Growing Livers In Lymph Nodes, A Lesson On Working With Nature
By Tyler Menichiello, contributing editor
Last month, LyGenesis dosed its first patient with LYG-LIV-001, an allogeneic and regenerative cell therapy for patients with end-stage liver disease that aims to do something straight out of science a fiction movie — grow functioning, ectopic livers inside of patients’ lymph nodes.
Ahead of this first patient dosing, I had the pleasure of meeting with LyGenesis CEO, Dr. Michael Hufford, Ph.D. If you’ve never heard of Michael or LyGenesis, I urge you to check out this episode of the Business of Biotech (ep. 144), hosted by my brilliant colleague, Matt Pillar. In it, Hufford shares his drug developer’s philosophy on working with nature as opposed to working against it. This sentiment underscores his confidence in LyGenesis’s technology, and in my opinion, should be a guiding principle across the CGT industry. We spoke about the company’s clinical strategy, the science behind LYG-LIV-001, and why it shines as an example of leveraging nature in therapeutic development.
Lymph Nodes: Nature’s Bioreactor
“When you are trying to encourage biology to do things it already wants to do, you tend to encounter far less inertia and fewer off-target effects,” he tells me. In many ways, LyGenesis’s lead program, LYG-LIV-001, exemplifies this approach. “The lymph node is this incredibly powerful bioreactor that nature made to cultivate our T cells,” Hufford tells me, “and we’re hijacking that biology to do something similar, but different.”
The treatment starts with hepatocytes taken from donated livers, which have already been screened and approved for transplant. These hepatocytes are then implanted into one (or more) of the patients’ lymph nodes endoscopically, where they then grow into functioning liver tissue. “The hepatocytes want to divide, and they have enough collective intelligence to actually form ectopic organs,” he tells me excitedly. After enough time, these mini livers even form their own vasculature.
This science-fiction approach is an amalgamation of allogeneic and autologous cell therapy — the engrafted hepatocytes are, of course, allogeneic, but the surrounding and supporting tissues that form are autologous. “There are biochemical signals that trigger the native environment to form vasculature and bring other cell types to the area,” Hufford explains.
Hufford tells me this ectopic liver growth is the result of a “very complex, partially understood homeostatic mechanism” called hepatostat, in which the body maintains a certain amount of liver mass to meet its metabolic needs. He calls this liver organogenesis a “remarkable example” of working with native biology. “LyGenesis didn’t engineer hepatostat,” he says. “Millions of years of evolution gave us that mechanism.”
The Chasm Between Science And Commercial Viability
LyGenesis’s goal is to provide a more affordable and accessible alternative to liver transplants, and Hufford believes the company’s approach is simpler than other methods being developed, e.g., xenotransplantation. “If we were trying to use CRISPR to humanize pig organs, the path forward to convince the FDA that it is going to be a safe therapy is incredibly onerous,” he says. “We’re taking organs that have already been screened and green-lit to transplant, isolating and suspending the cells without genetic manipulation, and engrafting them with a procedure that takes 10 minutes under light sedation. If you ask me to put my FDA-hat on and say which is the shorter CMC path relative to CRISPR or xenobiological approaches, what we’re doing is incredibly straightforward.”
While the cell and gene therapies being developed today are nothing short of remarkable, Hufford thinks it’s easy to get lost in how exciting the science is and overlook the regulatory challenges these advanced therapies can present. “A lot of cell therapy approaches are very complex from a safety standpoint, and it’s an incredibly huge lift,” Hufford says. “Very often, the originators and the folks that make scientific discoveries that underpin them have no insight into what it takes from a regulatory perspective to get them over the finish line.”
This chasm, as Hufford describes it, exists between cutting-edge therapeutic discoveries and viable, commercial products, and it’s one he cautions drug developers and investors about. “It’s like a siren call from the Odyssey,” he says, “where the science is so sexy and cool and you think, oh, we can do this. And scientifically, you can, but has the FDA ever approved a therapy that had that science as the backbone?” He thinks developers and investors need to take a broader view of the regulatory challenges new therapies present to realistically understand how much money and time it will take to commercialize them.
He recounts Dr. Eric Lagasse’s early work (LyGenesis’s CSO and co-founder), the level and depth of which he considered unusual. “When I met with Eric, I realized he had done the small animal work, the large animal work, multiple disease models, and multiple doses,” he explains. “He’d done a lot of the kind of programmatic things you would do as a drug developer.”
Moving Beyond The Liver
LyGenesis began its Phase 2a trial for LYG-LIV-001 in April with the first cohort of patients, which will receive one injection of the cell therapy into a single lymph node. “The day the safety monitoring board gives us a thumbs up, we move on to the second, medium dose cohort,” Hufford says. This second cohort will receive injections into three different lymph nodes (approximately 50 million hepatocytes per injection). The high dose group will receive five different lymph node injections, amounting to a quarter-billion hepatocytes.
The company has other programs in its pipeline to further explore the bounds of lymph node-grown organs. “We have a pancreatic islet program where we can rescue animals with diabetes by engrafting islets into their lymph nodes where they continue to glucose-sense and insulin-secrete,” Hufford tells me. “And the kidney program has been a subject of a lot of academic research and is something we’d like to move forward with, where we can potentially develop ectopic kidneys for patients with end-stage renal disease.”
If LYG-LIV-001 succeeds in the clinic, it will not only make liver transplant wait lists a thing of the past — it will change the way we think about regenerative medicine. It may also serve as a reminder to drug developers that nudging biology into its natural course of action is much less of a lift than trying to control its complexity. Despite all the tools at our disposal, sometimes groundbreaking treatments can arise by simply asking — what happens if I put this hepatocyte inside a lymph node?