CRISPR-Cas9 genome editing therapy has been shown by the Salk Institute team to suppress the accelerated aging observed in mice with Hutchinson-Gilford Progeria syndrome; and provided insight into the molecular pathways involved in accelerated aging, and how to reduce toxic proteins via gene therapy.
Having an early onset and fast progression progeria is a severe form of degenerative disorder caused by LMNA gene mutations; signs of accelerated aging include DNA damage, cardiac dysfunction, and dramatically shortened lifespan. LMNA genes produce lamin A and lamin C inside a cell, progeria shifts production of lamin A to progerin which is a toxic shortened form of lamin A that accumulates with age and becomes exacerbated with the condition.
Progeria currently has no cure, and is an ideal model as it allows researchers to devise and intervention, refine it, and then retest it quickly. Then end goal is to diminish toxicity from mutated LMNA genes, CRISPR-Cas9 technology was believed to possibly be able to treat progeria by targeting lamin A and progerin.
Using CRISPR-Cas9 technology to deliver therapy into cells of progeria mouse models an adeno-associated virus was injected containing 2 synthetic guide RNAs and reporter gene to deliver the Cas9 protein to a specific location on the DNA where it would make a cut to render progerin and lamin A nonfunctional, without disrupting lamin C; and help to track the tissue infected with the AAV.
The animals were stronger, more active, with improved cardiovascular health, decreased degeneration of major arterial blood vessels, and delayed onset of bradycardia in just two months after they had therapy. The treated animals had activity levels similar to that of normal mice, and their lifespans increased by about 25%.
Researchers are confident once they improve the efficiency of their viruses to infect a wider range of tissues they will be able to increase lifespan even further, which will help future efforts to be eventually refined for human use. When taken together findings suggest that CRISPR-Cas9 technologies can improve health and lifespans of progeria mice; and provide new understandings of how researchers may be able to target molecular drivers of aging in human.
