University of Alabama at Birmingham

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.

Phentermine-topiramate reduced incident type 2 diabetes by nearly 80%.

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Patients with prediabetes and/or metabolic syndrome demonstrated significant weight loss and a markedly reduced progression to type 2 diabetes after 2 years of treatment with phentermine-topiramate extended-release plus lifestyle modifications, according to data published in Diabetes Care.

The medically assisted weight-loss intervention was highly effective in preventing diabetes among high-risk patients by 78.7%, W. Timothy Garvey, MD, chairman of the department of nutrition sciences at the University of Alabama at Birmingham, told Endocrine Today.

“If we can prevent 80% of diabetes in America, we’d go a long way toward reducing health care costs and the burden of diabetes on patients and the suffering that it causes,” Garvey said.

The researchers conducted SEQUEL, a subanalysis of the phase 3, randomized, placebo-controlled, double blind CONQUER trial, consisting of overweight or obese patients (BMI ≥27 to ≤45) with more than two comorbidities, according to data.

Patients with prediabetes (n=292) and metabolic syndrome (n=451) were included in the subanalysis.

After 108 weeks of random assignment to either placebo or phentermine-topiramate (Qsymia, Vivus), the cohort lost 10.9% of their body weight in the phentermine-topiramate 7.5-mg/46-mg treatment arm and 12.1% of their body weight in the 15-mg/92-mg treatment arm (P<.0001), compared with 2.5% in the placebo group.

There also was a 70.5% decreased annual incidence rate of type 2 diabetes for those assigned to 7.5 mg/46 mg and 78.7% for those assigned to 15 mg/92 mg (P<.05), compared with placebo.

“Here, we have two diagnostic codes for prediabetes and metabolic syndrome; you identity those patients, you know they have high risk for diabetes and cardiovascular disease and risk factors,” Garvey said. “These can be improved with weight loss. In this case, medicine-assisted weight loss particularly yielded up to 10% or more loss of body weight.” – by Samantha Costa

Proteins Identified That May Help Brain Tumors Spread.

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Scientists at the University of Alabama at Birmingham have identified a molecular pathway that seems to contribute to the ability of malignant glioma cells in a brain tumor to spread and invade previously healthy brain tissue. Researchers said the findings, published Sept. 19, 2013, in the journal PLOS ONE, provide new drug-discovery targets to rein in the ability of these cells to move.

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Gliomas account for about a third of brain tumors, and survival rates are poor; only about half of the 10,000 Americans diagnosed with malignant glioma survive the first year, and only about one quarter survive for two years.

“Malignant gliomas are notorious, not only because of their resistance to conventional chemotherapy and radiation therapy, but also for their ability to invade the surrounding brain, thus causing neurological impairment and death,” said Hassan Fathallah-Shaykh, M.D., Ph.D., associate professor in the UAB Department of Neurology. “Brain invasion, a hallmark of gliomas, also helps glioma cells evade therapeutic strategies.”

Fathallah-Shaykh said there is a great deal of interest among scientists in the idea that a low-oxygen environment induces glioma cells to react with aggressive movement, migration and brain invasion. A relatively new cancer strategy to shrink tumors is to cut off the tumor’s blood supply – and thus its oxygen source – through the use of anti-angiogenesis drugs. Angiogenesis is the process of making new blood vessels.

“Stop angiogenesis and you shut off a tumor’s blood and oxygen supply, denying it the components it needs to grow,” said Fathallah-Shaykh. “Drugs that stop angiogenesis are believed to create a kind of killing field. This study identified four glioma cell lines that dramatically increased their motility when subjected to a low-oxygen environment – in effect escaping the killing field to create a new colony elsewhere in the brain.”

Fathallah-Shaykh and his team then identified two proteins that form a pathway linking low oxygen, or hypoxia, to increased motility.

“We identified a signaling protein that is activated by hypoxia called Src,” said Fathallah-Shaykh. “We also identified a downstream protein called neural Wiskott-Aldrich syndrome protein (N-WASP), which is regulated by Src in the cell lines with increased motility.”

The researchers then used protein inhibitors to shut off Src and N-WASP. When either protein was inhibited, low oxygen lost its ability to augment cell movement.

“These findings indicate that Src, N-WASP and the linkage between them – which is something we don’t fully understand yet – are key targets for drugs that would interfere with the ability of a cell to move.” said Fathallah-Shaykh. “If we can stop them from moving, then techniques such as anti-angiogenesis should be much more effective. Anti-motility drugs could be a key component in treating gliomas in the years to come.”

