Lyfebulb, in partnership with Columbia University, presents a virtual education series, sponsored by Veloxis Pharmaceuticals, to address key topics of living from late-stage disease through the transplantation process and beyond. Providing informative patient education is key to improving the patient experience, health communications, and health outcomes.

This session discusses different areas of advances in transplantation including tolerance induction, bioengineering, biological markers, regenerative medicine, and artificial intelligence (Al). 

Engineering Tissues and Organs

The cells in the body create the tissue that make up our organs. The scaffold of each organ and tissue is the structure that the cells replicate on to create the fully formed and functioning tissue. And bioreactors are the chambers in which these components, combined with necessary regulatory factors that facilitate nutrient and oxygen availability to allow the cells to function, are combined to engineer new living tissue. 

With this understanding, researchers tried to create an anatomically correct jaw bone in a pig. First, they removed the bone, cleansed it of all cells and living tissue, which left the scaffold. Then they took stem cells from bone marrow tissue or fat tissue of the pig and added it to a bioreactor culture and the scaffold. After a few weeks, it became living bone. Then, this bioengineered bone was placed back into the pig to see how it integrated with the native bone over time. Over the span of 6 months, the bioengineered tissue and the naïve bone were nearly identical. 

In the human body, engineering tissues like whole organs is vastly more complicated. The lung, for example, has more than 50 cell types and a complex structure of airways and vasculature. There are 145 meters of gas exchange surface, which is half of a tennis court. With current technology and innovation, it’s not possible to engineer lungs, yet. 

But, because of the shortage of organs that are suitable for transplant, instead of growing new organs, trying to repair organs that are rejected is the near-term future of transplant innovation and research.  

This very intervention is being researched in lung transplant where the lung is placed on a ventilator and connected to the organ recipient’s blood flow for a few days to complete lung repair before it is put into the recipient patient. To test this, studies were conducted on weakened lungs that were out of the body for a considerable time, which leads to damage from blood loss. These lungs were connected to the patient externally using the method of rehabilitating the lung and after 24 hours the function of the lung dramatically improved. To determine the health of the lung, the pressure volume in the lung is tested to ascertain the quantity of much air flow.

Immune Tolerance

The immune system recognizes what is part of our body and what is not. There are proteins and carbohydrates on the surface of the organs of other people’s bodies that our immune system recognizes and tries to fight off when an organ is placed in the body for transplant. Research is being devoted into trying to reprogram our immune system so it doesn’t attack the transplanted organ and only attacks bacteria and viruses as it normally should. This is called immune tolerance. 

So, how does immune tolerance work? Our bone marrow determines what is recognized as foreign and what is not. When we are born, the immune system hasn’t created immune memory yet, which is required to remember infections we have been exposed to so they can be fought off quicker in the future. These memory cells have to be reprogrammed to not have immune recognition and then reject the organ. To do this, bone marrow cells of the donor can be transplanted along with the transplanted organ into the recipient to minimize this immune recognition of a foreign body. Those unique proteins and carbohydrates from the donor are now part of the recipient’s body and will not reject. 

In kidney transplant, there have been some studies done where kidney and bone marrow transplant were done together. Patients were able to stop immune suppression over time and they all developed immune tolerance.  

Liver transplant is the most effective organ to transplant that will create spontaneous immune tolerance as this is where bone marrow stem cells survive. Research is also looking at what are the cells and inflammatory markers that are characteristic of people that don’t reject their organs. Hopefully, this can be translated to other organs in the future. 

AI and Transplantation

There is technology being used that can predict future organ rejection. This AI technology is called AlloSure – a marker of donor organ injury and rejection. It is being developed to be used for all organ transplants, and currently is used in determining transplanted kidney health and function. Data is collected from the following results added together to predict, with 85% accuracy, if a patient will experience rejection present on a biopsy: kidney function at the time of biopsy, data history of rejection, antibodies against donor and DNA. The score determines whether the patient should be biopsied or not. A low value indicates a low probability of rejection, and a higher value where rejection is likely.

This technology would be used any time after the first 2 months and then quarterly after the first year.  Data is collected every year after transplant to predict long term outcomes of transplantation. In addition, there will be less need for conducting long term trials in the future for new drugs and interventions as outcomes can be accurately predicted. 

