21 June 2017

Liz Parrish's Gene Therapy

Trying to figure it out

Yuri Deigin, Geektimes

In light of my dreams of gene therapy using Yamanaki factors, I decided to refresh my memory of the details of Liz Parrish's self-experiment. What if she agrees to act as the first patient for yamanach therapy? No, I'm joking, of course, but there is some seriousness in this joke. I really think that epigenetic rollback gene therapy has therapeutic potential. And for some 15-20 million dollars, this potential can either be brought to the start of clinical trials, or refuted.

But, returning from heaven to earth – what did Liz Parrish introduce to herself? According to her assurances, Liz injected herself with 2 different gene therapies using adenoassociated viral (AAV) vectors: the hTERT telomerase gene and the follistatin FS gene (designed to inhibit myostatin).

It should be clarified that, most likely, it was not two varieties of AAV, but much more, since Liz needed to prepare a specific AAV for each type of target tissue. And then she had to deliver this particular AAV to this target fabric. This is what I understood from this interview with Liz on Longecity Now.

It is worth noting that AAV is not purposefully integrated into the genome – that is, for those cells that divide, daughter cells will NOT receive those genes that were delivered to the original cell using AAV. But they will have elongated telomeres, provided that the hTERT gene works as intended in their mother cell.

The fact that Liz actually injected herself with some kind of injections (yes, skeptics, I hear you) is confirmed by the director of a documentary about her, who filmed this procedure in Colombia:

"MIT Technology Review tried to confirm aspects of Parrish's story by talking to Matthew Andrews, a Los Angeles-based filmmaker who said he filmed Parrish's treatment in September–it was a modest doctor's office attended by one doctor and one nurse who also collected blood tests. “It was a treatment room, there were no particularly high-tech gadgets. She was lying on the bed, without anesthesia, receiving injections and connected to a drip," he said. "It was a bit boring from the point of view of an outsider, although of course I don't know what was going on inside the body.""

By the way, according to Liz, AAV therapy successfully delivered the hTERT telomerase gene to only 20% of her cells. She stated this at her presentation at Digital October in Moscow, June 22, 2016 (the moment is about 1:46:41 in this video):

Why did Liz choose these particular treatments? Michael Fossell and Bill Andrews have been talking about the rejuvenating potential of telomerase for many years. The specific approach of using TERT therapy has been confirmed Maria Blasco in mice, where she prolonged both the average survival and the maximum age of mice in two groups – one received TERT injections at the age of 420 days (an increase in median survival by 24% and an increase in maximum life expectancy by 13%), and the other at the age of 720 days (an increase in median survival by 20% and increase in maximum life expectancy by 13%).

By the way, Michael Fossel said that he consulted Liz several times, as he is working on starting clinical trials of a very similar approach of hTERT therapy for patients with Alzheimer's disease:

"Our biotech firm, Telocyte, intends to do almost the same thing, but with some important differences: we will use only one therapy – therapy with the telomerase gene (hTERT), and we intend to conduct full-fledged human trials, having received FDA approval, with the IRB approval procedure, as well as using GMP standards for the production of therapy.

At the same time, I applaud Liz's courage in using herself as a research subject. Using herself as a subject removes much of the ethical criticism that would have been more relevant if Liz had used other patients. Like many others, we see an urgent need to develop and implement more effective therapeutic interventions: patients not only suffer, but also die while we are trying to move forward. In the case of Alzheimer's disease, for example (our main therapeutic target for Telocyte), unfortunately, there are currently no effective treatments, and a huge population of patients is forced to die while we develop a new therapy for their treatment. A slow, measured approach to finding treatment is hardly welcomed by them in such a situation."

And yet…

"We decided to follow the standard approach – with FDA approval of human trials – for three reasons that we consider important: 1) we want to ensure security, 2) we want to ensure efficiency, and 3) we want to ensure trust. The question of safety is not simple: Alzheimer's disease is associated with a fatal outcome, so safety here may seem less important than efficiency. And we really believe that there is no reason not to try experimental therapy on desperate patients if easily avoidable risks are removed in advance (for example, using safe production processes for viral vectors). The question of effectiveness is also not easy: someone says that it is necessary to try any therapy, even remotely effective. But we see no reason to use minimally effective therapy if we can provide the most effective therapy using only a little more foresight and care. The question of trust is also not simple: someone claims that it will be enough just to cure at least one patient from Alzheimer's disease. This is true, but only on the condition that they believe us that we really cured him. But if no one believes us, the fact that we cured one person will not help millions of other patients in any way." 

As for the second therapy of Liz using the follistatin gene, as I understand it, this approach was previously tested by Liz's partner and co-owner of BioViva, Jason Williams. Williams, by the way, had previously developed several other experimental gene AAV therapies, and also has his own clinic in Colombia, where he offers some of these therapies to patients (but Liz did not undergo her procedures in his clinic).

