The cutting-edge cellular therapies aiming to ease America’s organ shortage

Although the United States is the wealthiest nation in the world. Kidneys are followed by livers. While the liver is the only human organ known to be able to regenerate itself, the only treatment is a transplant if you damage your organ badly enough — as do about 30 million Americans — for long enough. I assume the doctors will stay with you. Every year, the demand for surrogate livers exceeds the supply by tens of thousands.

“Only a third of those on the liver transplant waiting list will be transplanted, and demand for livers is projected to increase by 23 percent over the next 20 years,” a multidisciplinary team of researchers found in 2016 . “The donor pool is expected to continue shrinking due to the obesity epidemic, compounding the organ shortage problem. hepatic steatosis [aka ] is becoming more common in donors and is a significant risk factor in liver transplantation.”

To address this critical deficiency, the study authors note that physicians have explored a variety of cutting-edge therapies, from cell repopulation and tissue engineering, nanoparticles to genomics, mechanical devices to porcine-derived xenotransplantation, all with varying degrees of success. Cellular repopulation, a procedure in which healthy liver cells are injected through a portal vein into the patient’s damaged organ, where they attach to the existing cellular framework and grow into new, functional liver tissue, has been used for years.

Professor Karl Oldhafer, Chief Physician for General and Visceral Surgery at the Asklepios Klinikum Hamburg-Barmbek, shows a tumor in a piece of liver that was removed in one of the first operations of this type in Germany, using a tablet Computer for retrieving and visualizing planning data, in Hamburg , August 15, 2013. The tablet computer uses augmented reality, in which the liver can be filmed with an iPad and overlaid with virtual 3D models, which have been replicated from the real organ, during an operation. This method, developed by Fraunhofer MEVIS in Bremen, helps to localize critical structures such as tumors and vessels and is intended to improve the quality of the transfer of preoperative resection plans to the actual operation. REUTERS/Fabian Bimmer (GERMANY - Tags: HEALTH)

Fabian Bimmer / Reuters

“Creating a readily available and inexhaustible supply of functioning liver cells from autologous tissue would allow for early intervention in patients with liver failure and would allow liver cells to be infused over a longer period of time,” the authors of the 2016 study note. “Combined with recent advances in genome editing technology, such liver cells could be used extensively to treat devastating liver-based inborn errors of metabolism and eliminate the need for lifelong treatment with immunosuppressive drugs and their complications.” The downside of this technique is the speed at which the donor cells multiply, making it a poor remedy for acute liver failure.

Extracellular vesicle-based therapies, on the other hand, use the body’s intracellular communication pathways to deliver drugs with “high bioavailability, exceptional biocompatibility, and low immunogenicity,” according to 2020 . “They provide a means for intercellular communication and delivery of bioactive compounds to target tissues, cells, and organs,” including “fibroblasts, neuronal cells, macrophages, and even cancer cells.”

EVs are the mail letters that cells send to each other. They come in a range of sizes from 30 to 1000 nm and have outer membranes studded with multiple adhesive proteins that allow them to enter any number of different cell types. Harnessing the biological equivalent of a janitor’s keychain, researchers have begun putting therapeutic nanoparticles in electric vehicles and using them to discreetly inject treatments into target cells. However, these treatments are still experimental and are most effective for acute liver failure and congenital metabolic diseases rather than end-stage liver failure.


Mayo Clinic

Mechanical devices, the hepatocytic equivalent of a dialysis machine, such as that (SRBAL, above) are ideal for treating cases of acute liver failure, being able to remotely and immediately take over all of the patient’s liver function. However, such procedures are both expensive and temporary. The SRBAL can only support a patient for up to two weeks, making it more suitable for keeping someone alive until a donor can be found, rather than as a permanent, pacemaker-like solution.

These have also shown promise, although they are also still in early development and for the most part are nowhere near ready for widespread adoption. Interspecies transplants using genetically engineered pig organs are performed by surgeons last January (although he died of complications two months later). Pig and have been similarly transplanted into human recipients, often with less drastic side effects than death.

Regardless of where the transplanted organ came from, getting it into the patient always involves a significant surgical procedure. However, the recently introduced its non-invasive solution: getting the patient’s body to grow a series of small, ectopic liver “organoids,” like a crop of blood-cleansing potatoes.

For those of you who have dozed through high school biography, a quick recap of terms. The lymphatic system is part of the immune system that serves to circulate about 20 liters of it throughout your body, absorbing excess back into the bloodstream and incubating critical lymphocytes such as. Organoids, on the other hand, are, but do so ectopically by functioning in a different part of the body than the normal liver. Blood chafing potatoes are self-explanatory.

“Basically, Lygenesis uses the lymph nodes, which are your body’s natural bioreactors that are typically used for T cells,” Michael Hufford, the company’s CEO and co-founder, told Engadget. “We hijacked the same biology, we transplant our therapies into the lymph nodes to grow functioning ectopic organs.”

“We use an outpatient endoscopic ultrasound procedure, where we go through the patient’s mouth with standard endoscopic equipment,” Hufford continued. “We implant ourselves there in minutes under light sedation, so it’s very low medical risk and it’s actually quite cheap.” He notes that the average cost of a proper liver transplant in a hospital setting will set you back about a million dollars. Lygenesis’ outpatient procedure “gets billed at a few thousand or so,” he said.

More importantly, the lygenesis technique does not require a complete donor liver, or even a large fraction thereof. In fact, each donated organ can be divided among several dozen recipients. “With our technology, a single donor liver can reach 75 or more patients,” Hofford said. The process of converting a single donor liver into all of these transplantable specimens requires a team of three technicians, taking more than six hours and 70 steps. The process does not involve genetic manipulation, such as B. CRISPR editing.

This process is quite necessary as patients cannot donate culturable liver cells to themselves. “Once you have end-stage liver disease, you usually have a very ,” noted Hofford. “It will bleed at the slightest kind of intervention.” Even simply collecting cell samples can quickly become deadly if the wrong piece of organ is cut in half.

And it’s not just the transplant recipients themselves who can’t donate. Hofford estimates that between 30 and 40 percent of donated livers are too worn out to be successfully transplanted. “One of the advantages of our technology is that we use organs that have been donated but are otherwise discarded,” he said.

After being transplanted into a lymph node, the liver organoid grows and vascularizes over the course of two to three months until it is large enough to support the existing liver. Hufford points out that even in end-stage disease, a liver can retain up to 30 percent of its original functionality, so these organoids are meant to augment and support the existing organ rather than replace it entirely.

Lygenesis is currently in Phase 2A of the , meaning a small group of four patients each received a single transplant into a lymph node located in their central body cavity near the liver itself (the body has more than 500 lymph nodes and apparently this treatment can technically target any of them). Should this initial test prove successful, subsequent study groups will receive an increasing number of transplants, up to half a dozen, to help the company and federal agencies determine the optimal number of organoids to treat the disease.

While the liver’s inherent regenerative abilities make it an ideal candidate for this procedure, the company is also developing similar treatments for the kidneys, pancreas and thymus, as well as for congenital metabolic liver diseases such as . These efforts are all in much earlier stages of development than the company’s late-stage liver work. “Within the next five years, we would like to see our liver program submitted to the FDA and commercially available as a new biologic therapy,” said Hufford. “I think that would be a realistic timeframe.”

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