Telomeres and teloyears on my television?!

A little while ago I spoke on the proliferation of opportunities to interrogate one's own genes via the offering from the equally proliferative spate of new-age companies providing kits to peer into the murky depths of our individual genomes. As fun as it may be to learn certain things about one's ancestry and genetic make-up, there are clear dangers in coming to diagnostic and prognostic conclusions based on non-physician interpretation of such data. Especially when physicians are in fact not trained to analyse such data in the first place!

While watching TV on the weekend, my attention got suddenly grabbed by an advertisement berating us all to "Redefine your age in 2017!"; the name of the provider had the extremely intriguing moniker of "TELOYEARS" which I knew just had to mean telomeres!  I was kinda taken aback to be honest - while the terms DNA, and human genome, and personalized medicine have become quite commonplace in (social) media these days - is the general public now ready to be asking questions about their telomeres?!

I find it fascinating that something as specialised or even esoteric as telomere research is already out there in the public domain, with a tantalising little test on offer to inform you how well (or not) you are aging. Is the public sufficiently educated to truly understand what it is they are buying and what can of worms they may be opening, or is Teloyears just another biotech venture destined to make some serious money while simultaneously courting considerable controversy?

So what's the story? Well, briefly, telomeres are the protective nucleotide caps that keep the ends of our chromosomes intact and protected, via multiple repeats of the TTAGGG hexanucleotide sequence, with one hexanucleotide overhang at the very end. We are born with a few thousand of such repeats at the ends of our chromosomes, but this number is reduced with aging, due to the replication process not being complete at each cell division. Thus, a gradual shortening of our telomeres is part and parcel of the natural aging process, or even (as Teloyears imply) an unnaturally accelerated aging process. 

It's an enticing little story, even if it's the usual soft focus lens take on things, with glamorous, healthy, active people young and old simply  bursting with vitality, no doubt due to very sexy telomere counts! And that's all very well, in fact it is likely to be those active, fit, middle-aged folks who will be the major clients of such companies. In other words, I am fit and healthy, and the test confirmed my telomere length to be like ten years younger than me! 

That will feel good, no doubt. But what about those that felt they were doing great, and the test informs them they are actually older than their years? If their lifestyle is already top notch, what are they to do next to stop the onslaught of telomere shortening? So much of it is probably in the genes already, that if it's low, then it's low! Are people who have let themselves go, and can see it in the mirror and/or on the scale, likely to pay for a test that confirms their worst fears or what they already know? Will such a test be the single factor that will cause them to overhaul their lifestyle?

Again, what are physicians supposed to do when their patients come to them with the results of their Teloyears test? Maybe I am misinformed, but it's my opinion that if you stroll in all newly educated and tested to your doctor's office, exclaiming woe due to criminally short telomere repeat numbers, the doc is likely to say "Telo-whaaaaat?!" I just don't think the medical profession is ready to truly interpret and prognosticate based on such data, and at best one is likely to be told to eat less, exercise more, stress less and sleep more. Business as usual, in other words. 

Telomeres have been and are the focus of intense research, and not just in terms of cellular aging. Clearly, one advantage of shorter telomeres would be that it is not compatible with the cell division/growth seen in cancer, and in fact, maintenance of telomere length is a hallmark of cancer cells. Like almost everything in life, too much of a good thing is often a bad thing. So, overly short telomeres is a sign of cellular aging and contributor to cellular senescence, and overly long telomeres is a sign of cellular "youth" and contributor to cancer.

There are several key players in regulation of this process, including TERT (telomerase reverse transcriptase), the shelterin complex (including TRF1 and TRF2), and the newly discovered TZAP (telomeric zing finger-associated protein) which was the subject of a groundbreaking paper published in SCIENCE just this past week. In this case, rather than the currently fashionable issue of shortened telomeres, the authors studied the question of how longer telomeres would actually be a cancer risk, and how do healthy cells avoid the problem. 

It turns out that not only do our telomeres shorten with age, but we do have a mechanism in place to prevent them from becoming overly longas well, and that is driven by TZAP.  So, when telomere length becomes too long, the concentration of the shelterin complex goes down, permitting association of TZAP with telomeres, resulting in a trimming of telomere ends. Clearly, telomere shortening can also be considered a good thing, too! 

Almost certainly, telomere shortening is a factor associated with age-dependent diseases but the cause-and-effect relationship is far from clear, if it exists at all. Is it the shortened telomeres that caused the disease, or is it that the shortened telomeres are just another marker of aging process that inandof itself led to the disease? It's the chicken and egg question, again. Much more research is needed, of course, and one has to be careful about the claims being pushed at us by various companies making money off of our genes. 

