transplantation

Scientists transplant two gene-edited pig kidneys into human recipient

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 University of Alabama at Birmingham

kidney

The University of Alabama at Birmingham Marnix E. Heersink School of Medicine announces today the first peer-reviewed research outlining the successful transplant of genetically modified, clinical-grade pig kidneys into a brain-dead human individual, replacing the recipient’s native kidneys. These positive results demonstrate how xenotransplantation could address the worldwide organ shortage crisis.

In the study published in the American Journal of Transplantation, UAB researchers tested the first human preclinical model for transplanting genetically modified pig kidneys into humans. The study recipient had two genetically modified pig kidneys transplanted in his abdomen after his native kidneys were removed. The organs were procured from a genetically modified pig at a pathogen-free facility.

“Along with our partners, we have made significant investments in xenotransplantation for almost a decade hoping for the kinds of results published today,” said Selwyn Vickers, M.D., dean of the UAB Heersink School of Medicine and CEO of the UAB Health System and UAB/Ascension St. Vincent’s Alliance. “Today’s results are a remarkable achievement for humanity and advance xenotransplant into the clinical realm. With this study, our research teams have also demonstrated that the decedent model has significant potential to propel the xenotransplantation field forward.”

For the first time, the pig kidneys transplanted were taken from pigs that had been genetically modified with 10 key gene edits that may make the kidneys suitable for transplant into humans. This process demonstrates the long-term viability of the procedure and how such a transplant might work in the real world. The transplanted kidneys filtered blood, produced urine and, importantly, were not immediately rejected. The kidneys remained viable until the study was ended, 77 hours after transplant.

“This game-changing moment in the history of medicine represents a paradigm shift and a major milestone in the field of xenotransplantation, which is arguably the best solution to the organ shortage crisis,” said Jayme Locke, M.D., director of the Comprehensive Transplant Institute in UAB’s Department of Surgery and lead surgeon for the study. “We have bridged critical knowledge gaps and obtained the safety and feasibility data necessary to begin a clinical trial in living humans with end-stage kidney failure disease.”

Gene editing in pigs to reduce immune rejection has made organ transplants from pigs to humans possible, which could offer help to thousands of people who face organ failure, disease or injury. The natural lifespan of a pig is 30 years, they are easily bred and can have organs of similar size to humans.

Genetically modified pig kidneys have been extensively tested in non-human primates. In addition to testing in non-human primates, evaluating genetically modified pig kidneys in a human preclinical model research may provide important information about the potential safety and efficacy of kidneys in human transplant recipients, including in clinical trials.

“This human preclinical model is a way to evaluate the safety and feasibility of the pig-to-non-human primate model, without risk to a living human,” Locke added. “Our study demonstrates that major barriers to human xenotransplantation have been surmounted, identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans, and lays the foundation for the establishment of a novel preclinical human model for further study.”

This effort is supported by biotechnology pioneer United Therapeutics Corporation, which awarded a grant to UAB to launch the innovative xenotransplantation program. Revivicor, Inc., a subsidiary of United Therapeutics, provided the genetically modified pig that was the source of the investigational xenotransplant kidneys called UKidney.

“All of us at Revivicor are in awe of the historic achievements at UAB with our investigational 10-gene xenokidney, or UKidney,” said David Ayares, Ph.D., Chief Scientific Officer of Revivicor and a trailblazing genetic engineer since his early work cloning the world’s first pigs and the first alpha-Gal knockout pigs. “We feel confident that this UKidney may turn out to be a life-saving solution for thousands of people on dialysis, subject to successful completion of our clinical trials and achievement of FDA approval in the next several years.”

UAB announces first clinical-grade transplant of gene-edited pig kidneys into brain-dead human
Jayme Locke, M.D. Credit: UAB

About the study

The peer-reviewed research is a study of ambitious scope and great significance, given that more than 800,000 Americans are living with kidney failure. Most never make it to the waiting list, and far too few human organs are available to put a dent in that number. Although dialysis can sustain life for some time, transplantation offers a better quality of life and a longer life for the few individuals who can gain access to transplantation. Each stage of this decedent xenotransplant study approximated the steps that might be taken in a Phase I xenotransplant clinical trial:

  • The kidneys were removed from a donor pig housed at a pathogen-free, surgically clean facility. The kidneys were then stored, transported and processed for implantation, just as human kidneys are.
  • Before surgery, the brain-dead recipient and donor animal underwent a crossmatch compatibility test to determine whether the genetically modified pig kidney and its intended recipient were a good tissue match. A crossmatch is done for every human-to-human kidney transplant; however, this pig-to-human tissue-match test was developed at UAB and marked the first time a prospective crossmatch has been validated between the two species.
  • The pig kidneys were placed in the exact anatomic locations used for human donor kidneys, with the same attachments to the renal artery, renal vein and the ureter that carries urine from the kidney to the bladder.
  • The brain-dead recipient received standard immune-suppression therapy used in human-to-human kidney allotransplantation.

