The University of Pittsburgh spinout that is set to take over the tissue replacement market, one mini-organ at a time.
So your organs are failing? Not to worry, says LyGenesis’ CEO Michael Hufford, we’ll grow you some mini-organs in your spare lymph nodes.
It sounds weird, we know, but it might just be an idea that is, to paraphrase Hunter S Thompson, too rare to die. Take a view of the more conventional areas of the organ replacement market (bioprinting, xenotransplantation and cybernetics) and you’ll see a lot of interesting technologies facing some very intimidating technical challenges. And, as we reported after the abandonment of Organovo’s pioneering work in bioprinting, the direct solutions to these challenges may be further away than the financial solvency of the spinouts that are attempting to find them.
And that could mean that LyGenesis, a spinout of the research of Pittsburgh’s Eric Lagasse, could have the upper hand. They aim to use patient’s own lymph nodes as bioreactors to grow ectopic ‘mini-organs’ that support or replace the diseased originals, and they’ve garnered quite a bit of promising investment, having acquired $3m in Series A funding from Juvenescence back in May. Now, with their first, rather Promethean, focus on liver regeneration slated to enter human trials at the beginning of next year, Longevity.Technology sat down with CEO Michael Hufford for an exclusive chat on how he and his team plan to deliver their liver.
Longevity.Technology: Let’s spend a little bit of time talking about your therapy. Let’s say I hop into a time machine and go to the future, to whatever time it may be for it to have fully hit the market. What’s your procedure going to look like?
Michael Hufford: So let’s start with the present. Today, when a person needs a new liver, then a major transplantation surgery is their last option. This is an expensive and major operation – if you ever do a Google image search for “liver transplantation,” you really do want to brace yourself.
And then there’s our approach, which uses endoscopic ultrasound to engraft cells into a patient’s lymph nodes, and transforms the transplantation process into an outpatient procedure. That’s one of the fundamental value propositions of our technology. Instead of the costly and high-risk organ transplantation procedure that is available today, the patient would be put under light sedation, the endoscope would be moved into a place where it can access your lymph nodes — the mesentery, in your abdominal region — and thirty minutes later you’d have multiple ectopic cell clusters placed there, engrafted by a cellular therapy, and you’d potentially even be able to leave the same day.
Over the course of the next few weeks and months your lymph nodes would serve as bioreactors to grow multiple ectopic organs – a process called ‘organogenesis’ – that would begin filtering your blood and providing life-saving support. That’s our vision of the future for our lead candidate in liver regeneration.
Longevity.Technology: So the question that follows from that is: is this a therapy that would be a final procedure? Or is it a stopgap for those who are waiting on a transplant list for a full replacement?
Michael Hufford: There are multiple groups of patients who could benefit from our therapy.
One group of patients, for whom we hope this will be a single procedure and a curative therapy, are the many people with end stage liver disease. Those who have gradually and progressively lost liver function over time. Right now, once you get to a certain threshold where you’ve lost enough liver function, if you’re healthy enough (and don’t have any contraindicated medical comorbidities) you might make it onto the liver transplant list. Once you’ve made it on there you’ll wait, oftentimes hundreds of days, or even longer, to receive an organ. And that’s if you’re lucky.
Now, here in the United States there’s a 10:1 ratio for you to even get on the liver transplant list. For every patient on the list, there are about 10 patients that are too sick, or have medical comorbidities that prevented them from getting on there. So there’s a huge unmet need. Patients need a new liver, but they’re too ill and that prevents them from being eligible for a full organ transplantation. Right now there’s no viable therapy for these people. So we think our therapy will be the first in line therapy for those patients.
There’s also going to be a second group of patients, ones that are really going to need a complete new organ. They need a “bridge to transplant,” — something to buy them time to wait for their full transplant. And that’s also where we hope that our therapy will be very helpful.
Longevity.Technology: Just to flesh out these two patient categories a little more – those in the second group will need a completely new liver because they’re going to lose all function in the one they have. Am I right in thinking that the first group are those who only suffer from partial loss of liver function?
Michael Hufford: That’s exactly right. Not to complicate the story too much, but there’s actually a third group as well.
There are a number of orphan indications [Longevity.Technology: conditions that affect a very small amount of the population and therefore don’t have designated therapies] particularly in children who have single enzyme deficiencies. Believe it or not, there are a lot of small children who receive full liver transplants because there’s no other way to fix those single enzyme deficiencies.
