SENS Research Foundation 2017-2018 Annual Report

The latest annual report from the SENS Research Foundation is out, covering progress in 2017 and early 2018. The SENS Research Foundation remains one of the very few philanthropic organizations focused on speeding the development of rejuvenation therapies - something we hope to see change in the years to come, as more support arrives for this field. The foundation staff use the charitable donations provided by our community to fund research programs specifically focused on areas of biotechnology that are presently blocked or neglected, but that can potentially give rise to ways to repair, remove, or work around the cell and tissue damage that causes aging. They also support networking, advocacy, and conference series designed to build bridges between academia and industry in order to smooth the road towards commercial development of advances developed in the laboratory.

Along with the Methuselah Foundation, where the SENS rejuvenation research programs started, the SENS Research Foundation has done a great deal to change the way in which the scientific community and broader public view aging. Back at the turn of the century, when the SENS program was proposed, and Aubrey de Grey presented his synthesis of existing evidence for seven broad categories of molecular damage that caused aging, the leaders in the research and funding communities actively suppressed any effort to work on or discuss the treatment of aging as a medical condition. It was career suicide to openly work towards that goal. The change achieved since then has been profound, and now researchers openly debate how best to go about treating aging to extend healthy life spans. This required a great deal of hard work.

A few strands of rejuvenation research have moved into clinical development in recent years: the removal of senescent cells, and clearance of a few kinds of harmful metabolic waste. As a part of its efforts, the SENS Research Foundation can now point to the ongoing development of startup biotechnology companies that it helped to seed fund, in some cases in partnership with the Methuselah Foundation. We will be seeing more of this in the years ahead: successful young companies can typically raise a great deal more funding than is available via philanthropy, and their efforts also go a long way towards attracting more validation and attention to the field.

SENS Research Foundation 2018 Annual Report

The valley of death - the chasm between innovation and availability that has become such a common theme in drug development - is especially wide for the field of rejuvenation biotechnology. Besides the time and resources required to develop any medicine, the few who initially strove to develop this field faced the added challenge of demonstrating that we could feasibly intervene to prevent age- related disease by redressing the underlying damage that causes such disease. There is scarcely a biotech organization that hasn't used, at some point, a 'bridging the gulf' metaphor to address the valley of death. But it has been such an integral part of our identity that we built it into our brand; the multi-colored ribbon of our logo having been designed to evoke both double-helix and suspension bridge imagery (and yes, it's always had seven twists).

Upon the launch of his project to build the Golden Gate Bridge, Chief Engineer Joseph Strauss had this to say: "It took two decades and two hundred million words to convince people the bridge was feasible." We have at times wondered whether even that would be sufficient. But with the diligent efforts of our own research teams and those of a growing number of institutions, the question of feasibility has increasingly fallen away. Today we see our research programs successfully translating into development, our former students becoming rejuvenation biotechnologists and developers, new collaborative energy from the investment arena, and the groundwork being laid for regulatory models for rejuvenation interventions.

Programmatic Investments

Antoxerene, a portfolio company of Ichor Therapeutics, is a small molecule drug discovery company that focuses on molecular pathways of aging. To our knowledge, Antoxerene is the first and only company with small molecule hits on the p53/FOXO4 pathway, which has been implicated in cellular senescence. Antoxerene is developing these hits for eventual clinical use.

Lysoclear, a portfolio company of Ichor Therapeutics, is an ophthalmology company developing an enzyme therapy for age-related macular degeneration and Stargardt's disease. In 2017, the company completed pivotal proof-of-concept studies with its first generation enzyme lead and conducted extensive mechanistic work to clarify the role of retinal lipofuscin in the onset and progression of macular degeneration. These results have been submitted for peer-reviewed publication. Lysoclear is now optimizing its enzyme into a drug candidate in preparation for IND enabling studies.

Oisín is developing a DNA construct that recognizes that a cell has become senescent and then destroys it, and safely and efficiently delivering this construct into cells throughout the body. Both goals have been achieved in pioneering proof of concept experiments in 2016. Now they are embarked on experiments that will show improvements in both healthspan and lifespan in model organisms from mice to primates.

