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BioViva Claims Success in Initial Human Telomerase Gene Therapy

Initial data appears to show success for the telomerase gene therapy undergone by the BioViva CEO last year. Similar gene therapies extend life in mice, most likely though increased stem cell activity and thus improved tissue maintenance. It doesn't seem to raise cancer risk in mice, but there is a concern that this may still be an issue in humans, with our quite different telomere and telomerase dynamics. Measuring the length of telomeres as presently accomplished in white blood cells is a proxy metric of dubious value for the endpoint of improved stem cell function, unfortunately, but it is the technique presently available at reasonable cost and reliability. Average telomere length in immune cells is only tenuously related to age, statistically over large populations, and does tend to change over time in both directions in individuals due to changing health and other circumstances. The alteration here is large enough and rapid enough, however, to indicate that the gene therapy worked in the sense of delivering telomerase. Finding out whether it worked in other senses, producing a more youthful tissue environment, would require a biomarker of biological age, such as the DNA methylation measures presently under development.

In September 2015, then 44 year-old CEO of BioViva USA Inc. Elizabeth Parrish received two of her own company's experimental gene therapies: one to protect against loss of muscle mass with age, another to battle stem cell depletion responsible for diverse age-related diseases and infirmities. The treatment was originally intended to demonstrate the safety of the latest generation of the therapies. But if early data is accurate, it is already the world's first successful example of telomere lengthening via gene therapy in a human individual. Gene therapy has been used to lengthen telomeres before in cultured cells and in mice, but never in a human patient. Telomeres are short segments of DNA which cap the ends of every chromosome, acting as 'buffers' against wear and tear. They shorten with every cell division, eventually getting too short to protect the chromosome, causing the cell to malfunction and the body to age.

In September 2015, telomere data taken from Parrish's white blood cells by SpectraCell's specialised clinical testing laboratory in Houston, Texas, immediately before therapies were administered, revealed that Parrish's telomeres were unusually short for her age, leaving her vulnerable to age-associated diseases earlier in life. In March 2016, the same tests were taken again by SpectraCell revealed that her telomeres had lengthened by approximately 20 years, from 6.71kb to 7.33kb. This implies that Parrish's white blood cells (leukocytes) have become biologically younger. These findings were independently verified by the Brussels-based non-profit HEALES (HEalthy Life Extension Company), and the Biogerontology Research Foundation, a UK-based charity committed to combating age-related diseases.

"Current therapeutics offer only marginal benefits for people suffering from diseases of aging. Additionally, lifestyle modification has limited impact for treating these diseases. Advances in biotechnology is the best solution, and if these results are anywhere near accurate, we've made history.". Bioviva will continue to monitor Parrish's blood for months and years to come. Meanwhile, BioViva will be testing new gene therapies and combination gene therapies to restore age related damage. It remains to be seen whether the success in leukocytes can expanded to other tissues and organs, and repeated in future patients. For now all the answers lie in the cells of Elizabeth Parrish, 'patient zero' of restorative gene therapy.

Link: http://bioviva-science.com/2016/04/21/first-gene-therapy-successful-against-human-aging/

Comments

Are they seriously reporting a claim based upon the experience of one person, said person being the CEO of the company, or am I reading this wrong?

Posted by: JohnD at April 22nd, 2016 11:01 AM

@JohnD: No, I read it the same way.

This sort of careless sensationalism is toxic to the field of aging research.

Posted by: BigB at April 22nd, 2016 12:20 PM

They had to report on something after all and what they had was one patient: "It remains to be seen whether the success in leukocytes can expanded to other tissues and organs, and repeated in future patients".

I wouldn't call this "careless sensationalism that is toxic to the field of aging research", or at least not to the type of research that we would like to see in the absence of a more forgiving regulatory environment. Whatever the results of this experiment, Bioviva is opening the path for much needed translational efforts.

Posted by: Barbara T. at April 22nd, 2016 1:15 PM

I would be open to having this gene therapy in 5-10 years, myself. Hopefully by then, we would be fairly confident that the therapy is safe and effective.

I admire the CEO for doing this and hope it opens the door to more potential anti-aging therapy even if it means going outside the U.S. I hope she can get others to try it so they can test the effects of it.