The study was conducted to meet the standards directly comparable to those that would apply to a Phase I human clinical trial, mirroring every step of a standard transplant between humans. It included Institutional Review Board and Institutional Animal Care and Use Committee approval, a tissue compatibility confirmation before starting the operations, using the standard procedures of human-to-human transplants to remove, preserve, transport and transplant the kidneys into a human, and giving the standard immunosuppression therapy to the recipient.

Transplant recipient Jim Parsons helps open doors to the future of organ transplantation

This scientific and medical breakthrough would not have been possible without Jim Parsons, the recipient, or his family.

Parsons, 57, was a registered organ donor through Legacy of Hope, Alabama’s organ procurement organization, and he had longed to have his organs help others upon his death; but his organs were not suitable for donation. His family permitted UAB to maintain Parsons on a ventilator to keep his body functioning during the study. His native kidneys were removed, and two genetically modified pig kidneys were transplanted.

“Mr. Parsons and his family allowed us to replicate precisely how we would perform this transplant in a living human. Their powerful contribution will save thousands of lives, and that could begin in the very near future,” Locke said. “Mr. Parsons’ gift honors his legacy and firmly establishes the viability, safety and feasibility of this preclinical model. Because of his gift, we have proposed this to be known as ‘The Parsons Model.'”

Parsons’ ex-wife, Julie O’Hara, and their children, Ally, David and Cole, made the decision (along with Jim’s sisters and mother) to take part in the study after they were approached by Alan Spriggs with Legacy of Hope and Locke.

“Jim was a never-met-a-stranger kind of guy who would talk to anyone and had no enemies—none,” O’Hara said. “Jim would have wanted to save as many people as he could with his death, and if he knew he could potentially save thousands and thousands of people by doing this, he would have had no hesitation. Our dream is that no other person dies waiting for a kidney, and we know that Jim is very proud that his death could potentially bring so much hope to others.”

The critical need for other organ donation options

Kidney disease kills more people each year than breast or prostate cancer, according to the National Institute of Diabetes and Digestive and Kidney Diseases. Although transplantation is the gold standard treatment for end-stage kidney disease, fewer than 25,000 kidney transplants are performed each year in the United States and 240 Americans on dialysis die every day. Many of these deaths could be prevented if an unlimited supply of kidneys were available for transplant.

The wait for a deceased donor kidney can be as long as five years, and in many states, it is closer to 10 years. Almost 5,000 people per year die waiting on a kidney transplant.

Assessment of knowledge of Organ Donation and Transplantation

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SURVEY BY: HANSEL MISQUITTA & DR. ANMOL SHARMA
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Most organ and tissue donations occur after the donor has died. But some organs and tissues can be donated while the donor is alive. Nearly 6,000 living donations take place each year. That’s about 4 out of every 10 donations.Most living donations happen among family members or between close friends. Some people become altruistic living donors by choosing to donate to someone they don’t know.Live Donation is from a healthy and living person. This can only be done in the case of a liver or a kidney (because the liver can grow back to its normal size, and a donor can survive on one kidney). So if a near relative of yours needs a liver or a kidney, anyone in the immediate family can donate to them.
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When we talk about pledging your organs or about organ donation, we are talking about Deceased organ donation or cadaver organ donation. This is organ donation from a person who has been declared brain dead by a team of authorized doctors at a hospital. A person is said to be brain dead when there is an irreversible loss of consciousness, absence of brain stem reflexes and no spontaneous respiration.
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Brown Fat Injections Reverse Weight Gain in Obese Mice

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Transplantation of brown adipose tissue (BAT) from donor animals appeared to reduce weight gain in leptin-deficient Ob/Ob mice, presumably by enhancing the activity of endogenous brown fat, researchers reported.

In a series of studies in obesity and predisposed transgenic mice, BAT transplantation led to significant reductions in weight gain and decreased total body fat, lead researcherWanzhu Jin, PhD, of the Chinese Academy of Sciences, and colleagues, wrote in the journal Endocrinology.

