The Pros and Cons of Non-Heritable Stem Cell Reprogramming Using the Approach of Breda et al.
"In vivo hematopoietic stem cell modification by mRNA delivery"
I was asked to “Debate This” by a netizen of the Twitternet to a tweet of mine:
In vivo hematopoietic stem cell modification by mRNA delivery https://www.science.org/doi/abs/10.1126/science.ade6967
Pro-Bone Marrow Stem Cells Reprogramming Argument
1. No chemo: Traditional bone marrow transplantation methods require high doses of chemotherapy or radiation as conditioning regimens, which have severe side effects. In contrast, the reprogramming approach can potentially mitigate the risks and discomfort associated with conventional methods.
2. Bypassing donor requirement: The approach Breda et al. used doesn't require the use of stem cells from a donor, eliminating the need for compatible donor matching, which can be time-consuming and difficult to find, saving the donor from potential complications from harvesting, as well.
3. Genetic disorders cure: By leveraging gene editing, this new technique allows for the correction of genetic disorders within the body itself, potentially providing a cure for conditions that were previously untreatable or could only be managed symptomatically.
4. High efficiency: The use of lipid nanoparticles for mRNA delivery and targeting of hematopoietic stem cells is reported to show high efficiency, with near-complete correction of hematopoietic sickle cells.
5. Expansion of treatment accessibility: By removing the need for donors and reducing the potential risks of treatment, this method could make the treatment of blood disorders more accessible to a larger number of patients.
Con-Bone Marrow Stem Cells Reprogramming Argument
1. Early-stage technology: This is a novel method that, while promising, may require more rigorous testing and research to fully understand the long-term effects and potential complications, especially given the “non-specific effects” of mRNA COVID-19 injections (aka, adverse events, evidence of genomic integration (likely mutagen), and more (see below).
2. Immunological implications: The immune system's response to the in vivo gene editing process isn't entirely clear, and there could be unforeseen consequences related to immune reactions.
3. Off-target effects: Gene-editing technologies, despite their precision, can sometimes interact with non-target genetic material, causing off-target effects which could lead to adverse consequences.
4. Uncertainty around complete disease eradication: While the technique shows near-complete correction of hematopoietic sickle cells, the 'near-complete' caveat implies some diseased cells may persist, potentially causing relapse or continuous disease symptoms.
5. Ethical and regulatory concerns: The utilization of gene-editing technologies in humans has raised ethical and regulatory issues. The long-term implications of such changes deserve careful and serious evaluation, not FDA rubber-stamping for headlines and advocacy. Regulations and public opinion could potentially slow down the advancement and implementation of this technique; activism for this method could thwart the emergence of other alternatives that are not as “sexy”.
On balance, and in principle, I would want to see the long-term health effects of this therapy in animals (I am truly sorry animal rights activists, I don’t want to give people cancer).
Seems like the Pro Stem Cells Reprogramming argument might be summarized as: the conventional approach is very imperfect.
The other major (an very relevant) aspect that is overlooked is the targeting technology built into the LNP: "We developed CD117/LNP–messenger RNA (mRNA), a lipid nanoparticle (LNP) that encapsulates mRNA and is targeted to the stem cell factor receptor (CD117) on HSCs. " The research group used LNPs that had antibodies that bind to CD117 (c-Kit).
"CD117 is internalized after the binding of SCF (stem cell factor), which we hypothesize may facilitate or augment LNP internalization" - "By decorating the surface of LNPs with targeting moieties, we have demonstrated effective targeting to specific cell types, such as endothelial cells and T cells, with therapeutic efficacy upon single intravenous injection in mice, as described in our previous reports (9–11)." - "Humanized" antibodies carry a great deal of immunologic risk.
The language of "effective targeting" omits an important component to "safe and effective" gene editing for non-heritable stem cells": specificity of target. In the text they admit that there is off-target internalization of the LNPs: "Intravenous administration of CD117/LNP-Luc generated luciferase activity in the femur at 24 hours, whereas IgG/LNP-Luc did not (Fig. 3A). Both control IgG/LNP-Luc and CD117/LNP-Luc showed comparable luciferase activity in the liver because LNPs bind apolipoprotein E (ApoE) and are non-specifically targeted to the low-density lipo-protein (LDL) receptor, which is expressed on hepatocytes (8)." There was also the observation that lung cells were affected by the LNPs.
This is technology applied in mice and the level of work done by this group is heads-and-shoulders better than the data FDA received from either Pfizer, Moderna or whatever R&D group supplied the "safety" data to the FDA for the COVID jabs.