Posted by: Robert Church at April 22nd, 2016 1:28 PM

Congratulations to Elizabeth Parrish, she may well go down in history as the first person who tried gene therapy to treat aging. You can see how a million time more efficient this process is compared to the FDA. No billions of USD and no decades were needed to translate research into clinical practice. If the patient is willing to take the risk it is his decision and his decision only.

Posted by: Carl Elser at April 22nd, 2016 2:56 PM

Even though I support these therapies, I'm a little disappointed in myself. My first reaction to reading about a biotech CEO using herself as a test subject for longevity treatment was to think of sci-fi horror. It seems that media is biased towards dystopian views of technology. Dystopia probably does better at the box office and the x-box.

Posted by: Jordan Viray at April 22nd, 2016 5:35 PM

Hi all !

This is really great!! Congrats to her!!, I was very intrigued and curious almost 10 months ago
when Elizabeth Parrish first announced she was going to be test patient zero using her company's own
therapies. It is about time, finally, we get her telomere results !!

Exactly, what I had predicted...

This concords exactly with TERT gene therapies results in mice in terms of
Telomerase/hTERT/hTERC activity and final results; and especially, telomere lengthening
dynamics by telomerase enzyme. The fact that :

''In September 2015, telomere data taken from Parrish's white blood cells by SpectraCell's specialised clinical testing laboratory in Houston, Texas, immediately before therapies were administered,
***revealed that Parrish's telomeres were unusually short for her age***, leaving her vulnerable to age-associated diseases earlier in life''

her telomeres were shorter than for someone (average caucasian woman) of 44 years old (biologically she showed an older immune system for her chronological age).
It made sense for her to 'try' her company's therapies; because of her weakened/age immune system. I, also read, somewhere else, that she took part in the creation of Bioviva - because she had family genetic problems (which created a 'possibly compromised' immune system in her and feared health complications down the line) and she wanted to solve them (with the creation of Bioviva; it's pretty obvious - but this is a very 'personal' thing (it concerned her health from the start); if she ends up saving others (after being the patient zero) I think it would have been worth being her company's own first guinea pig (that sounds so wrong)).
I'm sure it was for her and everybody else; but to accept being the guinea pig, you need to have valid reasons, it's the major reason why.

Since her leukocyes telomeres were shorter than average, she had a 'normalization' effect to about the lenght of regular people (who have a more active TERT telomerase activity in their immune cells).
Her telomerase 'averaged' 'upwards' the telomere length to the 'standard' for someone around 44 years old. Meaning her telomerase worked on her disproportionately smallest telomeres and did not touch her taller ones.
This made a 'final' telomere size of 7.3 kb (proving that telomerase is selective to shortest telomeres (out of urgency/system instability and shortest telomere uncapping).

''Interestingly, we observed a significant decrease of very short telomeres (telomeres below 2, 3 and 4 Kb, Fig. 3b,d) in the 1 yr and 2 yrs old TA-65 treated groups at 3 months post-treatment, indicating a significant and consistent capacity of TA-65 to promote rescue of short telomeres both in vitro (MEFs) and in vivo (mice). ''

''Additionally, a significantly increased of average telomere length was observed in G3 Terc+/- cells when treated with 10 µM of TA-65
****(37.87 Kb to 42.68 Kb, Fig. 1d).**** ''

Mouse telomeres + TERT :
37.87 Kb -> 42.68 Kb

Proportional human equivalent (for mouse telomeres, divived by 5.643) :
6.71 Kb -> 7.56 Kb

Real human telomeres + TERT :
6.71 Kb -> 7.33 Kb

That is almost a perfect final telomere length increase correlation match (7.56 Kb (mouse) vs 7.33 Kb (human) from mouse to human TERT therapy results.
The article says this is equals 20 years healthspan rejuvenation, which means Mrs.Parrish is now 24 years old biologically (which is dramatic compared to average 44 year old woman, it's almost a 50% decrease in 'biological age'.
Still, it does not mean a 50% reduction in telomere rate of shortening, she is simply back to 20s but at regular telomere shortening speed; although higher telomere lengths may lightly reduce telomere rate/speed of shortening because of improved redox (lower oxdidative stress) in higher telomeres (since it is short telomeres that are uncapped and unstable; long telomeres are stable/capped/less y-H2AX telomere lesion foci in them)
And, thus, most of the phenotypical mouse effects will be translatable somewhat even if different specie.

