However, mice treated with a catalytically inactive TERT (AAV9-mTERT-DN), and despite showing increased CyclinD1 mRNA levels as well as decrease p16 levels in the tissues tested, in agreement with the proposed role of TERT regulating the Wnt pathway in a telomerase activity-independent manner (Park et al, 2009), were not paralleled by a rescue of short telomeres and increased health span and longevity. These could indicate that the non-canonical role of telomerase could not impact on the health status per se, but could have a synergistic effect in the context of a telomerase positive background.
Our TERT-based gene therapy of aging also improved several molecular markers of aging. On one hand, and as expected from the canonical function of TERT as the catalytic component of telomerase, mice treated with AVV9-mTERT vectors showed telomere elongation in a variety of tissues, which was concomitant with a significant decrease in the abundance of short telomeres, in turn responsible for chromosomal aberrations.
Eye diseases are another success story. In three trials that are “kind of biblical in impact,” Friedmann says, eyesight improved, sometimes dramatically, in 28 of 30 patients with Leber's congenital amaurosis, a type of inherited blindness, after gene therapy using an adeno-associated virus (AAV) to deliver a curative gene to the retina. The Children's Hospital of Philadelphia (CHOP) plans to apply this fall to the U.S. Food and Drug Administration to conduct a phase III trial for this treatment. Gene therapy trials for two other blindness diseases are under way.
Gene therapy is working for neurologic diseases, too. The San Raffaele Telethon Institute has treated four patients with a devastating brain disorder called metachromatic leukodystrophy, following a report published in 2009 from a team in France that used a similar strategy to halt the progression of a related disease, adrenoleukodystrophy. So far the treatment seems safe and the patients' blood cells are producing the corrected enzyme, Roncarolo reported.
Gene therapy will work only if we can deliver a normal gene to a large number of cells - say, several million - in a tissue. And they have to be the correct cells, in the correct tissue. Once the gene reaches its destination, it must be activated, or turned on to produce the protein encoded by the gene.
The best gene therapy is the one that lasts. Ideally, we would want a gene that is introduced into a group of cells to remain there and continue working. For this to happen, the newly introduced gene must become a permanent part of each cell's genome, usually by integrating, or "stitching" itself, into the cell's existing DNA.
Gene therapy involves transferring genes into patients to treat their diseases. In this case Glybera uses a virus injected into a patient to deliver a working copy of a gene for producing lipoprotein lipase (LPL). LPL deficiency affect no more than one or two people in a million.
Back in 2004 China became the first country to approve a gene therapy product for commercial use, with a treatment for cancer. But Europe and the United States have yet to endorse any gene therapy treatments and the field has been plagued by issues such as carcinogenicity.
U.S. gene-therapy research was set back substantially after 18-year-old Jesse Gelsinger, who suffered from an inherited liver disease, died of multiple organ failure in 1999 while participating in a gene-therapy experiment at the University of Pennsylvania. News of the death prompted an uproar in the scientific community and hearings in Congress, with the teenager's father, Paul Gelsinger, and others accusing the Penn researchers of being too hasty to test the treatment in people. According to the Food and Drug Administration, the researchers had not sufficiently warned Gelsinger and his family of the experiment's risks.
The prospect of using gene therapy to treat diseases—particularly inherited diseases that involve one errant gene, such as sickle cell anemia and cystic fibrosis—has tantalized scientists for decades. If there were some way to give a patient a good version of an implicated gene, the thinking goes, it might repair or prevent damage caused by the inherited bad one.