Scientists have used gene therapy to successfully treat a mouse model of Hutchinson-Gilford progeria syndrome (HGPS), a lethal condition with many features of accelerated aging. The advance has ramifications for the use of viral vectors to deliver targeted gene editing machinery to cells throughout the body.
HGPS is one of the laminopathies, a suite of degenerative disorders resulting from defects in nuclear lamins, the proteins that give the nucleus its structure. (Lamins also provide important support for key nuclear functions such as transcriptional regulation.) In HGPS, a mutation in lamin A causes accumulation of a variant protein called progerin, which causes the nucleus to become deformed and functionally abnormal.
Patients with HGPS exhibit symptoms of rapid aging, including premature decline in the functions of multiple tissues and organs, and survive less than 15 years on average. There are currently no effective treatments for HGPS. Farnesyltransferase inhibitors, which prevent a lipid modification of progerin and thereby block its association with the nuclear membrane, are currently in clinical trials, but there are major concerns about their potential side effects—emphasizing the need for orthogonal strategies to treat or even cure this devastating illness.
This week in Nature Medicine, and international collaboration of researchers from the US and Spain announced their successful use of gene therapy to reverse the molecular defect in HGPS model mice. At a cellular level, the treatment ameliorated the nuclear deformation that is the hallmark defect of the disease. This alleviating the progeroid symptoms in the mice, improving their overall health and vigor and extending their median lifespan by 50% (relative to the very sick untreated controls, that is—the mice receiving gene therapy still only lived 25 weeks, about a quarter of the normal mouse lifespan).
Specifically, the authors used the CRISPR/Cas9 system—rapidly becoming the molecular biologist’s Swiss army knife for gene editing applications—to knock down expression of progerin. (Concomitantly, lamin A expression was also downregulated, as the genes encoding the normal and mutant proteins differ by only one nucleotide. Fortunately, lamin A seems to be dispensable for a long life, and indeed lamin A null mice live longer than wild-type controls.)
Notably, the authors achieved a systemic therapeutic effect, i.e., they were able to achieve delivery of the gene editing vector to almost every tissue and organ in the mice, although the bulk of gene editing occurred in the liver. To this end, they used adeno-associated virus [AAV], which is a workhorse of gene therapy technology because it can’t replicate on its own, but can still infect cells and deliver nucleic acid payloads. Systemic delivery is essential for treating genetic diseases whose effects are experienced in multiple organs.
This is important because all too often, discussions of how to translate fundamental research into cures arrive at a final step that amounts to “…and then deliver the gene expression or knockout vector at high efficiency to every cell in the body.” It’s one thing to remove a specific type of cell from the host and perform genetic manipulations ex vivo, as is now done for CAR-T cell therapy against cancers, but quite another to administer a viral vector capable of delivering its payload to the vast majority of cell types in an intact, living body.
Although the therapeutic effect was modest relative to a notional complete cure, the authors speculate that wider-spectrum delivery that targets organs more evenly (i.e., without the bias toward liver) could achieve an even more dramatic improvement in lifespan in the HGPS model mice.
For today, the demonstration that this AAV-based vector could reach enough of a mouse’s cells to achieve a systemic effect on an organism-level readout like lifespan suggests that gene therapy approaches may be nearing readiness for more general application in the clinic.