We have a long-term path to pursue multiple orphan indications. So there’s a third group of patients who only need a little bit of liver mass to correct that single enzyme deficiency. There’s Phenylketonuria (PKU) and another one called maple syrup urine disease (MSUD). So with just single enzyme deficiencies, all you’re doing is correcting inborn metabolic enzyme deficiencies. And we also think our therapy would be an enormous improvement on current methods for those children.
Longevity.Technology: Inside how many lymph nodes, on average, would you need to place ectopic livers for this to work? Are there going to be any side effects from this process?
Michael Hufford: Great question. So we’ve had two meetings with the FDA, and we’ve discussed these issues with them in some detail.
Right now, our best guess is that we will be grafting ectopic livers into, probably, three to five lymph nodes. You spread the mass of the ectopic organs across multiple lymph nodes, not just a single lymph node. That’s our best guess and clinical development plan right now.
In the research we’ve been doing for almost decade now, we’ve tried everything from a single lymph node to 20 lymph nodes or more, in the different animal models. And we’ve seen no adverse effects in terms of the transition from the lymph node to an ectopic organ.
One thing we stress is that when you look at what happens over time, the lymph node disappears. The lymph node acts like a bioreactor in this process — once it’s kicked the organ growth into gear, the organ takes over and the lymph node disappears. And because our bodies have hundreds of lymph nodes distributed throughout, we don’t expect that losing a handful of them will produce any untoward effects.
[Picture: One of LyGenesis’ radio-labelled hepatocytes or ‘mini-livers’]
Longevity.Technology: Right, and what about the next stage of the process? Say I’ve had your transplant procedure, and I’m in that second group of patients we described earlier — my liver is only partially functional. Will the ectopic livers boost my liver into regenerating its normal function, leaving the ectopic ones to disappear? Or will they instead form an equilibrium relationship and share the work?
Michael Hufford: It really depends, both outcomes exist, and our preclinical data shows that we’ve restored liver function through both.
The first thing to talk about is the notion of a hepatostat. Just like a thermostat aims to regulate the temperature of house, a hepatostat aims to regulate the total amount of liver mass that the body has. So, you and I may have different sized livers. If both of us were to lose 30% of our livers, our bodies would try to regrow that 30%. For me, that 30% could be one size and for you it might be another. But the beauty of the natural biology that we’re leveraging is that the liver does try to regrow itself naturally.
I always tell investors that the Greeks really had it right. The legend of Prometheus is thousands of years old and they nailed the biology. We all know the story — Prometheus stole fire from the gods, gave it to humanity, and was punished by Zeus. He was chained to a rock and, every night, his liver was feasted upon by an eagle, only for it to grow back ready for the eagle’s torturous return.
The liver really does have amazing powers of regeneration, but it can’t always get there on its own. In the aftermath of a serious liver disease, the liver is a horrible environment and it can’t regenerate. So this is where the two possible routes you’ve mentioned in your original question come in; we’ve seen them emerge in our animal work.
The first is that the ectopic organs continue to thrive; for example, providing around 75% of liver function and the liver the remaining 25%. And they settle in that equilibrium.
The second path is one we saw in a study we’ve recently done with the Mayo Clinic. We radio-labelled the hepatocytes in pigs so that we could track exactly where they went in their bodies. And, fascinatingly, we saw that some of the radio-labelled hepatocytes had made their way back to the native liver. They had repopulated there and helped reconstitute it. Then, as the native liver began to restore itself, the ectopic livers shrank. That’s exactly what you would presuppose based on this understanding of the hepatic staff, right.
Longevity.Technology: How could this enhance people’s Longevity going forward?
Michael Hufford: I think to really answer that question we have to conceive of what we’re doing here as a platform. Aubrey de Grey, amongst others, has said that we need to move towards regenerative medicine as a goal. The body’s different parts break, and we need to foster their ability to repair and restore themselves. And that’s exactly the natural biology we’re leveraging with the lymph nodes — as bioreactors to regrow organs.
Have you heard of NASH? NASH is Nonalcoholic steatohepatitis, quite a mouthful. It’s basically a condition of fatty livers, and it’s an epidemic at the moment. When we look at the obesity epidemic, the public is aware of diabetes, but oftentimes they’re not aware that they have a fatty liver disease until it’s really quite advanced, bringing on a second wave of morbidity and mortality.
Another great regenerative medicine story from our platform is based on our work on the thymus, which is fascinating.