The world of personal health and fitness is unquestionably a brave new world, with various wearables poised to revolutionise healthcare as we know it. Now you can have a device on your wrist that can measure your activity, your resting heart rate, your sleep patterns, stairs climbed, and some even offer blood pressure monitoring. So we are more and more likely to be monitoring such parameters, and sharing that information with our doctors. But I feel we are still some way off from discussing the results of 23andme's inherited genetic risk factor data or our telomere length issues with them! 

Happy new year to two newly minted newcos!

             

What better way to kick off the new year than with news of a couple of key AmorChem investments converting into full-blown but virtual (for now!) biotech companies?! It's only early January but we are starting the year in the fashion in which we intend to continue, i.e. putting our money and support behind those prior investments that have succeeded in their early endeavours and now merit/need additional help to cross the great divide. 

First up, we were delighted to launch Corbin Therapeutics, a new company focused on the USP15 deubiquitinase (DUB) target discovered by Dr. Philippe Gros of McGill University. With a seed financing of $1M in place, the team is now poised to begin screening for small molecule inhibitors of USP15 as novel candidate therapeutics for neuroinflammation, with multiple sclerosis as the primary indication. 

There's a lot of buzz in the UB/DUB space in general, with many referring to the them as the next generation of drug targets, in correlation with kinases/phosphatases, but of course specificity is always going to be a key factor in developing inhibitors. USP15 itself is seeing quite a bit of attention in the literature, and seems to play key roles not only in neuroinflammation, but additionally in viral replication/stability as well as in p53 biology and cancer.  

This exciting new target's role in inflammation was identified by Dr. Gros and his team in an elegant genome-wide mutagenesis screen in which a single point mutation was sufficient to be protective in various animal models of neuroinflammation. In a recent paper published in Nature Immunology, the team demonstrated that USP15 regulates the type I interferon response and is directly involved in the pathogenesis of neuroinflammation. 

Essentially, we see huge potential not only in the USP15 target but also in the team that discovered it, and so we wanted to capture that potential and further nurture it, allowing the program to mature and evolve such that it may become an acquisition target for a larger biotech or big pharma interested in the UB/DUB (and inflammation) space. In fact, given not only the expanding role of USP15 as outlined in recent literature, but also discovery of other targets by Dr. Gros and his team, Corbin is positioning itself as a drug discovery platform. On that note, best of luck to Corbin, the first 2017 spin-off from our AmorChem fund - here's hopiung that we are on the c-usp of something big! 

Next up is another spin-out newco, SemaThera, via the pioneering work of Dr. Mike Sapieha of the Maisonneuve-Rosemont Hospital (HMR). Dr. Sapieha has been working on the involvement of a key new target (SEMA 3A) in diabetic macular edema (DME), and his team have generated a series of ligand-based traps that permit investigation of the roles of both SEMA 3A and VEGF in animal models of disease. 

The team has demonstrated that SEMA 3A is linked to vascular leakage that is z hallmark of DME, but importantly, they have shown that the levels of SEMA 3A rise earlier than those of VEGF in disease modeling, which may facilitate earlier intervention in the disease than the current standard of care. This is a most pertinent point in that almost half of all DME patients do not respond well to treatments targeted at VEGF, and thus the targeting of SEMA 3A may provide new hope for those living with the condition. 

SemaThera is also the recipient of $1M seed financing from AmorChem, and this financing will permit the company to select a lead candidate for preclinical development, from their bank of SEMA 3A traps. This is a hot target already getting a lot of attention from big pharma, and we believe that a lead trap which has been through preclinical development will be very much on the radar both in terms of pharma partnering and/or acquisition. 

When one considers that DME is a very common feature of many retinopathies, and that as many as a quarter of diabetes sufferers exhibit some degree of DME, then the significance of an earlier, targeted therapy is ultra-clear. We wish SemaThera a very happy new year and all our best wishes for an action-packed year with no blurred lines! 

Although it may appear that we are reverting back to the older Quebec biotech model that crumbled back in the late 2000s, it's worth noting that we learnt serious lessons from previous failures. These newcos are being seeded by AmorChem to elongate their runway, whilst existing within the confines of a virtual newco that remains housed in founder labs and institutions. 

One socioeconomic positive arising from such newcos is that it allows the retention of highly skilled and trained research personnel who become central to the chances of success of our funded projects. So even though we are not creating new infrastructure, we are contributing to maintenance of such jobs and growth of a skilled life science workforce here in Quebec, and that's a very important bonus in our newco strategy.

There will be a degree of both professionalisation and further development within these newcos that should augment their chances of success, and it will be both their ongoing evolution and various market forces that will dictate the outcome. We are fine with that! With these two spin-offs, we are now at #4 from our AmorChem fund, with one major announcement still to come - we have Mperia, Corbin and SemaThera thus far - for more info on the mysterious missing link, watch this space! 

