The Scientist on BioViva's Initial Test of Human Gene Therapies

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.

First Data from Anti-Aging Gene Therapy

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 MarĂ­a 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.

Comments

I still say what Elizabeth did was a good thing. Maybe a little unorthodox but in this over regulated world, we need to speed some thing us alot. As they say, you are not getting any younger, and in this case, the phrase has literal serious meaning.

I hope her and her company will spurn other companies to do the same. Yes, we need safety protocol, but if someone is 80 or 90 years old, I think they would be more than happy to take a risk. Someone on the 50's or 60's maybe not, at least not until there has been some resonable testing or significant others have gone before.

I hope there will be several anti-aging treatments available in the next 5-10 years within medical tourism. Ok, maybe 10-20 years.

Posted by: Robert Church at April 25th, 2016 8:56 PM

Slow news day?

"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." - Reason

Regarding people in the sciences being upset at those that find ways around regulations, I think that you are wrong here. The only people this upsets are the regulators themselves. Scientists despise the increase in red tape that has occurred over the past 40 years or so, and I trust that many would applaud someone who was able to workaround regulations in a legal way and accomplish something meaningful.

But...

In this case, it does not appear that BioViva has accomplished anything meaningful (other than self-promotion).

The argument that you outlined above works beautifully for dismissing ALL criticisms of BioViva. Have a valid argument against BioViva? Nah, you're just a hater!

My issue with BioViva / Liz Parrish is that there are simply very few reasons to believe that either is legitimate, but many reasons to form the opposite conclusion:

Who is Elizabeth Parrish? What is her experience? Education? Is any of this verifiable?
Where and what are their facilities?
How many employees? (paid full-time)
What are their products? Who developed them? When? Where?
Why is their website nothing but pretty fluff?
In what ways does BioViva function as, or resemble, an actual real company?
Do any of the BioViva "team" actually work full-time for BioViva (other than Parrish)?
How many one-person companies has Elizabeth Parrish formed and appointed herself as "CEO"?

It is very troubling to me that an administrative assistant with no scientific education or training is giving talks and interviews on aging science and is being taken seriously by anyone. This is NOT a step forward.

Posted by: BigB at April 25th, 2016 9:10 PM

@BigB: Those are pretty silly objections to field against an early stage startup. Take a look at their advisory board, or the Deep Knowledge Life Sciences partnership, or the fact that Heales and the Biogerontology Research Foundation were involved in tests. There are clearly connections and trust here, built over the past few years, and that doesn't just magically happen, or happen to any random individual joining this community. Assuming BioViva can turn attention into funding and partnerships, they will go on to work on more of their plan; that's the way bootstrapping works in the business world.

Posted by: Reason at April 25th, 2016 9:23 PM

@Reason: If they are going to make bold claims then they better be able to back them up- it doesn't matter if they have been in business for 1 week or 20 years. Legit "bootstrapping" is not claiming to be something that you are not and then refusing to answer criticisms.

From the BioViva website:

We are gene therapy innovation leaders. We develop therapies to treat severe genetic disorders and cellular aging. We are working on several patents...At the heart of Bioviva's product creation efforts is its broadly applicable gene therapy platform for the development of novel one time treatments for diseases with either ineffective or no clinical options.

Certainly the "gene therapy innovation leaders" have a facility and staff of scientists, no?

Posted by: BigB at April 25th, 2016 9:52 PM

Agree with the above the whole thing stinks. And when you criticize it and try to remind people it's only early data you are marked a hater. I am far more confident blasco or fossell will deliver telomerase therapies via safe and approved channels.

Although bigb I disagree with the comment about being an administrative assistant, you don't need a PhD to read and understand science and one can study hundreds of papers and educate oneself to a level able to talk accurately about science. Not suggesting Parrish can but in general. I don't have a PhD but I'm certainly able to read, understand and discuss scientific research with PhD and higher level academics.

Posted by: Steve h at April 26th, 2016 1:05 AM

My trusted expert source of information is the SENSRF and this blog, so I believe that telomrase therapy won't do anything, or may increase cancer risk. The follistatin therapy is interesting.

I think the main achievement of Bioviva has been to get a conversation going. Still, I think if Liz Parish really wanted to kick the hornet's nest then Bioviva would offer to use CRISPR in vivo to delete the extra parts of the ducheene gene that lead to DMD. Most readers will be aware of the passionate debate going on between patient family advocates and the FDA over a bunch of drug treatments that don't seem to do anything in clinical trials at the moment. It would be a bit cynical, but Bioviva could make use of DMD to force the FDA's hand on gene therapy.

Posted by: Jim at April 26th, 2016 2:10 AM

@Jim: I think that the problem with gene therapy is that it isn't mature yet. The tissue coverage is poor and highly variable.

As for Liz Parry's experiment, I don't understand why so much hype. From a 1 person trial you can conclude almost nothing. And in this particular case, telomere lenght measurement is highly problematic (it varies a lot from person to person, and even in the same person at different times). You really need a high number of people to say that it worked, that is, you need a real trial.

Posted by: Antonio at April 26th, 2016 2:44 AM

@Steve h: I absolutely agree with what you are saying. I didn't mean to imply that one needs a PhD to read, understand, or speak intelligently about science. In this particular case, I see no evidence that she has put in the time and effort to understand the science well. Her talks are riddled with scientific misstatements. Combined with the fact that the academic credentials aren't there either, I find no reason to take any of her scientific talks/lectures seriously. I don't fault her for talking about the subject, but it isn't right to portray oneself as an expert and have nothing to back up the claim.