This effect is akin to Astragalus radix herb (which contains cycloastragenol) which activates TERT/telomerase in mice and humans. And also, gives about
the same 20% increase in health span (although here, they say Mrs.Parrish is getting 20 years back = 45% (20 of 44 years), which is dramatically more.
This is extremely close in effect to the cancer-free type (Sp53/Sp16/SArf/TgTert) of mice who reach a dramatic 50% extension of healthy lifespan when transduced with tgTERT.

''In this subgroup of mice, whose
life spans are determined by aging and not by cancer, the impact
of TgTert expression was even more evident, resulting in a me-
dian life span extension of 18% and 38% in Sp53/TgTert and
Sp53/Sp16/SArf/TgTert mice, respectively, compared with the
Sp53 and Sp53/Sp16/SArf controls (Figure S9). Furthermore,
combined TgTert and Sp53/Sp16/SArf transgenes resulted in
a 40.2% extension of the median life span when compared to
single Sp53 mice (our reference for normal longevity), which
was further increased to 50% when considering cancer-free
mice (Figure S9).''

Although, TERT increase did not increase maximum lifespan (though via TA65 not TERT gene therapy) :

''TA-65 treatment enhances health-span in female mice...
TA-65 treatment increases metabolic fitness...
TA-65 treatment delays some age-associated pathologies...

***TA-65 intake does not impact on mean or maximum longevity of female mice...****
Analysis of the Kaplan-Meier survival curves of control versus TA-65 treated female mice
demonstrated no significant effects of TA-65 intake on survival (Fig. 6a,b).
Accordingly, TA-65 administration for 4 months did not change statistically the mean or maximal lifespan of female mice under our experimental conditions.
''

Though TERT therapy, by 50% increased healthspan, dramatically increase the *percentage of surviving *cancer-resistant* mice reaching to the *maximum specie's lifespan* :

''To estimate whether TgTert expression had an effect on maximum longevity, we studied the group of lon-
gest-lived mice of each genotype. First, the percentage of micethatreachedtheextremely oldage of 3yearsissignificantly
largerfor Sp53/Sp16/SArf/TgTert mice than for their Sp53/Sp16/SArf controls (42% versus 8%;
Figure 5B), and this extreme old survival is further increased when considering cancer-free mice
(up to 50%; Figure S9 ). Second, the mean age of the upper longevity quartile is significantly higher in
Sp53/Sp16/SArf/TgTert mice than in their Sp53/Sp16/SArf controls (163 weeks versus 146 weeks; p < 0.01;
Figure 5 C). These observations indicate that TgTert expression changes the longevity curve of mice, sig-
nificantly extending the median life span and significantly increasing the percentage of mice that reach extremely old
ages.''

***************
This means Bioviva's therapy gives the mega chance to average genes short-lived people to reach the human MLSP of 122 years old - something incredible !
***************

Althoug, it's clear that TERT can not increase maximum lifespan at all (or not really that much).
Thus, humans will live healthy to about 120s max using Bioviva's TERT therapy.

Cancer occurence with telomerase TERT was only detected in men's prostate, because *shorter* telomeres were associated with - less - cancer, not more.

Astragalus is safer for men, it gives TERT telomerase without the danger of prostate cancer by TERT therapy.
Women gain more from the therapy since most of their cancers are reduced by TERT telomere lenghtening (aka short leukocyte telomere correspond to inflammation and a weak 'aged' immune system that cannot detect/destroy cancerous cells; your immune system is primordial, its white blood cells telomeres must be maintained at higher length):

I'm very happy for Mrs.Parrish and now she may live to a 120 cancer-free and healthy.
I can not wait for this therapy to be mainstream, it is that powerful.
Astragalus is the safer lesser solution for men wary of prostate cancer risk (since astragalus blocks most cancers, blocks prostate cancer yet increases hTERT too - at the same time, lenghtening critically short telomeres in healthy non-malignant cells).

I know SENS is all about totally removing telomerase, but this shows we might win a lot
from keeping telomerase and combining with SENS therapies, except the one to block telomerase.

''Conclusion and Impact: There is suggestive evidence that short surrogate tissue TL [telomere lenght] is associated with cancer; the strongest evidence exists for bladder, esophageal, gastric, and renal cancers.''