Arigos has made great strides towards the banking of human organs, demonstrating functional and structural recovery of similarly-sized tissues from below -120°C. Their ability to cryopreserve large, complex tissue structures is a breakthrough in medical research. Stable banking for larger tissue structures and organs could more than double the number of transplants performed each year and would eliminate five of the current organ waiting lists within a few years.

Research

The MitoSENS team is working on a potential rejuvenation biotechnology to sustain and recover electron transport chain (ETC) function: allotopic expression of functional mitochondrial genes. Allotopic expression involves placing "backup copies" of all of the protein-coding genes of the mitochondria in the "safe harbor" of the nucleus, which can then deliver the proteins mitochondria need to build their ETC and continue producing energy normally, even when the original mitochondrial copies have been mutated. The team is working to establish a "landing pad" in mouse cells to enable reliable and safe gene therapy for animal studies, via the Maximally-Modifiable Mouse Project. They expect to soon begin preliminary in vivo testing of allotopic ATP8 in transgenic mice. Meanwhile, they are also looking to expand the strategy to other mitochondrial genes and further improve allotopic expression of the ATP6 gene.

A major cause of crosslink accumulation in aging is Advanced Glycation Endproducts (AGE), and one AGE in particular - called glucosepane - is currently thought to be the single largest contributor to tissue AGE crosslinking, with consequences such as arterial stiffening. The Yale team is developing new reagents and approaches to accelerate glucosepane research. They now are able to synthesize all three conformational variants (diastereomers) of glucosepane that may occur in vivo. They are also working to generate antibodies that can then be used to label glucosepane crosslinks in tissue samples and in vivo. Further, the Yale team has identified some potential glucosepane-breakers, about which we hope to be able to make further announcements this year pending publication in a peer-reviewed journal.

One of the reasons why senescent cells secrete inflammatory signals is to attract Natural Killer (NK) immune cells, which then clear senescent cells from the tissue. Despite this, senescent cells accumulate over the course of the lifespan. A critical question is therefore that of how some senescent cells are able to escape immune surveillance and what might be done to overcome their defenses. Dr. Judith Campisi, a renowned pioneer in senescence research, is answering this question and developing strategies to enhance immune clearance of senescent cells. Campisi's group has already discovered that one of the key NK cell binding markers on the surface of senescent cells begins to disappear within weeks of the cell becoming senescent. Without this marker ligand, NK cell binding cannot occur, and the NK cells' killing ability cannot be unleashed. Early results suggest some potential strategies for restoring NK cell immunosurveillance of senescent cells.

Aggregates composed of aberrant tau protein accumulate with age, both inside and outside of neurons. These aggregates are an important driver of neurodegenerative diseases of aging. One possible basis for this intracellular accumulation may be as a consequence of age-related lysosomal dysfunction that is driven by the accumulation of other kinds of intracellular aggregates. As such, this deleterious accumulation might be reversed if lysosomal function could be restored. This line of investigation will inform strategy: do we need a custom solution just for intracellular tau aggregates, or will clearing other age-related lysosomal junk be sufficient to restore an existing capacity to eliminate these aggregates? The Andersen lab is testing this possibility using neurons that express mutant versus wild-type human tau.

Atherosclerotic lesions form when immune cells called macrophages take in 7-ketocholesterol (7-KC) and other damaged cholesterol byproducts in an effort to protect the arterial wall from their toxicity but ultimately fall prey to that same toxicity themselves. Dr. O'Connor's team has identified a family of small molecules that may be able to selectively remove toxic forms of cholesterol from human blood, which would help combat the development of atherosclerosis. They have been testing its effects and those of closely-related compounds in human blood samples, seeking potential modifications and combinations that would maximize selectivity for toxic cholesterol byproducts while leaving native cholesterol alone.

Comments

The Gensight allotopic REVERSE ND4 trial failed; https://www.gensight-biologics.com/product/gs010-for-lhon/
I clearly predicted this (to much criticism on this site) and stated why over a year ago, in numerous posts and a reviewed publication, ie.
https://www.blogger.com/blogger.g?blogID=5900123281843921168#editor/target=post;postID=7418413889248086268;onPublishedMenu=allposts;onClosedMenu=allposts;postNum=2;src=postname

Understandoing mitochondrial DNA is not trivial, so here isthe beginings of my contribution on how to do it for this week:
https://medicalxpress.com/news/2018-05-genome-imitochondrial-dna.html
and
https://phys.org/news/2018-05-mitochondria-art-dna-maintenance.html

Posted by: john hewitt at May 12th, 2018 8:21 AM

It didn't fail, John, not in the standard meaning of failure. Did you read the articles besides the titles? Probably not. That's a common trait I've noticed in posters on this blog and other places related to longevity.