The specific FS AAV therapy that Liz injected herself has already successfully passed the second phase of CI in Britain and is now undergoing the third:

Question: why test two such different therapies at the same time? Liz says that she expects a synergistic effect, and also that there is evidence that FS therapy can deplete stem cells, and hTERT therapy should help prevent this. 

The first results of therapy reported by BioViva are that Liz's lymphocytes lengthened from 6710 to 7330 base pairs after treatment. The statement that this is equivalent to “rolling back 20 years of telomere shortening”, although it sounds pathetic, but it has some scientific justification, since the average rate of shortening of leukocyte telomeres is about 30 base pairs per year. 

With normal aging, telomeres shorten in CD4+ T helper cells, CD8+ cytotoxic T cells, and antibody-producing B cells at an annual rate of 19-35 base pairs (1 and 2).

At the same time, some people note that telomere elongation by 9% is within 8-10% of the qPCR measurement error, but from what I have read about qPCR, 8-10% is an interlaboratory or inter-method error, and not an error when using the same equipment in the same laboratory. That is, you can see a 10% difference in results when testing the same sample in two different laboratories or using two different methods. But Liz claims that her telomeres were measured both before and after receiving treatment in the same laboratory – SpectraCell Laboratories. 

In addition, Liz claims that the results were confirmed by two other scientific organizations: the Belgian NGO HEALES and the British Foundation for Biogerontological Research. Therefore, the probability that the difference of 9% is due to a measurement error seems to me much less than the probability that this difference is due to real biological changes. Of course, for greater certainty, it would be necessary to analyze all the samples of Liz and other methods (not qPCR, but TRF, for example), and in other laboratories. I hope it will be done.

By the way, I have to note that the question of how independent the above-mentioned scientific organizations are remains open, since HEALES is affiliated with ILA (International Longevity Alliance), where Liz is a member of the board of directors, and the British Foundation for Biogerontological Research is headed by Avi Roy, who is also director of science at BioViva. 

By the way, at a press conference in Moscow, Liz said that she had sent some of her samples before and after therapy to the George Church laboratory at Harvard, which promised to conduct a detailed analysis of them, including tests evaluating the change in methylation (in the hope of seeing a "younger" profile of the methylation hours identified in the works Steve Horvath). Liz talks about it in the same video (around 1:48:41).

George Church is, of course, cool, because he is almost the Einstein of modern genetics, but... he is on the Scientific Council of BioViva. Hopefully, over time, there will be a completely independent third party who will undertake to confirm the results of Liz, preferably using a different method of measuring telomeres. At the same press conference, Liz said that she was ready to provide her samples for testing in independent laboratories, provided that they were truly authoritative.

In March 2017, Liz released a press release with her latest results of her tests. There she claims that the MRI data of her thighs show a decrease in the “marbling” of the muscles, that is, a decrease in the amount of intramuscular fat deposits, which can be regarded as a positive effect of follistatin therapy:


But perhaps the visual difference between the images is due only to the improvement in the resolution of the MRI: the old picture was taken on a 1 Tesla device, and the new one was 1.5 Tesla. In addition, it seems to me that the images were obtained from slightly different places in the hips – more recent images, judging by the distance between the legs, were taken from slices slightly lower from the pelvis than the old ones. And the lower the butt, the lower the percentage of fat in the legs. Although, maybe Liz just spread her legs a little wider in the last test.

By the way, in the recent data of Liz, it was interesting to see a fairly high (1.6) level of C-reactive protein before the introduction of gene therapy and a subsequent decrease in CRP to 0.2 in February 2016. It would be interesting to know what the value of CRP was in the round of tests in 2016 – Liz gives glucose and triglyceride values from August 2016, but not CRP.

In conclusion, I will mention a couple of critical remarks on the use of lymphocyte telomere length as markers of rejuvenation:

(A) measuring lymphocyte telomeres is not a good metric in principle, since they have too much variation in telomere length;
(B) the average telomere length, especially in white blood cells (WBC), can fluctuate naturally for a fairly short period of time (less than 2 years).

On point (A), Michael Fossell wrote a detailed post on his blog, so I'll just give him a link.

And according to point (B) – yes, the average telomere length can, apparently, sometimes spontaneously increase, although not as much as in the case of Liz, and this happens infrequently (in 10-15% of cases). Here are two good papers on the topic (1, 2).

This graph from the last work is especially indicative – as we can see, in 18 months, quite a lot of people's telomeres have lengthened (all points above zero): 


By the way, some hardcore skeptics demand proof that Liz really injected herself with the claimed genes. In principle, this could be tested cheaply and quickly using RT-qPCR on Liz lymphocytes before and after therapy: if AAV delivered their genes, we would have to see the difference in the curves. Perhaps George Church's laboratory could conduct such an analysis. But I don't think it's necessary, because it would be the height of idiocy to openly lie about injecting yourself with these genes, and then send your samples to George Church.

Portal "Eternal youth" http://vechnayamolodost.ru  21.06.2017

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