So, we have proof-of-concept data showing that we can regenerate the thymus ectopically inside the lymph nodes, as well. The thymus, as you may know, has a complicated biology; it does a lot of different things. But there is some indication that one of the effects of rebooting the thymus is to reboot the immune system — which absolutely could have regenerative, and therefore potential Longevity, effects.
We have try to be very careful about this, lots of things work in small animals that do not translate to people — there are jokes that the medical field has cured cancer in mice so many times over by now. We have to be careful when talking about Longevity. Here’s this dream of man since the beginning of time, to live longer. I think with some of the regenerative medicine and our understanding of biology we can start to make some inroads but, for what it’s worth, I’m very careful not to promise that we’re unlocking the fountain of youth. That’s not the case. We’re trying to develop science-based, FDA-regulated therapies to address unmet medical needs — even though, admittedly, the famous one would be potential downstream effects on aging and Longevity.
Longevity.Technology: What would you say gives you guys an advantage over people who are, say, developing tissue patches or looking to bio-print similar things?
Michael Hufford: There’s a lot of genuinely exciting innovation taking place, especially in liver disease. But in terms of our specific advantages over the other therapies that we’re aware of, I’d be remiss not to point you to the vascularisation problem. That’s the biggest challenge that the bio-printing and extracellular matrix folks have. How do you vascularise those tissues?
If I was a journalist or an investor, and I was asking those companies the questions, the first thing I’d ask is, “How do you vascularise that?” It’s just this enormous challenge that the entire field faces. A similar question comes up when you look at induced pluripotent stem cells: “Where are you going to put the cells that enable them to thrive and vascularise?” And if their answer is, “We don’t know,” then you really have a problem. That’s the fundamental biological rate-limiting step in a lot of this. Our advantage is that we do all of that inside the lymph node, and it happens without us having to design a solution for that step. A lot of the other bio-printing approaches are very sexy and cool. But my first question is always on vascularisation, and there’s yet to be many concrete answers.
Longevity.Technology: What about xenotransplantation methods, then?
Michael Hufford: There are folks using CRISPR to some very cool genetic modification techniques for humanising, say, pig livers. Again, that’s very interesting, but I think any human tissue is going to have advantages over when we try to take animal tissues and make it more humanised. The animal humanisation approaches tend to be both imperfect and very costly.
Longevity.Technology: You also get the tissue material for your ectopic organs from unused donor organs, that must also be a major advantage, right?
Michael Hufford: When you look at all of these alternative approaches, you have to look at it as a supply and demand problem. The demand, of course, is huge. As for the supply, others are trying to find some complex genetic modification, or engineer organs to bio-print, and neither approaches are anywhere near ready to meet demand.
For us, there’s a very large number of organs that are donated but never transplanted. So that means there’s an existing source of allogeneic cells and, if you can give them a place to engraft and grow, they can produce a therapeutic effect. And for each one of those organs (the liver being a good example) there are billions of hepatocytes in a single donated liver, and we only need to grab a few tens of million or so of them. Today, a single donated liver treats one patient. Using our approach, a single donated liver could treat 75 or more patients. It just fundamentally shifts that supply and demand, and does it in a way that’s very cost effective.
Longevity.Technology: You’re moving from animal to human trials now, what are the challenges involved in this step? You have great results in pigs, but some researchers have questioned how you’re going to make your ectopic organs scale.
Michael Hufford: Oh absolutely. Translational science is a challenge no matter what technology you’re working with. It’s always one of the highest risk, most scientifically intensive and technically daunting challenges to take any technology from animals to humans. You obviously have to have done all of your work to show that you expect the therapy to be, first and foremost, safe and, secondly, beneficial to the patient.
In terms of us, I would say that we already have two rounds of feedback from the FDA on our clinical trial plan, which involves selecting the right patient, choosing the right endpoints, defining how to rigorously track them over time… But it’s a tough process, the ‘blocking and tackling’ of moving any new technology into the clinic poses a lot of scientific and operational hurdles.
Longevity.Technology: How long will it be until your therapy hits the market?
Michael Hufford: That’s a great question. The phase 2a trial will definitely take at least a couple of years to complete. And then from there it really becomes something of a crystal ball game of will the data be sufficient to enable preliminary approval? Will we need additional data? And so, right now, I can’t give any guidance as to target year for commercial approval, only that we’re getting into the clinic as quickly as we can, as we know the unmet medical need for organ regeneration is great, and if you believe that your therapy can make a difference, then time becomes your most painful expense.