''Results: Shorter telomeres were associated with increased esophageal adenocarcinoma risk (age-adjusted HR between top and bottom quartiles of telomere length, 3.45; 95% confidence interval, 1.35-8.78; P = 0.009)...
Conclusion: Leukocyte telomere length predicts risk of esophageal adenocarcinoma in patients with Barrett's esophagus independently of smoking, obesity, and NSAID use. These results show the ability of leukocyte telomere length to predict the risk of future cancer and suggest that it might also have predictive value in other cancers arising in a setting of chronic inflammation.''

''...men with ***shorter telomeres*** appeared to have a lower risk of advanced prostate cancer (OR=0.81, 95% confidence interval (CI) 0.64-1.02, comparing the lowest quartile with the highest) (Mirabello et al, 2009). A Danish population-based cohort study of 47 102 individuals indicated an inverse association between shorter telomeres and prostate cancer incidence (hazard ratio (HR)=0.94, 95% CI 0.85-1.04, cases n=418), but not fatal prostate cancer (HR=1.04, 95% CI 0.87-1.25; deaths n=157) (Weischer et al, 2013).
In subgroup analyses, associations for high grade and advanced stage (OR=2.04, 95% CI 1.00-4.17; Pinteraction=0.06) or lethal disease (OR=2.37, 95% CI 1.19-4.72; Pinteraction=0.01) were stronger in men with a family history of the disease compared with those without. The minor allele of SNP, rs7726159, which has previously been shown to be positively associated with LTL, showed an inverse association with all prostate cancer risk after correction for multiple testing (P=0.0005).
Conclusion:
In this prospective study, longer LTL was modestly associated with higher risk of prostate cancer. A stronger association for more aggressive cancer in men with a family history of the disease needs to be confirmed in larger studies.
''

''A [astragalus] composition for effectively suppressing the growth of Prostate Cancer Cell, suppressing the Prostatic Hyperplasia and its preparation method, wherein this composition contains the Astragalusradix or its extracts with effective ingredients, which can either prevent or cure the Prostate cancer and suppress the Prostatic Hyperplasia as well. ''

Telomerase reverse transcriptase delays aging in cancer-resistant mice
1. http://www.ncbi.nlm.nih.gov/pubmed/19013273/

The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence
2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627294/

The Association of Telomere Length and Cancer: a Meta-analysis
3. http://cebp.aacrjournals.org/content/20/6/1238.abstract

Leukocyte Telomere Length Predicts Cancer Risk in Barrett's Esophagus
4. http://cebp.aacrjournals.org/content/16/12/2649.full

Circulating leukocyte telomere length and risk of overall and aggressive prostate cancer
5. http://www.nature.com/bjc/journal/v112/n4/full/bjc2014640a.html

Composition comprising Astragalus radix extracts for treating prostate cancer
6. http://www.google.com/patents/EP1808178A1?cl=en

Posted by: CANanonymity at April 22nd, 2016 5:58 PM

I was cheering or rather I would still love to cheer for BioViva that they get this therapy really going. But when I am reading that "(...) in March 2016, the same tests were taken again by SpectraCell revealed that her telomeres had lengthened by approximately 20 years, from 6.71kb to 7.33kb (...)" my eyeball turned upward. Not these guys again.

I tested with SpectraCell few years ago. And I followed-up by talking to their scientist and looking at some papers on telomeres testing. They could not guarantee even 10% precision of their results. (It could be far worse, but I just don't remember numbers now. I was very disappointed at the precision. It felt like the test results are useless.) The test that they sell is good for scientific experiments on large number of people or samples, maybe like 100 or hundreds of samples, but not on a single test. In fact, I wonder if BioViva ordered the test many times from SpectraCell to achieve higher confidence of the given result. I like the fact that they were confirming the results with other company. And finally I agree that with Reason that more suitable tests are really needed if BioViva can prove to clients that their product is working. ... Gosh, look at that precision 6.71 kbases, 1 is totally meaningless.)

Posted by: veriti at April 22nd, 2016 8:27 PM

In terms of scientific value this isn't adding much.

