Ingrid Hein

October 31, 2016

FLORENCE, Italy — Kidney organoids grown with pluripotent stem cells are providing biomedical scientists a new way to model diseases and test drugs, and might eventually be a source for cell-based transplants.

"In the long term, we might be able to partially repair an organ and functionally replace or totally replace kidneys," said Melissa Little, PhD, from the Murdoch Childrens Research Institute in Melbourne, Australia.

However, "for now, there are limitations to what we can do," she told a jam-packed auditorium here at the European Society of Gene and Cell Therapy (ESGCT) 2016 Annual Congress.

Dr Little and her team are growing kidney organoids, sort of immature "mini-kidneys," in Petri dishes.

"This is a tiny model of an early-development tissue. These are not a 70-year-old kidneys going into chronic kidney disease," she told Medscape Medical News.

The researchers then model inherited kidney disease by comparing organoids from a child developing kidney failure with organoids grown from a close relative's cells.

"We now know more about which genes cause these diseases," she reported.

100 Nephrons and Counting

Among the many challenges to overcome is finding ways to grow bigger kidneys with more nephrons, said Dr Little. A mouse kidney, for example, contains about 16,000 nephrons, whereas a human kidney has 1 million to 2 million.

The kidney organoids her team is growing are about 6 mm long and are composed of about 100 nephrons. The organoids are immature and cannot move urine out of the kidney. They are somewhat equivalent to the kidney of a fetus at the beginning of the second trimester of pregnancy.

In 2007, research showed that human somatic cells can be reprogrammed to become pluripotent and form any type of cell (Development. 2016;143:905-906). This led to the development of protocols to "convince" human cells to achieve a specific end point, making it possible to grow heart, lung, and kidney organoids in a dish, Dr Little explained. "You can form and choose their fate based on their 'friends' and the environment they're sitting in. The growth factors come from the cells above, below, and beside them."

Because the Petri-dish organoids resemble the kidneys of a very young child, her research team started with early-onset kidney diseases in children, such as genetically inherited diseases.

Kidney disease is inherited in 10% to 20% of cases, but in children, the rate is closer to 50%. Often, the mutation that causes the disease in unknown. "For this, a model of an early kidney is probably not bad. It's much closer to the reality than the kidney of an aging adult," she explained.

To date, Dr Little's team has modeled kidney disease in about 12 different families to help clarify what happens as a result of genetic or environmental damage during development.

To pinpoint where and when the child's mutation might have occurred, the researchers grow three kidney organoids: one with cells from an affected child with recessive early-onset kidney failure, a control with cells from a close but unaffected relative, and a second control with cells from an unrelated person.

Next they use gene-editing technology, such as CRISPR–Cas9, to correct those genes.

Personalized Drug Testing

"We use a lot of organoids in our lab, like cortical organoids, to model brain disorders," said Giuseppe Testa, PhD, MD, from the University of Milan, Italy.

Different fields of medicine are going to benefit from organoids in different ways, he told Medscape Medical News. For example, they can be used "as a tool to study cancer outside the body or as a way to screen for personalized treatments. And in the future, they could be used to make predictions about what combinations of drugs can be used."

Organoids will likely serve a very important role in personalized drug testing. "Some of the most transforming developments in medicine are going to come from the use of organoids sourced from a patient's cells modeled for drug discovery," Dr Testa explained. "I think this will have a tremendous impact much earlier than the actual regeneration of entire organs for the purpose of transplantation."

We haven't changed the way we treat kidney disease for 60 years. Dr Melissa Little

One in ten Australians show signs of kidney disease ― rates are comparable around the world ― so research in this field is important, Dr Little pointed out. "And kidney failure due to diabetes is increasing at 10% per annum," she reported.

"Despite this, we haven't changed the way we treat kidney disease for 60 years; it's been either transplant or dialysis," Dr Little noted.

But each of these treatments has drawbacks: dialysis severely limits quality of life, and only 1 in 4 patients are lucky enough to undergo transplant. And with increasing rates of obesity leading to even more kidney failure, "we have a desperate need to find a better way to treat patients," she said.

She hopes that by understanding the molecular basis of both normal kidney development and renal disease, her team will be able to develop therapies that will prompt the kidney to heal itself.

Eventually, scientists will probably be able to take cells from a patient and grow a personalized kidney for them, but that is a long way off and is "a really big challenge," she said.

We've just started to build the tools. Dr Melissa Little

Because "an adult patient goes into renal failure really slowly, most nephrologists know for a really long time what is coming." For a patient with 60% renal function, "it's not unrealistic to think that in the future, you could create a tissue-based organ," Dr Little explained.

Although she said she sees progress toward this goal, she is not sure it will be achieved in her lifetime.

"Researchers have been able to grow heart muscle cells, but they can't get them to work in unison with the heart that's already there in the body," she explained. "At the moment, we've just started to build the tools."

European Society of Gene and Cell Therapy (ESGCT) 2016 Annual Congress. Presented October 20, 2016.


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