Source: Thailand Medical News Nov 18, 2019 5 years, 3 days, 14 hours, 54 minutes ago
Salk Institute researchers have developed a new gene therapy to help decelerate the aging process.
Aging is a leading risk factor for a number of debilitating conditions, including heart disease, cancer and Alzheimer's disease, to name a few. This makes the need for anti-
aging therapies all the more urgent.
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The research findings, published in the journal
Nature Medicine, highlight a novel
CRISPR/Cas9 genome-editing therapy that can suppress the accelerated aging observed in mice with Hutchinson-Gilford progeria syndrome, a rare genetic disorder that also afflicts humans. This treatment provides important insight into the molecular pathways involved in accelerated
aging, as well as how to reduce toxic proteins via gene therapy.
Dr Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory and senior author of the paper told
Thailand Medical News, "
Aging is a complex process in which cells start to lose their functionality, so it is critical for us to find effective ways to study the molecular drivers of
aging. Progeria is an ideal
aging model because it allows us to devise an intervention, refine it and test it again quickly."
Due to early onset and fast progression, progeria is one of the most severe forms of a group of degenerative disorders caused by a mutation in the LMNA gene. Both mice and humans with progeria show many signs of
aging, including DNA damage, cardiac dysfunction and dramatically shortened life span. The LMNA gene normally produces two similar proteins inside a cell: lamin A and lamin C. Progeria shifts the production of lamin A to progerin. Progerin is a shortened, toxic form of lamin A that accumulates with age and is exacerbated in those with progeria.
First author Hsin-Kai Liao, a staff researcher in the Izpisua Belmonte lab further commented "Our goal was to diminish the toxicity from the mutation of the LMNA gene that leads to accumulation of progerin inside the cell.We reasoned that progeria could be treated by
CRISPR/Cas9-targeted disruption of both lamin A and progerin."
The medical researchers utilized the
CRISPR/Cas9 system to deliver the gene therapy into the cells of the progeria mouse model expressing Cas9. An adeno-associated virus (AAV) was injected containing two synthetic guide RNAs and a reporter gene. The guide RNA ushers the
Cas9 protein to a specific location on the DNA where it can make a cut to render lamin A and progerin nonfunctional, without disrupting lamin C. The reporter helps researchers track the tissues that were infected with the AAV.
Sixty days after the delivery of the therapy, the mice were stronger and more active, with improved cardiovascular health. They showed decreased degeneration of a major arterial blood vessel and delayed onset of bradycardia (an abnormally slow heart rate), two issues commonly observed in progeria and old age. Overall, the treated progeria mice had activity levels similar to normal mic
e, and their life span increased by roughly 25 percent.
Dr Pradeep Reddy, a postdoctoral fellow in the Izpisua Belmonte lab and an author of the paper said, "Once we improve the efficiency of our viruses to infect a wide range of tissues, we are confident that we will be able to increase life span further."
The results suggest that targeting lamin A and progerin using a
CRISPR/Cas9 system can dramatically improve the physiological health and life span of progeria mice. These results provide a significant new understanding of how scientists may eventually be able to target molecular drivers of
aging in humans.
Coming efforts will focus on making the therapy more effective and will refine it for human use. Currently, there is no cure for progeria, so the symptoms are managed and complications are treated as they arise.
Dr Izpisua Belmonte, holder of the Roger Guillemin Chair commented, "This is the first time a gene editing therapy has been applied to treat progeria syndrome,". "It will need some refinements, but it has far fewer negative effects compared to other options available. This is an exciting advancement for the treatment of progeria."
Reference: : Ergin Beyret et al, Single-dose CRISPR–Cas9 therapy extends lifespan of mice with Hutchinson–Gilford progeria syndrome, Nature Medicine (2019). DOI: 10.1038/s41591-019-0343-4
