Researchers at the Salk Institute have moved a step closer to a possible therapy for Hutchinson-Gilford progeria syndrome, a rare genetic disorder that is often described as accelerated aging, as people with it appear to age far faster than normal. Using a new CRISPR/Cas9 gene therapy in a mouse model, they were able to slow down the pace of the condition, improve health, and increase lifespan.
What is Hutchinson-Gilford progeria?
Progeria is a degenerative disorder caused by a mutation in the LMNA gene. This disease has an early onset and progresses rapidly, and animals and humans with progeria show symptoms that are similar to regular aging, only on a much-accelerated timescale, giving them drastically shorter lifespans than normal. Humans with this condition rarely live very long, with the average being only 13 years old.
LMNA is a gene that creates two very similar proteins: lamin A and lamin C. There is also a mutated form of lamin A that causes the gene to produce progerin, a shortened, harmful form of lamin A that builds up over time and drives progeria.
Progeria is not normal aging, but it may provide some insights
Hutchinson-Gilford progeria syndrome and similar progeric conditions are not really representative of normal aging, though they do share some characteristics, such as DNA damage, changes to nuclear lamins, and a decline of cardiovascular function. It is these and other shared characteristics that interest scientists studying aging.
Professor Juan Carlos Izpisua Belmonte from Salk’s Gene Expression Laboratory, the primary author of the paper, believes that progeria is a useful aging model as it allows researchers to test interventions against aging, refine them, and rapidly test them again to get data sooner.
There is some merit in this approach, and many research labs working on aging do study interventions on progeric mice, as the data they provide can be informative and help guide subsequent steps. This is most often in combination with regular aging mice which experience aging at a normal, not accelerated, pace; the data from the progeric mice generally comes in months ahead of the regular mice, allowing researchers to learn and refine their process before applying it to regular mice. In this respect, progeric mice have their place in aging research.
Hutchinson–Gilford progeria syndrome (HGPS) is a rare lethal genetic disorder characterized by symptoms reminiscent of accelerated aging. The major underlying genetic cause is a substitution mutation in the gene coding for lamin A, causing the production of a toxic isoform called progerin. Here we show that reduction of lamin A/progerin by a single-dose systemic administration of adeno-associated virus-delivered CRISPR–Cas9 components suppresses HGPS in a mouse model.
Gene therapy to the rescue
The researchers aimed to reduce the harmful effects of the mutated LMNA gene and thus reduce the build-up of progerin in cells. They achieved this by using CRISPR/Cas9 gene therapy to disrupt lamin A and progerin production and build-up. Using an adeno-associated virus (AAV), the Cas9 protein was delivered to the location on the DNA responsible for lamin A and progerin production.
The Cas9 protein was then able to make a snip, thus silencing the target gene. At the same time, a reporter gene was also delivered, which allowed the researchers to measure the number of cells to which the AAV successfully delivered the Cas9 protein.
After two months, the mice showed improved strength, improved cardiovascular function, and an increased level of activity similar to regular aging mice. Internally, there was a reduced level of degradation of arteries and a delay to the onset of bradycardia, both of which are typically seen in progeria. The mice lived approximately 25 percent longer than usual.
As this approach was only able to deliver the gene therapy to a limited number of cell types, the researchers are now refining the approach to deliver it to a wider variety of cell types and tissues, as they believe that this may increase the lifespans of the progeric mice even more.
Ultimately, the team hopes to adapt this approach for human use in order to offer a therapy for people suffering from Hutchinson-Gilford progeria and related conditions.
While not truly representative of normal aging, there are potential insights to gain from such research that could help inform the future direction of aging research and progress.
As there is currently no cure for Hutchinson-Gilford progeria and related conditions, having a solution to these horrific diseases would be very welcome news indeed. We live in an age in which eradicating genetic disorders and inherited conditions with gene therapies is becoming increasingly plausible as the technology is refined; if we can end such suffering, we surely must.