, the patient can be first treated, e.g., by radiation, to destroy the bone marrow cells before the re-introduction. However, this may not be necessary for patient who already has significant destruction of immunity by HIV.