They didn't meet their target because BOTH the injected eye and the "placebo" eye improved their vision. Which goes to show their vector is significantly better than they thought. If anything I'd say their trial result is an unexpected boon because it seems they can completely evade any problems which typically arise when injecting in the eye like increased pressure because the vector infects everything - unfortunately this probably makes their therapy illegal in a lot of places because it travels across the bloodstream and there's a good chance it reaches the germline.

So in that way it failed because it cannot be marketed. But it didn't fail at making the patients see better.

Posted by: Anonymoose at May 12th, 2018 11:07 AM

Hi John,
It is due that many promising rituals will fail. And most genetic defects will be extremely hard to cure in vivo.
For example moving the mitochondrial genes to the nucleus is a very complex exercise and dig it on cell culture can easily take decades. And after that we will have to replace or ale ask eye living cells. Not sure if it can be done for the neurons.

On the other hand, senolitics and anti cholesterol plaque treatments seem quite plausible

Posted by: Cuberat at May 12th, 2018 11:51 AM

@anon. It's just sad all around. I would like to have seen any new mito therapy be a success, and to be proven wrong, to havve learned, and for the field to have more successes, but alas all they manadged to prove was that injected placebo into your eye might have some small benefit if you are already screwed.
Not just a total fail, but as you observe, FATALITY.
'Rescue, Reverse, Reflect, then finally, Reality'
https://mitochondrialdiseasenews.com/gs010/

Posted by: john hewitt at May 12th, 2018 12:32 PM

Again, I have to point out that the therapy DID NOT FAIL.

Posted by: Anonymoose at May 12th, 2018 12:33 PM

A clinically meaningful improvement of +11 ETDRS letters reported in the 37 subjects in both eyes

It failed to beat placebo. BECAUSE IT WORKED IN BOTH EYES. Are you illiterate or just daft?

Posted by: Anonymoose at May 12th, 2018 12:36 PM

And I should point out that they said "clinically meaningful" which is opposed to statistical significance which might be irrelevant for most people.
In just one sentence they are saying - this is f**king home run.

The question whether it works or not has been answered unequivocally.
As I said they need to work on their vector because I'm pretty sure they can't sell this if it's this potent, at least not currently, but what is important for our community is the concept, not this therapy in particular.

You were wrong. Just move on with your life for goodness sake...

Posted by: Anonymoose at May 12th, 2018 12:44 PM

I cannot see the blogger page, it asks for password. And in the Gensight's page there are no results yet. Also there are no results in clinicaltrials.gov either.

Posted by: Antonio at May 12th, 2018 3:28 PM

Also, john hewitt, you got so much criticism on this site because your ideas about mitochondria are totally non-sense.

Posted by: Antonio at May 12th, 2018 3:35 PM

I'm afraid the investors didn't see it that way, stock dropped 50% immediately after their announcement of zero (0) benefit over sham.
CEO offered that the treatment might have affected both eyes, which is certainly possible, especially, if you design your too big to fail study where the treated person also happens to be the placebo too. Unfortunately those with money where their mouth is weren't buying it.
Report says 'structural studies' done later looked at the eye anatomy and have apparently not borne that idea out, but fortunately they will still continue to assess the patients so maybe some hope.
As you know from my posts the optic nerve is a great one for mitochondrial transexudation, even if it is just for transmito[hagy, but who knows, maybe some nucleoids get taken up before they can be degraded, assuming ND4 made it there. But that is a longer shot, we know better know the subunit assembly and compartmentalization and it seems quite rigid, as researchers showed again the other day here, 'Mitochondrial OXPHOS complex assembly lines' https://www.nature.com/articles/s41556-018-0098-z

Posted by: john hewitt at May 12th, 2018 9:40 PM

An intervention not working is not evidence that the underlying technology is flawed. The failure, or to be more accurate, inconsistent results, could be due to a number of other reasons such as delivery issues, or lack of long term expression of a gene therapy that is not inserted into the chromosomes. we are all aware of the long and difficult history of gene therapy.

