The waiting lists for organ transplants are long, and people die daily waiting for transplants that never become available. For those that get a transplant, there is a risk that their immune system could reject it. Using organs from pigs is an alternative to human organs since many are a similar size. However, there is a major risk of rejection, so pig organs aren't suitable for transplantation into humans in an unmodified state. Miromatrix, a company based in Minnesota, is working hard to find ways to make pig organs more suited to individual human patients. They have developed a "reprogramming" process, in which mild detergents are pumped through freshly removed pig organs, stripping them of their constituent cells and leaving a blank "scaffold" onto which the patient's own cells can be seeded and grown. Eventually, the organ could be transplanted into the patient, and, theoretically, would have a reduced risk for immune rejection, since it is composed of the patient's own cells.
The company is preparing to initiate a major preclinical liver trial later this year and are targeting their first human transplant for 2020.
Medgadget asked Miromatrix CEO Dr. Jeff Ross some questions about the concept.
Conn Hastings, Medgadget: Can you tell us about the current challenges facing transplant patients, such as immunorejection and transplant shortages, and the need for donor-free alternatives?
Jeff Ross, Miromatrix: The chronic shortage of transplantable organs is the largest challenge facing patients today. Over 115,000 patients are on the national transplant waiting list, but only around 30,000 patients receive an organ annually. The true need for transplantable organs to solve life-threatening diseases is estimated to be much greater. Sadly, an average of 20 patients die each day while waiting for an organ to become available. In addition to the shortage, the other challenge facing patients is the lifelong immunosuppression needed to avoid graft failure following a successful transplantation. That failure carries many complications with it, including the increased risk of serious infections and cancer due to the patient's suppressed immune system. There is a tremendous need to address both the overall shortage of life-saving organs and define new ways to avoid long-term immunosuppression.
Medgadget: What challenges are biotech companies facing in trying to develop donor-free transplant alternatives?
Jeff Ross: One of the greatest challenges facing many new biotech companies is the task of overcoming some of the past promises those in the regenerative medicine field made too early. For example, when stem cells first gained prominence, they were touted as a 'cure for everything'. Unfortunately, investors in stem cell companies weren't pleased with the results or their returns. The tide is starting to turn, however, with the reemergence of gene therapy, along with CAR T-cell therapy. The investment into regenerative medicine is starting to flow once again, given the vast potential to bring needed therapies and cures to the market.
When we started Miromatrix in 2009, we determined that it was critical to demonstrate that our perfusion decellularization technology could be commercialized. Our first products — MIROMESH® and MIRODERM®– are developed from valuable acellular decellularized pig livers. Like our bioengineered organs, we remove all of the liver's cells while still leaving its blood vessels and natural properties intact. From there, we take sections of the livers and turn them into high surgical meshes and wound therapy products. As such, we have successfully commercialized MIROMESH® for soft tissue reinforcement and MIRODERM® for the management of wounds.
Regulatory hurdles have also been significant challenges to biotech companies, but recent legislation, such as the Regenerative Medicine Advanced Therapy (RMAT) Designation in the 21st Century Cures Act, is giving cellular and tissue engineered products an accelerated path through the FDA approval process. As such, those products may be able to help those with serious medical conditions and address unmet medical needs sooner.
Medgadget: Can you explain the Miromatrix approach to preparing pig organs for transplant, and how this compares with other approaches that other companies are currently attempting, such as 3D printed organs, or genetically modified organs?
Jeff Ross: Our approach is really quite simple and builds upon what nature has already created. We start by taking a pig organ, one that is already being harvested as a byproduct of the meat industry, and remove all of its cellular material with our patented perfusion decellularization technology. This is analogous to remodeling a house — think of the drywall as cells. Once you remove all of the drywalls, you are left with the structure of the house, including the architecture and plumbing. The same is true with the organ. Once we remove all of the organ's cells, the result is an ideal substrate with the appropriate architecture, vascular networks and overall design to be repopulated — or recellularized — with human cells to create a functional organ.
The limitation with 3D printing is one would need to understand all of the micro concentrations of numerous proteins, source them, then print everything, including the vasculature. Currently, the technology isn't there; and from a cost standpoint, starting with a whole organ is far superior.
Another approach that hopes to solve the transplant need is to genetically modify pigs so their organs can be directly implanted into humans. The challenge is that there are many unknowns in terms of identifying and modifying the appropriate genes, regulatory pathways, and removing various viruses known to reside in the pig genome without making modifications. If this proves possible someday, the patient will still need to be immunosuppressed, given the cross-species transplantation.
The advantage of perfusion decellularization and recellularization is the long-term potential to seed the patient's own cells on the decellularized matrix, resulting in a patient-specific organ and negating the need for immunosuppression. We view this as the 'holy grail' of organ transplantation.
Medgadget: What organs is Miromatrix currently investigating as potential candidates for this system? Do you envisage any ethical or religious objections from some patients?
Jeff Ross: Our lead organ in development is a transplantable liver to address the need that 40,000 patients die annually of end-stage-liver-failure because there are no drugs, dialysis or devices to help these patients. The only known therapy is a transplantable liver. Our second organ in development is a transplantable kidney. There are over 450,000 patients on hemodialysis today, with a five-year survival rate of about 30% compared with more than 75% with a kidney transplant. Our starting organ scaffold will be pig-derived, and while we remove the pig's cells through our decellularization process, there could be some religious concerns for some patient populations. Future development of the organs based on different starting animal sources could be developed to overcome this concern.
Medgadget: Are there any challenges to getting the technique to work at present? In the case of heart transplants, is it necessary to make sure that the tissue can beat before the transplant?
Jeff Ross: Each organ presents its own challenges. With the liver and the kidney, you only need approximately 20% of the total organ function to provide the needed organ function to save a person from liver failure or remove them from dialysis. The heart is more complicated, in that, it requires a 100% function at the time of implant.
Medgadget: Can you tell us about your upcoming liver trial and planned first human transplant?
Jeff Ross: Using our patented technology, we will grow a liver in the lab. We'll remove the native organ, then transplant the bioengineered organ into a large animal model. Our goal is to demonstrate that an engineered liver graft allows the animal to survive. Successfully achieving this milestone will then allow us to quickly move towards the clinic, with a goal of performing the first human transplants by the end of 2020.
Link: Miromatrix homepage…
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