With advances in improving the shortage of lung supply, increasing regulatory collaboration, and improved transplant drugs, the future of transplant is bright!

Listen to the full webinar and learn more about these conversations and further research and information about life with transplant. This, and future webinars can be found on transplantLyfe.com/webinars.  

Panelists

  • Dr. Vunjak-Novakovic, Professor of Biomedical Engineering and Medical Sciences at Columbia University 
  • Dr. Griesemer, Professor of Surgery and Transplantation at Columbia, Head of Pediatric Renal and Liver Transplant.
  • Dr. Srinivas, VP of Digital Development and Clinical Integration at CareDx

Moderators

Lyfebulb, in partnership with Columbia University, presents a virtual education series, sponsored by Veloxis Pharmaceuticals, to address key topics of living from late-stage disease through the transplantation process and beyond. Providing informative patient education is key to improving the patient experience, health communications, and health outcomes.

This session discusses three different areas of advances in transplantation including xenografts, islet cell transplants, and microbiotics. 

Xenograft

Organ supply remains the number one unmet need in transplantation. Pigs are the most appropriate donor animal for xenotransplants. These types of transplants have been performed on patients who are brain dead and cannot donate their organs. Because they are technically deceased, the FDA doesn’t weigh in on this kind of research, so the data can be used to justify future clinical trials in living humans. 

At NYU, a genetically modified pig kidney was put into such a patient to study how it would initially function in the human body. After 50 hours, there was no evidence of inflammation or rejection. In addition, two recipients received heart transplants from genetically modified pigs. Because of these recent experiments, interest has reignited for xenotransplantation, which is on the cusp of successful pig to human life-altering transplants.

So how are the pigs genetically modified? There are a number of companies that are gene editing the germ line, which means that the pigs have human genes permanently in their bodies and their offspring will as well. From this point, they can be easily bred for research purposes. They look like normal pigs; the only differences are that their cells produce some human proteins. 

Unfortunately, with xenotransplantation, there will still be need for immunosuppression therapy, because the human body has an even stronger immune response to the transplanted pig organ than another human. There is some research investigating how the immune response can also be modified genetically to reduce the response. 

Islet Transplantation

In pancreas transplantation, while the success rate is about 90%; there is risk of bleeding and other surgical complications. In order to reduce that risk, islet cell transplant was developed. This process involves taking the pancreas from the deceased donor, then taking the islet cells and infusing them into the liver of the recipient. They stay in the liver and produce insulin and modulate glucose levels. This type of transplant has been optimized for 20 years. Islets can provide long term insulin independence for patients however, immunosuppression for the patient is required.  

Researchers are attempting to develop a way to make islet cells out of embryonic stem cells to have a greater supply of cells for transplant. Some companies are engineering islets from human stem cells, but there is limited success. Islets engineered from human stem cells would provide an unlimited supply, but would require the same immunosuppression therapy as normal transplant. 

To circumvent the need for immunosuppression, using a pouch to immunoprotect the cells from the body of the recipient may avoid the need for immunosuppression. There is research being done in this space as well. 

The outcomes for islet transplant are about the same as whole pancreas transplant, with about 60% of patients being insulin independent after 5 years but, the surgery requires experience from physicians and requires patient’s adherence to be successful as any other transplant. 

Currently, the FDA has not approved islet cell transplant, so it is not reimbursable through insurance. Thus, often they are not able to be performed for patients. This issue requires legislative action to push FDA to approve islet transplant as the same as any other organ transplant to allow for insurance payments. The United States is the only country that is regulated in this way. 

Microbiotics

In intestinal transplant the microbiome in the gut has been shown to be tied to rejection episodes. The intestines are full of bacteria, both commensal (good bacteria), and pathogens, (bad bacteria). There are bacteria that are vital to our survival; some of which help us break down foods, and some release chemicals that are necessary for the body’s functioning. This ecosystem of bacteria is called the microbiome. The interplay between the microbiome and the immune system is tied because an imbalance of the microbiome can cause an increase in immune cells or T cells, causing the body to be in an inflammatory mode versus a regulatory mode. One area of recent research is trying to determine whether rejection is due to the change that occurs in the gut bacteria populations when they are introduced to the recipient’s body’s gut bacteria. 