The stage 2 data was decent, suggesting that the treatment is doing something, just not consistently.

Personally I doubt Gensight's hope that the treatment is somehow being injected into one retina, but then somehow reaching the other eye's retina.

Posted by: Jim at May 13th, 2018 4:21 AM

@Anonymoose, if this is the case and their vector is really effective -- that is well, because we really need to targed all the cells for example, in MitoSENS and LysoSENS programme.

Posted by: Ariel at May 13th, 2018 6:46 AM

Most people with LHON would be in the legally blind range.
An improvement of 10 to 16 letters is non-trivial.
It's the difference between 20/200 and 20/100 vision.
So it is an easily detectable difference in visual acuity.

The only way to interpret the results as a failure is if you're implying Gensight are outright lying about the result. Which is not impossible I'll grant you that, there have been a number of high profile biotech frauds in the last 5 years but jumping to that conclusion is premature at this time.

Posted by: Anonymoose at May 13th, 2018 8:37 AM

The fact is a quarter or more of LHON patients show spontaneous improvements in vision over time anyway.
When Gensight announced the trial I contacted them many times, quite supportingly and optimisticaly, with a few technical questions for media coverage. They refused to address any of them, zero response. That speaks volumes to me. I have no respect or trust for this.
Is it not equally valid that the placebo injection is what really caused the alledged improvement, the placebo effect?

Posted by: john hewitt at May 13th, 2018 9:46 AM

"The improvement of visual acuity in sham-treated eyes was unexpected based on the natural history of LHON, for which partial spontaneous recovery is reported in only 8 to 22% of patients with the G11778 ND4 mutation "

"The critical secondary endpoint of the change in retinal ganglion cell macular volume measured from baseline to week 48 demonstrated a statistically significant difference (p = 0.0189) between all GS010-treated eyes and all sham-treated eyes, with untreated eyes losing 0.038 cubic mm of macular ganglion cell volume while treated eyes preserved their ganglion cell volume (-0.003 cubic mm)."

I must agree with Anonymoose. All of this screams "successful trial" - investors just pulled because they expected others to pull. I myself put a tiny bit in, which i've now sold since i'm fairly certain the next trial will similarly fail (and scare off others), due to the same methodology (mostly) being used. As soon as they improve their method, I think the drug will shine through - likely late next year.

From a longevity perspective, that's a non-issue, since this therapy will only be useful in conjunction with the other 12. From a financial perspective... The stock price drop from the upcoming trial combined with the current will create a window of opportunity for a lot of people to get a lot of money back. At least a few of those will be in our community, so a possible uptick in donations?

Posted by: Patrick Deane at May 13th, 2018 7:12 PM

"BECAUSE IT WORKED IN BOTH EYES." So why didn't the put a tracker in the injections that would allow them to follow the migration of the medicine around the injection site? Isn't their a relatively long half-life, low dose radio-isotope they could have used in combination with a very sensitive and high resolution detector optimized to the particle energy released by that isotope?

Posted by: Tom Schaefer at May 14th, 2018 7:29 AM

Much easear and safer is taking a sample from placebo eye and sequencing it

Posted by: Ariel at May 14th, 2018 10:57 AM

@Tom Schaefer its forbidden to insert any positive marker like GFP or luc into patients in clinical trials. Its not approved by the FDA.

Posted by: Or alfi at May 14th, 2018 12:55 PM

surely they could isolate a little a little mtDNA from tears, however mitos/mtDNA could have arrived there from many sources. The lacrimal nerve is derived from the ophthalmic nerve supplies the sensory component of the lacrimal gland; greater petrosal nerve, derived from the facial nerve, supplies the parasympathetic autonomic component, and couldevern exchange mitos along its course from V1/V2 divisions of the trigeminal nerve.

Posted by: john hewitt at May 14th, 2018 5:02 PM

Has there been any advancement of the 7-ketocholesterol destroying enzymes that were discovered several years ago? Last I heard that had been farmed out to some company that has been ineffectively sitting on it.

Posted by: Dennis Towne at May 15th, 2018 3:23 PM

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