The paper of the week reports using base-editing, a kind of gene-editing, to reverse mutations associated with rapid aging syndromes, generally called progeria, but there are a lot of other interesting pubs to recommend for reading this week. I go over it all in this post.
Gene-editing to fight premature aging syndromes
In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice, Nature. This work comes from a team led by David Liu. It rightly made a big splash in the media. While it’s still a long, difficult road ahead to develop this as a treatment for people with progeria, this paper lays a remarkable foundation for that. They used a number of models. They were able to use base-editing to correct mutations in human fibroblasts. In addition they were able to achieve phenotypic rescue in transgenic mice using a prototype base-editing viral treatment approach:
“In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20–60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days.”
There will be challenges to try to develop this as a treatment for patients with Hutchinson-Gilford and other progeria syndromes, but I think there’s real hope long-term. One of the hurdles will be figuring out safe and effective delivery in people.
The possible safety issues relate to potential off-target effects, indels, and potential aberrant transcriptional events that can arise from the specific sites were the virus integrates in the genome, which can also be monitored by WGS and other assays. More whole-genome sequencing or WGS likely required in future studies.
What percent of the cells in the human body would need to be gene-edited to achieve a meaningful treatment? In humans, which tissues will be most crucial to target? Much likely depends on which organs are most responsible for the most harmful aging phenotypes in a particular syndrome and patient, but you’re going to need to give patients a massive amount of virus to treat premature aging.
Also, what will be the optimal timing of treatment after diagnosis?
I’d expect that this approach may require multiple treatments as well and as the authors point out, to be effective base-editing may be combined with other progeria treatments as well.
Finally, would you consider this kind of potential future gene-editing treatment to prevent a rapid-aging syndrome a form of regenerative medicine? I think so.
More recommended pubs
Sequential fate-switches in stem-like cells drive the tumorigenic trajectory from human neural stem cells to malignant glioma, Cell Research. Thinking about these trajectories brings to mind a Waddington Landscape Model that invokes oncogenic transformation. See one below that my student Taylor Seamount and I put together years ago.
- Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes, in Contrast to Adipose Tissue-Derived Stromal Cells, Efficiently Improve Heart Function in Murine Model of Myocardial Infarction, Biomedicines. While the heart may not normally have its own stem cells, there has been encouraging research suggesting that some kinds of regenerative therapies could potentially help heart conditions in the future.
- Studying leukemia stem cell properties and vulnerabilities with human iPSCs, Stem Cell Research. More disease modeling research using IPS cells. So far, it seems IPS cells have had more clinical and translational impact via modeling than by use as a basis for making cell therapy products for transplantation. That could change over the next decade as more trials unfold.
- Non-canonical Wnt/PCP signalling regulates intestinal stem cell lineage priming towards enteroendocrine and Paneth cell fates, Nature Cell Biology.
- Analysis of the stability of 70 housekeeping genes during iPS reprogramming, Scientific Reports. Do housekeeping genes get enough respect?
- Platelets Facilitate the Wound-Healing Capability of Mesenchymal Stem Cells by Mitochondrial Transfer and Metabolic Reprogramming, Cell Metabolism
- Notch signaling induces either apoptosis or cell fate change in multiciliated cells during mucociliary tissue remodeling, Developmental Cell
- A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis, Science. From some of the scientists from BioNTech now of COVID mRNA vaccine fame.