Hitting the ground running in 2017!

Well, 2017 is now very firmly with us, and it's shaping up to be another very interesting year ahead! Personally speaking, this is the beginning of my fifth year at AmorChem, and while it is true to say that occasionally it still feels like yesterday, a lot of water has flowed under my bridge in that time corresponding with a lot of new challenges faced, much new experience gained, and many solid lessons learned - and that's what it's all about! 

This is a big, big year for us at AmorChem, having reached the end of the investment cycle of our first fund, and various key projects now having matured from early stage discovery assets into those that are increasingly the focus of business development (BD) activities, garnering enthusiasm from BD personnel working for various potential external partners. This is both an exciting as well as rewarding development in that it underlines that we must be doing something right - right?!

We are poised to do it again this year, bigger and better, having learned a lot about the complexities and challenges in investing in life science discovery projects that remain housed in the laboratories of inventors. This experience is fairly unique to us (province-wide if not Canada-wide), and the need for such translational funding isn't going away anytime soon, so this is why we are ideally positioned to expand on our success and therefore are currently fundraising for an AmorChem 2. 

We weren't totally sure at the outset or early on during the vesting period of our first round whether the submission of new opportunities and deal flow would significantly slow down after 3-4 years, or would be sustained. While it's always easy to be cynical or pessimistic, we were in on the inside, busier each passing year, with confidence that the need for our presence in the local ecosystem was not about to dry up. And guess what - it didn't!

In fact, our thermometer remained on the warmer side consistently, and it is accurate to say that the door has never really stopped knocking. Word of mouth has spread about our fund and what we do, and increasingly, people come to us now in a fashion typified by classical inbound marketing campaigns. This trend has been facilitated by our annual KNOCK OUT™ competition, whereby local hopefuls enter the ring in front of our panel of biopharma heavyweights and duke it out for a chance at a grand prize of a $500,000 AmorChem investment. The quantity and quality of our applicants has steadily improved and last year we found ourselves in the somewhat luxurious (bot not enjoyable!) position of having to turn down projects that were just a little too early - even for us. 

The take-home message here is that demand remains high, the need for external funds to get early stage projects across the "valley of death" is deeper than ever (like the valley itself) , and it is apparent that academic granting agencies can only do so much in this regard. You only have to mention the acronym "CIHR" to researchers young and old, to be hit with a barrage of tales of woe about lack of funding or even basic trust in the process. This is why we exist, and I don't think it is a stretch to suggest that the need for our continued existence is palpable - given the number of calls we receive from local tech transfer offices asking about our rumoured next round of financing, with a hot new project to put forward for it - it's more than evident that we meet a key, urgent need. 

As exciting a time as it is for us, 2017 presents many challenges in the life science and pharma sector, and recent or upcoming elections can be expected to impact those challenges further. Here in Canada, we have Justin Trudeau as a newly elected Prime Minister, representing a shift of government from Conservative to Liberal, while south of the border, we have had the raucous (and occasionally trainwreck) presidential campaign trail that ultimately saw the Trumpster seeing off Obama and the Dems. 

One currently red hot drug development area is the immuno-oncology space, which saw some record-breaking fundraising and dealmaking in 2016. Perhaps most prominent are companies like Juno, Kite, Cellectis, Bluebird, and making the news more recently was the UK's Immunocore,  which scored a European record-breaking financing round of $320M for their T-cell-mediated attack approach on cancer. This type of huge fundraising is reminiscent of North American record-breaking rounds such as Cambridge's (MA) Moderna, which raised a whopping $450M in 2015 for their mRNA therapeutic approach. In fact, since 2011, Moderna has raised an amount just shy of $1B, which is staggering. 

Speaking of immunotherapy, AmorChem bought into this overall approach early on, having invested in a personalised cancer immunotherapy program that uses minor histocompatibility antigens (MiHAs) as T-cell targets in cancer. This exciting program is about to enter Phase I clinical trials here in Canada, and we are already fielding multiple inquiries from potential partners who see the huge potential in the approach, and we are optimistic that the future for MiHA-directed immunotherapy is looking very bright indeed. This year should see new, susbtamtial investment in the assets of this program and for updates on that, watch this space!

Things look optimistic in spite of various challenges the pharma industry faces; such issues will probably sort themselves out in the coming year or so, once corporations find out exactly who and how the next President is, in a business sense. Having said that, an industry with a global revenue stream in the hundreds of billions of dollars (and predicted to be in the trillions before very long!) is a juggernaut that barrels forward with considerable force, and even lawmakers can only hope to do so much to slow it down. Time will tell on the outcome of big pharma pricing wars and the increasing accusations of price gouging from the public, payers and governments alike. Until then, let's stay optimistic and look forward to an amazing 2017 ahead!