Gene Therapy to Disable Lamin A as a Potential Treatment for Progeria

Hutchinson-Gilford progeria syndrome (HGPS), or simply progeria, is a very rare condition caused by mutation in the lamin A gene. Patients exhibit a condition that superficially resembles greatly accelerated aging. They typically die very young from forms of cardiovascular disease usually only found in much later life. Lamins are important structural proteins, and the broken form of lamin A in progeria patients, known as progerin, results in cells with misshapen nuclei and significant dysfunction. In the sense that aging is an accumulation of damage and dysfunction, progeria can thus resemble aging, but the type of damage and the details of its progression bear little resemblance to normal aging.

In the research noted here, scientists report the interesting finding that progeroid mice are actually better off with lamin A disabled than they are with progerin in circulation; this can be achieved via gene therapy. We watch work on progeria because researchers have determined that progerin is present to some degree in normal aged individuals. It remains an open question as to the degree to which this contributes to the dysfunction of aging: is it significant in comparison to all of the other forms of molecular damage that degrade cell and tissue function? We will probably not gain an answer to that question until such time as a therapy to eliminate progerin is deployed and then tested in old people as well as in progeria patients. The example here is most likely not that therapy: I would expect disabling lamin A entirely to cause more harm than help in old people who only exhibit small amounts of progerin.

With an 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.

The 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.

Two months 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 mice, and their life span increased by roughly 25 percent.



Todd is an important proof of concept that we can at least partially did genetic diseases. I remember there was an analogy of running the car without oil and then fixing the oil pump. You v stop the further damage but have little bearing on hold to fix normal old cars....

Nevertheless, if this therapy and vector prices to be safe it can be used for other minor conditions like increased risk of cardiovascular issues or macular degeneration.

Posted by: Cuberat at February 22nd, 2019 5:55 AM

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