As mentioned in this session, senescent cells could become resistant to senolytic drugs at some point. So this sparked my imagination! I wondered if we could use CRISPR as a non-traditional senolytic therapy?
Basically, the idea is that CRISPR would be used to target specific gene(s) to drive apoptosis in senescent cells specifically. For example, the senolytic drug navitoclax inhibits BCL-XL, and this causes apoptosis in senescent cells. Using a similar approach, we could downregulate the BCL2-like 1 gene (encodes BCL-XL) with CRISPR repressors, and this would hopefully induce apoptosis in senescent cells.
There are various CRISPR technologies out there. There is the traditional gene editing, base editing, transcriptional regulation, etc. CRISPR based transcriptional regulation doesn't permanently change the DNA; it regulates the gene expression levels of a specific gene. This is contrary to traditional CRISPR gene editing, which makes permanent changes in the genetic code. CRISPR is a versatile tool; it has many applications and can be used to target multiple genes at once.
CRISPR based transcriptional regulation uses a dead Cas (dCas) with a transcriptional activator or repressor attached to it. A specific guide RNA is used to guide the dCas to the specific gene. The specific gene will be upregulated or downregulated depending on the transcriptional factor attached to dCas.
The Possible Target Genes
We might be able to remove senescent cells by targeting SCAPs or SASPs related pathways:
BCL-2 family (BCL-2, BCL-XL, etc.)
Here are some things to think about:
Which gene(s) should be targeted?
How will the senescent cells be specifically targeted?
Are CRISPR based transcriptional regulators the best option to go with?
Can genes be upregulated and downregulated simultaneously with CRISPR?
How long would the CRISPR components stay in the body?
Suppose things went wrong like for example healthy cells being targeted. How could we ensure safety?
What do you think of the idea? Do you think this idea could be further upgraded?
Yosef, Reut, et al. "Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL." Nature communications 7.1 (2016): 1-11.
Adli, Mazhar. "The CRISPR tool kit for genome editing and beyond." Nature communications 9.1 (2018): 1-13.
Maeder, Morgan L., et al. "CRISPR RNA–guided activation of endogenous human genes." Nature methods 10.10 (2013): 977-979.
Kirkland, James L., and Tamara Tchkonia. "Cellular senescence: a translational perspective." EBioMedicine 21 (2017): 21-28.