Source: http://www.sciencedaily.com

Obesity treatment paradigms should target those at risk for diabetes.

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Lifestyle modifications, weight-loss medications and bariatric surgery are the three major modalities that will have clinical implications on the prevention and treatment of obesity, according to data presented here.

“With effective options in all of these three treatment modalities, we can now evolve rational data-driven models of care that treat obesity as a medical illness,” W. TimothyGarvey, MD, professor and chair in the department of nutrition sciences at the University of Alabama at Birmingham, and senior scientist at the Nutrition Obesity Research Center, told Endocrine Today.

W. Timothy Garvey

Emerging therapies

During a presentation on emerging obesity therapies, Garvey reported recent data on phentermine-topiramate (Qsymia, Vivus) and lorcaserin (Belviq, Eisai), both of which gained approval in adults with an initial BMI of at least 30 or in those with a BMI of at least 27 and at least one weight-related condition, such as hypertension, type 2 diabetes or dyslipidemia.

“We’re in an exciting phase of drug development for obesity, with two drugs approved in the summer of 2012 that appear to be safe and effective for the treatment of obesity,” Garvey said.

“In addition, we have two other drugs that have finished or will soon finish phase 3 trials.”

One of these is bupropion/naltrexone (Contrave, Orexigen), an experimental agent now finished with phase 3 clinical trials. According to Garvey, a cardiovascular outcomes study is currently ongoing as requested by the FDA before approval. “The BP did not increase with the drug, but it didn’t go down to the extent that you’d predict with the weight loss achieved,” he said. “This will be the first cardiovascular outcomes study with a weight-loss drug where the data will be available in, perhaps, 2014.”

About an 8% weight loss was demonstrated and sustained during 1 year compared with 2% with placebo, Garvey said.

Furthermore, he referenced recent data from a 56-week, double blind, phase 3a clinical trial investigating higher-dose liraglutide (Victoza, Novo Nordisk) as a potential treatment for maintained weight loss in overweight or obese patients with type 2 diabetes. The manufacturer recently released the second phase 3a trial results from the clinical development program for liraglutide 3 mg as an obesity treatment.

“About 4 kg were lost on lifestyle intervention alone, and up to 9 kg were lost with high-dose liraglutide. There are 2-year data indicating that its efficacy for sustaining this weight loss is evident,” Garvey said.

Bariatric surgery

However, Garvey said medical and surgical interventions provide the best outcomes in obese patients with complications, and optimal benefit–risk occurs when weight loss is used as a tool to treat these complications of obesity.

As an adjunct to lifestyle modification, the aforementioned new medical therapies can result in a 10% loss of body weight, but if a patient begins with a BMI of 38, he will likely be obese when therapies are complete, Garvey said.

“However, that 10% loss of body weight is sufficient to improve insulin sensitivity, glucose homeostasis, lipid levels, BP, diabetes prevention, CVD risk factors and better control of both glucose and BP in patients with type 2 diabetes. We’re achieving an amount of weight loss here that’s in fact beneficial in terms of cardiometabolic disease,” he said.

Moving forward

Garvey concluded with the economic burden of diabetes and obesity on the United States health care system. He told Endocrine Today that for the clinical research community to address the diabetes and obesity epidemics, the progression from prediabetes to diabetes should first be considered.

“A rational and effective obesity treatment paradigm that targets resources to patients who are at highest risk will be cost-effective in preventing diabetes,” he said. “The numbers vary, but it costs much more per year to take care of a patient with diabetes than it does to take care of a patient without diabetes.”

Source: Endocrine today

 

Lower Oxygen Saturation Levels in Preemies Associated with Higher Mortality by Discharge .

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The question of which oxygen-saturation level is best for very premature infants remains open after the publication of two studies over the weekend. Commentators suggest that levels under 90% should be avoided, however.

Researchers in the BOOST II study (published in the New England Journal of Medicine) report outcomes at hospital discharge for some 2400 infants randomized to lower (85 to 89%) or higher (91 to 95%) saturation levels. Interpretation is muddied somewhat by the fact that the oximeters had a measurement flaw that wasn’t discovered until halfway through the study. Among infants measured with corrected oximeters, mortality was higher for those receiving lower oxygen saturation (23% vs. 16%). Retinopathy was lower with lower saturation.

In JAMA, COT study researchers found no significant differences in the rates of mortality or retinopathy by 18 months in some 1200 infants similarly studied.

Commentators say the best interim course would be to target saturation levels between 90% and 95%, realizing the dangers of retinopathy.

Source: NEJM