In terms of getting treatments to people faster, I am not sure it is adding that much either. Most people won't pay for a treatment that hasn't at least had some safety testing in humans (I think Michael Rae said the other that 70% of new investigational drugs fail in stage 1 due to toxicity).once a treatment is in stage 1, well it is only 4-6 years away from being approved or rejected, so Bioviva wo

Posted by: Jim at April 22nd, 2016 11:56 PM

Peer review or it didn't happen. If this was blasco or fossell I would be taking this seriously but this is a self promoted piece from a company website. Colour me highly skeptical

Posted by: Steve h at April 23rd, 2016 12:31 AM

@veriti

Hi veriti ! I understand your doubt, reading what you said also casted some doubt in me.
Let's hope it isn't so. I don't think this is entirely inaccurate and false;
It would have been false if it dramatically deviated from results seen using TA-65 or astragalus telomerase activators in mice and humans; or TgTert telomerase therapy in mice. The results concur almost exactly (7.56 Kb mouse vs 7.33 Kb human) giving validity to Spectra's telomeres test results. It is valid enough because all these methods rely on the same underlying element :
Telomerase enzyme lengthening telomeres (by the TERT/TERC/catalytic subunit that adds TTAGGG telomeric repeats). They all need telomerase and, from the similarity of the results, we can infer the results as reliable/true enough; since telomerase is giving maximal activity in all these studies. Demonstrating, that it's 'all (the same) Telomerase' doing 'the doing'; and that Telomerase has a regulated 'limit' in its telomeres processivity/capping/repeats adding - thus activity and expression; and it shows in all of these studies results that depend on the very same element in the first place - in the same body (Telomerase doesn't magically change from one therapy to another upon it being requested; its dynamics and limits still apply).

Otherwise, Astragalus (TA-65 is (purified from) Astragalus root and TA-65 astragalus increases mice healthspan by its cyclo/astragenol/astragalosides constitutents) is a proven, safer (prostate cancer) and max-telomerase solution for men's telomeres lengthening. It is also, unsuprisingly, a strong immune system booster (from WBC leukocytes telomeres lengthening)) used in Asian folk medecine for thousands of years to heal people.

Posted by: CANanonymity at April 23rd, 2016 12:46 AM

Ps: I understand there needs to be more tests, rigor and reviewing to make sure it is safe; still, this promising, because TA-65 has been through rigorous testing and peer reviewing - so peer reviewing or not, it does not change anything about the fact thatt TA-65 astragalus increased telomeres length. And, this, right here, does, if true, the same. Me thinks, it's more true than false baloney.

Posted by: CANanonymity at April 23rd, 2016 12:54 AM

Pps: BioViva used *** AAV hTERT *** type of telomerase delivery method in Mrs.Parrish.

This method has been rigorously tested, peer reviewed and demonstrated as having longevity effects in mice, giving creedence to SpectraCell telomeres results.

''Treatment of 1- and 2-year old mice with an
***adeno associated virus (AAV) of wide tropismexpressing mouse TERT [= AAV hTERT]***
had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging.... Finally, telomerase-treated mice, both at 1-year of age and at 2-year of age, had an increase in
median lifespan of 24 and 13%, respectively.''

7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494070

Posted by: CANanonymity at April 23rd, 2016 1:36 AM

I dont doubt the validity of the approach but I would feel more confident hearing it from Blasco or Fossell at Telocyte than this company. As I have said I want to see Peer reviewed research of this in people and it independently reproduced by another group before I consider this "story" news.

Posted by: Steve Hill at April 23rd, 2016 3:41 AM

And by independent I mean properly independent not the Biogerontology Research Foundation of which the Bioviva CSO Avi Roy is president and HEALES which has connections to the ILA on which Parrish is on the board. Show me a fully independent replication of the work and peer reviewed data and I will take it seriously. Until then I am waiting on Blasco and Telocyte to deliver the evidence using proper scientific process.

But as I have said many times Telomeres and Telomerase are a valid approach to aging, I have not changed that view but I also work on damage repair to complement that eg, Senolytics and stem cells.

Posted by: Steve Hill at April 23rd, 2016 3:45 AM

I was vastly more interested and optimistic about this work before I read this press release, which is very clearly written so as to disguise itself as a news story by an independent publication, is light on scientific detail, big on inferred and dramatic claims, and doesn't even pay lip service to peer review. I'm all for scientists going rogue in order to get their research done outside the normal channels, because those channels are very plainly stifling, but when it comes to reporting on one's findings, certain standards have to be upheld if anyone is to take you seriously. The way in which this has been handled calls the entire project into question.

Posted by: Ben at April 24th, 2016 2:42 PM

Yeah the entire "story" stinks. Full of hype light on science. Until this is repeated by a respected independent group or passes peer review its a non story.

Posted by: Steve Hill at April 25th, 2016 8:48 AM

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