There are immune cells that are specific to the bacteria that live in the gut and, when the immune cells die off along with the bacteria from the donor’s gut, in the recipient’s body, this can cause an imbalance and lead to rejection. This has been studied in liver transplant. 

An overall decrease in diversity of bacteria, meaning fewer different types of species, is associated with inflammation. Rejection can be potentially modulated by restoring the balance of good and bad bacteria. It must be a targeted treatment of introducing certain foods and compounds that foster the growth of certain bacteria, which can then change the body’s immune response. 

The next webinar session will focus on research into biotechnology and artificial organs with experts in the field. 

Listen to the full webinar and learn more about these conversations and further research and information about life with transplant. This, and future webinars can be found on transplantLyfe.com/webinars.  

Panelists

  • Dr. Griesemer, professor of Surgery and Transplantation at NYU, Head of Pediatric Renal and Liver Transplant 
  • Dr. Piotr Witkowski, Director of the Renal and Pancreas Islet Program at University of Chicago
  • Dr. Joshua Weiner, Assistant Professor of Surgery at Colombia, Head of Intestinal Transplant and an expert on microbiosis

Moderators

Lyfebulb, in partnership with Columbia University, presents a virtual education series, sponsored by Veloxis Pharmaceuticals, to address key topics of living from late-stage disease through the transplantation process and beyond. Providing informative patient education is key to improving the patient experience, health communications, and health outcomes.

This session discusses an overview of identifying the gaps and unmet needs in innovation, and although science is on the verge of significant advancement, efforts are needed in advocacy, regulatory and financial strategies, and formalizing observational studies to trigger innovation, funding, and research. 

What Areas Are Being Addressed? 

Some particular areas in transplantation where there exist unmet needs are antibody mediation and inhibiting antigen development, as these are common causes of organ rejection, and for which there are no preventative or treatment therapeutics available. Transplant medications for suppressing the immune system are far from perfect, often causing numerous side effects and long term, almost inevitable organ rejection. Medications that can effectively offset these two significant issues are desperately needed. Delayed graft function, the condition in which the transplanted kidney doesn’t work immediately, occurring in about 20-50% of deceased donor kidneys, requires patients to be on dialysis after the transplant for some time. This significantly affects quality of life and there is an unmet need for prevention of this issue as well. 

From an industry perspective, the areas of focus for transplant innovation fall into the categories of incremental improvements in daily quality of life, including developing less toxic immunosuppressives, less frequent dosing requirements, and fewer and less severe rejection episodes. Immunological innovations are another area of focus, with the developments in better organ matching through the use of genetic testing, machine perfusion to allow for the organ to be outside the body for long for better testing and diagnostic, and lastly, the expanded use of non-human/xenotransplants using stem cells and 3D organ printing. 

What Are the Hurdles in Transplantation Research?

There exist numerous hurdles in conducting research in the transplant population. From drug developers’ perspectives, transplant patients typically have various health issues and there is concern about the inclusion of transplant patients skewing data to affect the approval of a drug for a larger patient market. Often, once a drug is approved for other indications, the research in transplant stops, especially when transplant is not the pharmaceutical companies primary target. For this reason, transplant drugs are often used off-label for transplant patients. Since drug companies want to also recoup costs of research and development, drug prices are quite expensive, so insurance companies don’t want to pay for off-label use. 

There are regulatory hurdles as well in developing and then getting validated surrogate endpoints approved. There are appreciable opportunities here, for example, currently the focus for measuring the success of a drug is on the rate of rejection and patient survival but rate of kidney function loss is a more precise endpoint to be measured.  

How Can A Patient Contribute to Research in Transplantation?

From a collaborative advocacy perspective, transplants occur as a result of a variety of diseases, so many patients are associated with the disease they had before transplant, yet they don’t have those diseases anymore so there isn’t a “home” community for the transplant community. This makes advocacy as one group pushing for innovation, policy change, and funding that much more difficult. Nonetheless, patient advocacy is important, for unmet needs and public campaigns make a difference for early research which leads to innovative therapies down the road. 

A focus on developing what are called enrichment trials, allows more information and research to be gathered from a population that did benefit from the drug, even if the drug didn’t meet its endpoints in trials. In addition, giving companies or academic institutions grants to do exploratory studies using a drug that may be approved for another indication, could be beneficial in transplant. However, overall, pulling a drug from another indication won’t be a huge innovation as they still have similar side effects and transplant rejection rates. 

