The Scientist has published a measured piece on the first results from BioViva's initial test of human gene therapy, telomerase and follistatin overexpression, and the broader context in which this single person test took place. The results indicate that the telomerase gene therapy most likely worked in the sense of delivering telomerase to a significant number of cells, including the immune cells used to measure average telomere length. That is an important thing to validate up front, before thinking about any sort of other outcomes, or expanding to a trial of some sort. Historically, gene therapies have proven to be highly varied in their effectiveness when it comes to uptake in target cells: in animal studies, the result might be 5% uptake, or it might be 60% uptake, or anywhere in between. A lot of work has gone into trying to make things more reliable over the past decade, but for many years yet there will be questions as to whether any particular formulation works well enough to build upon. That said, the error bars are large in these measurements, and further data is definitely called for.
Last year, Elizabeth Parrish, the CEO of Seattle-based biotech firm BioViva, hopped a plane to Colombia, where she received multiple injections of two experimental gene therapies her company had developed. One is intended to lengthen the caps of her chromosomes (called telomeres) while the other aims to increase muscle mass. The idea is that together these treatments would "compress mortality," by staving off the diseases of aging - enabling people to live healthier, longer. Last week, BioViva reported the first results of Parrish's treatment: the telomeres of her leukocytes grew longer, from 6.71 kb in September 2015 to 7.33 kb in March 2016. The question now is: What does that mean? The company announced Parrish's response as success against human aging, having "reversed 20 years of normal telomere shortening." Over the phone, Parrish was more measured in discussing the implications of the finding, which has not yet undergone peer review. "The best-case scenario would be that we added 20 years of health onto the leukocytes, and the immune system might be more productive and catch more of the bad guys. But we have to wait and find out. The proof will be in the data."
Much more data are needed before claiming success against aging, said Dana Glei, a senior research investigator at Georgetown University. "We haven't established a causal link between telomere length and health. If it's like gray hair, dying your hair won't make you live longer." An n of one won't give us the answer, but Parrish's personal trial is the start of what BioViva hopes to accomplish: the first clinical studies using a gene therapy to stall aging and increase health span. The company's approach is backed by preclinical evidence - in particular, that from María Blasco's group at the Spanish National Cancer Research Centre (CNIO). In 2012, Blasco's team reported the results of a telomerase gene therapy in mice. The enzyme telomerase, encoded by the TERT gene, lengthens telomeres. "We demonstrated that AAV9-Tert gene therapy was sufficient to delay age-related pathologies and extend both median and maximum longevity in mice," said Blasco, who is not involved with BioViva. "Many pathologies were delayed, including cancer."
There is another potential weakness of the BioViva data: measurement error. The 9 percent difference between Parrish's before and after telomere lengths is within the measurement error of most laboratories. Houston-based SpectraCell Laboratories conducted the telomere length assay for BioViva. Jonathan Stein, the director of science and quality at SpectraCell, said that most telomere-length assays have a variance of 8 percent, and his firm's test is in line with that number.
The other gene therapy Parrish received - the gene encoding the follistatin protein - is supported by human data, at least in the context of people with muscle disorders. (There are not yet data demonstrating the effects of follistatin gene therapy on aging-related muscle loss.) Follistatin inhibits myostatin, which puts the breaks on muscle growth and therefore makes it an attractive therapy for muscular dystrophies. Early clinical trials on six people with Becker muscular dystrophy, for instance, showed that four of them could walk longer distances after the follistatin gene therapy. Parrish said she expects MRI data on her muscles' response to the treatment in about a month. Working with regulatory agencies has been a sticking point for BioViva, hence Parrish's trip to Colombia. Her controversial move - to skirt oversight by the US Food and Drug Administration by receiving the gene therapies outside the country - prompted a member of the company's advisory board, the University of Washington's George Martin, to resign. Parrish said she is now traveling the globe to find a regulatory partner willing to approve human clinical trials. "When I started looking into this, it seemed like a crazy science," she said. "But it's a crazy science whose time has come."
If you read around online discussions of BioViva's work, you'll find opinions to be fairly polarized. It is clearly the case that a fair number of people in the sciences really, really don't like it when anyone departs from the standard regulatory script of spending a lot of money and time keeping various government agencies happy, and set off to do something adventurous and entirely legal in another jurisdiction that regulators disallow in their own. This might be something like crabs in a bucket, perhaps, but the scientific community has always fiercely attacked those who deviate from the orthodoxy. Maintaining the scientific method in the face of those who are in fact out to undercut its foundations is a constant battle, and this is understandable. Yet the present system of regulation is not the embodiment of the scientific method, and certainly not the only way to conduct technological development resulting from science. Someone has to be the first human subject after animal studies have proven promising, and medicine has a long and noble history of self-experimentation to prove safety and capability, or even for the purposes of discovery. Many of the people who did this, and in some cases suffered for it, and as a result succeeded in producing new and useful medicine are regarded as brave pioneers. Rightfully so, I think.
What do regulators add to this picture other than barriers and objections? It doesn't require a regulator to design and carry out ethical studies in human medicine, and the present state of medical regulation is so ridiculously overblown, costly, and constrained that if everyone went by the FDA book, it would be a decade or more before anyone could legally access gene therapies intended to compensate for aspects of aging. Even that would only happen after the expenditure of billions of dollars, ensuring that only very large entities could control and deliver this sort of therapy: Big Pharma and government work hand in hand to the tune of their perverse incentives, limiting rather than expanding opportunities for progress. If you want a dynamic market of many small competing groups, innovative and rapid, then the heavy hand of regulation has to go. At present the only realistic way to go about this is to embrace the medical tourism marketplace and transparency in development: fund small trials, make all the data public, license the technology widely, and let educated patients decide on their options.
Freedom to choose and differences of opinion on the utility of specific therapies are important. For my money, I'm happy to let someone else go first in the case of telomerase gene therapy, which seems riskier than myostatin or follistatin gene therapies given the current state of evidence. I would be made more comfortable by trials in something other than mice, a species that is quite different from us in terms of its telomere dynamics and thus cancer risk profile following this sort of treatment. While telomerase gene therapy actually reduces cancer risk in mice in some cases, perhaps by spurring greater immune activity, along with extending life and reducing incidence of disease, there is no guarantee that the various changes involved will balance in the same way in humans. The falling cost and increasing reliability of gene therapy these days means that there are enough interested people for this to move straight to human testing, however - which isn't unusual in many areas of medicine, I should add.
Even if the economics were different, it is clear that telomerase gene therapies would still be heading for human trials one way or another. There are research groups with enough data in mice and the interest to move forward: telomerase therapies appear to be in essence another way to spur greater activity in old stem cells, and thus improve health and extend life, and all such approaches are gathering attention these days. The established research groups may well continue to work within the regulatory gauntlet while those less impeded forge ahead much more rapidly. This will be a repeat of the development of the stem cell industry over the past two decades, parallel lines inside and outside the gilded cage of regulatory capture. It was just about a decade between the availability of stem cell therapies via medical tourism and the capitulation of the FDA allowing the first classes of treatment in the US, and it certainly would have been longer without the pressure of having these treatments available so widely elsewhere in the world.