 In earlier research conducted by these researchers and others, BAT transplantation was shown to reduce body weight in high-fat diet-induced obesity mouse models. The newly published research is the first to show the same outcome in mice genetically predisposed to become obese and it is also the first to link BAT transplantation with endogenous brown fat activity, Jin and colleagues wrote.

“The results of the current study show that transplantation of BAT reduced adiposity and improved glucose homeostasis in the Ob/Ob mouse by significantly increasing energy expenditure,” the researchers wrote. “These beneficial effects were most likely mediated by the enhancement of endogenous BAT activity. These results may open new avenues to develop a novel treatment option to target obesity and its related diseases such as diabetes.”

BAT Transplant Mice Had Less Body Fat

Leptin deficient Ob/Ob mice, which are widely used for the study of obesity-induced diabetes, have a lower metabolic rate and hypothermia due to a defect in BAT function, the researchers wrote.

To determine whether BAT transplantation could reverse these traits, they transplanted brown fat from 6 week old C57B/L6 mice into the dorsal subcutaneous region of age and sex matched Ob/Ob mice.

The BAT transplantation mice were found to gain less weight than sham-operated control Ob/Ob mice and this difference was seen as early as 3 weeks after transplantation (47.8 ±2.2 g vs. 50.6±3.1 g, P<0.03). This trend persisted through 12 weeks post transplantation.

When the researchers measured body composition using computerized tomography, they found an 11% decrease in total body fat percentage in the BAT transplant mice compared with the control mice.

“Compared with control mice, there was a significant reduction of adipocyte size in subcutaneous fat but not in epididymal fat after BAT transplantation,” the researchers wrote.

There was no change in circulating IL-6 levels or IL-6 mRNA in epididymal fat, however, suggesting that BAT transplantation disrupted adipose tissue hypertrophy without altering inflammation.

BAT transplantation was also found to reverse hepatic steatosis, improve insulin sensitivity, and increase energy expenditures.

BAT transplantation into streptozotocin (STZ) induced type 1 diabetic mice resulted in complete reversal of most diabetic symptoms without exogenous insulin treatment and it reversed diet-induced obesity in another mouse model.

Adiponectin May Activate Endogenous BAT

In a series of experiments, the researchers showed that transplantation also enhanced the activity of endogenous BAT.

“Serum adiponectin levels and beta 3 adrenergic receptor expression levels in both subcutaneous and epididymal fat were significantly increased after BAT transplantation,” Jin and colleagues wrote. “Increase of plasma adiponectin after BAT transplantation might enhance activity of endogenous BAT to consume more triglyceride as consistent with previous reports.”

The findings suggest that activation of endogenous BAT, and not transplanted BAT, was primarily responsible for the improved metabolic profile seen in the transplanted mice, the researchers noted.

No difference in energy intake and no change in circulating leptin levels were detected following BAT transplantation, suggesting that the improved metabolic profile was not due to circulating leptin alone.

“Increasing evidence suggests that BAT might serve as a secretory organ,” the researchers wrote. “Similar to white adipose tissue, BAT could synthesize and secrete numerous hormones, such as FGF21, to regulate the whole body energy metabolism.”

The BAT transplant mice in the study showed significant reductions in circulating FGF21. In addition, circulating IL-6 was not altered following BAT transplantation, suggesting that additional inflammatory factors or other factors might be involved in energy metabolism, the researchers noted.

The finding that BAT transplantation reversed diabetes in type 1 and diet-induced obesity mouse models suggest that BAT secretes adipokines that work through insulin-independent pathways.

“As an endocrine organ, BAT could serve as a fascinating new potential therapeutic target for obesity and its related diseases,” the researchers wrote … “In the present study, we demonstrated that BAT transplantation ameliorated the body weight and body fat gain in Ob/Ob mice. This is the first study showing that BAT transplantation enhances the activity of endogenous BAT, eventually leading to the improvement of whole body energy metabolism and glucose homeostasis.”

Everything you want to know about poop transplants.

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Fecal microbiota transplantation (FMT) also known as a stool transplant is the process of transplantation of fecal bacteria from a healthy individual into a recipient. It has been proven to be a highly effective treatment for patients suffering from Clostridium difficile infection (CDI), which produces effects ranging from diarrhea to pseudomembranous colitis.

 

http://www.sciencedump.com/content/everything-you-want-know-about-poop-transplant