Listen to the full webinar and learn more about these conversations and information about life with transplant. This, and future webinars can be found on transplantLyfe.com

Panelists  

  • Dr. Llyod Ratner, Chief of Kidney Transplantation at Columbia
  • Dr. David Cohen, Medical Director of Transplantation Service
  • Dr. Syed Husain,  Transplant Nephrologist
  • Kevin Kovaleski,  Pharmaceutical Industry Expert

Moderators

Lyfebulb, in partnership with Columbia University, presents a virtual education series, sponsored by Veloxis Pharmaceuticals, to address key topics of living from late-stage disease through the transplantation process and beyond. Providing informative patient education is key to improving the patient experience, health communications, and health outcomes.

This session discusses an overview of pancreas transplant and how patients can prepare for a transplant. Questions for discussion were curated from the patient community. 

Pancreas Transplant Surgery

When a person receives a pancreas, the person’s own pancreas remains in the body. The role of the pancreas is to manage blood sugar levels by making insulin and making digestive enzymes to break down food. The pancreas does not stop making these enzymes, so when the original pancreas is disconnected and the new one is placed in, these enzymes have to be sent somewhere for elimination from the body. It used to be connected to the bladder, from which it is easier to test for rejection from urine, but it is very uncomfortable as patients got inflammation of the bladder and significant pain. It is now done as a bowel drainage to help digest food. Originally, pancreases were not hooked up anywhere to eliminate the enzymes and this also caused serious inflammation in the gut. 

Regarding the risk of transplant with a pancreas, surgical issues used to be the primary risk, but now it is the possibility of rejection – both in the shorter and longer term – that is paramount. Over time, the pancreas does fail and patients revert to needing insulin. The average life of a pancreas is between 7 to 15 years.

Immunosuppressive Therapies

The immunosuppression treatment regimen after transplantation is the same for pancreas as other organs like kidney transplant. Immediately after surgery, it is given intravenously, and then maintenance oral anti-rejection meds are dosed. The same medications are used independent of the organ that was transplanted. Across the country, different transplant programs make different decisions on which medications they prescribe the most. In more rural areas for example, there may be more infrequent access to care and follow up, so the use of long-term steroids is more common but reducing the amount of steroid being used is the goal of most centers.  

The follow up care for pancreas transplant is longer than for organs like kidneys. In addition, renal immunosuppression can be reduced over time, but for pancreas this is riskier, especially if the patient received both a pancreas and kidney transplant from different donors, the risk of rejection is higher than getting either a kidney or pancreas by itself. 

Pancreas Supply and Demand

Selection of pancreas donors is based on age, which significantly impacts how successful a transplanted pancreas will be. Donors also tend to be lean individuals with healthy lifestyles. Pancreas transplant is very selective and has to be a high-quality donor. And because of lifelong immunosuppressive medications requirements, pancreas transplants aren’t performed on younger people often because of the abbreviated average length of time a pancreas works successfully after transplant.

In addition to deceased donors, living donor pancreas transplants can be performed, where a partial pancreas is placed in the patient, however, this procedure is no longer commonly performed because of numerous complications, for the patient and for the donor as well. 

As an alternative, islet cell transplant is a simpler procedure, but there is often a shortage of donor cells. It would require two separate donors, because there is an inflammatory reaction when the islets are injected into the liver, so a majority of the islet cells die quickly and there needs to be excess put into the body to account for the loss. The best results have 70% conversion of diabetes within 8 years because the cells get scarred and immune suppression is still required.

There are some clinical trials for using pig islet cells or growing them artificially – which is called induced pluripotent stem cells. Islet transplant surgery can also happen when they take the pancreas out from a person due to disease, and during surgery, remove the islet cells and put them into the kidney. This is called auto transplant and does not require immunosuppression since its cells emanate from the person’s own body. 

Future webinars will cover transplant innovations in new drugs and what research is being done in xeno (non-human) organ transplant, and upcoming cell and organ repair therapies. 

Listen to the full webinar and learn more about these conversations and information about life post-transplant. This, and future webinars can be found on transplantLyfe.com/webinars.  