Posted by: BigB at April 26th, 2016 8:02 AM

@BigB Yes I totally agree. Her scientific knowledge is poor and that is obvious when talking to her or her talks. Pure hype is what this is.

Posted by: Steve Hill at April 26th, 2016 8:23 AM

BigB:

1) How would you know whether Elizabeth Parrish has "put in the time and effort to understand the science well" or not? What is your "evidence" for this claim and what "evidence" would you need from her to disprove it?
2) Can you give an example of her "scientific misstatements"?
3) Can you point out where, exactly, she portrays herself as an "expert" scientist?

Your comments seem very much like an ad hominem attack.

BioViva's experiment isn't a randomized trial, obviously, but at no stage they claim it to be so. As for the treatment's effectiveness, Parrish herself says that "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", which is a very cautious statement to say the least.

As Jim said, Bioviva's main achievement is getting the conversation going, so if anything we should applaud them. No one who actually understands science has not understood that they are not making claims to have cured aging. The lab that tested the blood - someone linked to the company - is even admitting that the results could be due to measurement error, so I fail to understand why some people are getting so riled up about this press release.

Posted by: Barbara T. at April 26th, 2016 10:22 AM

I guess I must be the most gullible innocent one : P ...

I agree with most everyone's points, from one side, this looks like an achievement
(sort of) and from another it looks like false/fake/hyped; I believe that
is why people are riled up as they fear a snake oil therapy hiding behind a 'grand press - ''this is it, we achieved it''' kind of.
When it may possible there are errors in the results and thus render the whole thing
invalid and thus non-news/useless/more infuriating than making people happy (they see
through the lie of the therapy results that it's a blunder).

Although, as some have said, the level of indignation/attack may be bit as exaggerated or bit misplaced as the
therapy results themselves. This is not - all - bad; there is some good, like for
example by simply 'talking about it' and saying stuff about telomerase - around the world
via external clinic; like BioViva; which at first may do harm than good with snake oil/will
be branded a snake oil company/hamper clean ethical advancement in biology; but, on the other side, it is doing good
'good press, bad press' who cares, it's all (more) good (than bad) as long you are not invisible/ignored.
People need to 'hear/see/read' about telomerase therapy or other SENS therapy; this marketing by BioViva does
good to 'at large coverage' advancement of science - even if their own therapy results are a failure.
People will now think
''Hey..I 'heard' about 'some telomerase' therapy...BioViva..yeah, me too..they failed ...hum and, or tried, to fool us...yeah...But
she (Mrs.Parrish) was the first woman to try gene therapy or any 'Human gene therapy' for that matter, it's commendable and that's not nothing...we'll wait for
a comeback or someone else to takeover and brings us telomerase! Anyways, SENS is not going to bring telomerase ever..so, who else is there really (no one)..''....
That is good.

Why I was so hyped about this because I thought this is incredible
that a human does a genetic therapy for the first time and they happen to be the boss CEO
of the company doing the testing; it really is something. It is almost as if they wanted to play 'it safe' by 'doing it'
on the CEO...just in case it went wrong, if it had been on patient or anybody random outside of the company willing to be test zero.

But I understand that it is useless if the results are totally false and telomerase
does nothing/or increases cancer/some other secondary effect.

Although, humans and mice don't have same telomere and cancer dynamics; I still believe
this to be a bit valid and that reason, is because, the results are so close to telomerase
results from TA-65 astragalus and TgTert therapy in mice; so it's not so 'exaggerated/false-like' results;
yes, it's true, only if we replicate the results in many humans and with safety will this have any 'meaning/impact' (or else, as said, it's more non-news overt-hype).
It's ok to get excited too, just dosed.

Plus this :

''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.''

10 or so percent error - big deal..this is exactly what other study results deal with, there is
always 'some small' degree/percentage of deviation/error. Is that bad to make her results useless - I don't believe so; because these results corroborate very closely to other telomerase results (that is TERT/telomerase is capable of about 1 Kb extension (1000 base pairs telomeric repeats TTAGGG) in about less than a year on the smallest telomeres (which makes for more than 10 years of biological age slowing) - and thus are possibly quite true.
Safety is paramount, the only big one is prostate cancer; studies in mice (though not in humans) have shown reduction of cancer (all types, breast, esophageous, colon, skin, wbc, etc...), but some studies were capable of demonstrating
a paradoxal effect where Longer telomeres where associated with higher cancer prevalence (as in prostate). This may due to increase cell proliferation at high telomeres in certain tissues that will increase cancerous mutations odds (it's what happens with humans who have higher number of nevis (skin moles/cancerous malignant/non-malignant moles), they have higher skin telomeres (younger) yet they also have skin higher mutational load from more nevi count (demonstrating excessive 'youth-like/stem-cell-like property' cell proliferation is an 'enabling/abling' mechanism for mutational error formation).

Telomerase does increase cancer, but the question is then, is it more good than bad,
and it is more good, it reduces 'most overall' cancers vs increasing some (in mice at least, in humans not sure yet so for now, it's still dangerous/unknown until we know - and that brings me to a question :

Why have the tests not made a test for cancer in her - her immune system is boost (increased WBC telomeres) thus it would have more ease to destroy cancerous cells...
Check her tumor markers, any cancer/inflammation markers (p53, p16, p21, TNF-a, INF-g, IL-6, IL-10, plasma isoprostanes, Carbonyls, C-Reactive protein, homocysteine, etc... that (may or not) have changed in her - after the therapy...I will await that. The safest answer for anyone, take astragalus radix it does roughly the same.

Posted by: CANanonymity at April 26th, 2016 12:49 PM

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