Panelists

  • Dr. Geoffrey Dube, Nephrologist and Medical Director of the Pancreas Transplant Program
  • Dr. Casey McCune, Surgical Director of Pancreas and Kidney Transplant Programs
  • Gretchen Boyd, RN, MSN, CCTC, Chief Coordinator Kidney Transplant 

Moderators

  • Mark Hardy, Professor of Surgery at Columbia University 
  • Dr. Karin Hehenberger, CEO of Lyfebulb and Visiting Associate Researcher at Columbia
  • Brian Runge, Senior Coordinator of Donors 

Lyfebulb, in partnership with Columbia University, presents a virtual education series, sponsored by Veloxis Pharmaceuticals, to address key topics of living from late-stage disease through the transplantation process and beyond. Providing informative patient education is key to improving the patient experience, health communications, and health outcomes.

This session discusses an overview of pancreas transplant and options that exist for patients. 

Pancreas-Only vs Kidney-Pancreas Transplantation

Dr. Hehenberger shares her experience getting both a kidney and pancreas transplant. Being a person with diabetes for many years, and struggling with some of its complications, she was evaluated for a pancreas transplant. During evaluation, it was clear she needed both because she would be on dialysis within a year without getting a new kidney. She was able to receive a kidney from a living donor, which she received first and, 9 months later, received a pancreas. For patients who require both, she states that it may be ideal to get the kidney first because it eliminates some symptoms and she was able to be in better physical condition going into the pancreas transplant. 

Some people receive both a kidney and a pancreas transplant at the same time or the kidney transplant happens first for the patient to be able to get off dialysis and then receive the pancreas transplant. 

Sometimes, the kidney does not need to be transplanted and a patient can have a pancreas transplant alone. This is a patient who has atypical diabetes, which causes symptoms and impairments leading to issues beyond just insulin dependence such as hypoglycemic unawareness. A pancreas transplant candidate usually has comorbidities associated with their diabetes, such as heart disease, retinopathy, or neuropathy, so it is important to perform a benefit and risk analysis prior to deciding if transplant is right. It has to be determined that the patient is fit to undergo the surgery and will ultimately have a benefit from it. 

The Pancreas Transplant Procedure

Pancreas transplant takes about 4-8 hours. 1 in 20 transplants fail because of clotting of blood vessels. These risks need to be understood by the patient. To receive a pancreas transplant, the patient has to be healthy overall. During surgery, the old pancreas stays in the body and subsequently, it continues to make the digestive enzymes produced to help break down food that is consumed. The pancreas has an exocrine component, producing digestive enzymes that help digest food. Typically, patients do not have digestive issues for this reason. For those patients who didn’t have proper enzyme production before transplant, they would see an improvement in the digestive system once they received a new pancreas that was producing sufficient enzymes for digestion. 

Receiving a transplant can halt the worsening of other comorbidities and complications by improving in sensation of nerves, stop worsening of eye disease, and stop the progression of kidney disease. 

Monitoring for Rejection

After transplant, detecting rejection in the pancreas is not as easy as taking a biopsy of the kidney. There are, however, ways to monitor the function of enzyme production in the blood. Elevated enzyme levels over the course of a few weeks can indicate rejection and then Imaging and a biopsy are used to confirm. Rejection can be asymptomatic, but imaging can show inflammation and swelling. 

Limiting Factors

One may ask, why aren’t more pancreas transplants being done? Selection of pancreas donors is based on age, which significantly affects how successful a transplanted pancreas will be. Donors also tend to be lean individuals with healthy lifestyles. Pancreas transplant is very selective and has to involve a high-quality donor. And because of lifelong immunosuppressive medication requirements, pancreas transplants aren’t performed on younger people often because the average length of time a pancreas works after transplant before rejection occurs is about 10 years.  

Future webinars will cover how to prepare for pancreas transplants as well as transplant innovations in new drugs and what research is being done in xeno (non-human) organ transplant, and upcoming cell and organ repair therapies. 

Listen to the full webinar and learn more about these conversations and information about life post-transplant. This, and future webinars can be found on transplantLyfe.com/webinars.  

Panelists

  • Dr. Dube, a nephrologist and medical director of the pancreas transplant program
  • Dr. Casey McCune, surgical director of pancreas transplant programs
  • Dr. Sandoval, kidney and pancreas transplant physician and director of the chronic kidney program.

Moderators