Could the Next Blockbuster Drug Be Lab-Rat Free?

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In 1937, an American pharmaceutical company introduced a new elixir to treat strep throat – and inadvertently triggered a public health disaster. The product, which had not been tested on humans or animals, contained a solvent that turned out to be toxic. More than 100 people died.

The following year, Congress passed the federal Food, Drug, and Cosmetic Safety Act, which required drug companies to submit safety data to the US Food and Drug Administration before selling new drugs, helping usher in the era of animal toxicity testing. .

Now, a new chapter in drug development can begin. The FDA Modernization Act 2.0, signed into law late last year, allows drug makers to collect preliminary safety and efficacy data using high-tech new tools like bioengineered organs, organs on chips and even computer models instead of live animals. allows to do. Congress also allocated $5 million to the FDA to accelerate the development of alternatives to animal testing.

Other agencies and countries are making similar changes. In 2019, the US Environmental Protection Agency announced that it would reduce testing on mammals, with the goal of eventually eliminating it. In 2021, the European Parliament called for plans to phase out animal testing.

Experts said these moves have been driven by a confluence of factors, including animal-developed views and a desire to make drug development cheaper and faster. But what is finally making them viable is the development of sophisticated alternatives to animal testing.

It is still early for these techniques, many of which still need to be refined, standardized and validated before they can be routinely used in drug development. And even advocates of these alternatives acknowledge that animal testing is not likely to disappear anytime soon.

But momentum is growing for non-animal approaches, which could ultimately help accelerate drug development, improve patient outcomes and reduce the burden carried by laboratory animals, experts say. he said.

“Animals are simply a surrogate for predicting what’s going to happen in humans,” said Nicole Kleinstreuer, director of the National Toxicology Program’s Interagency Center for the Evaluation of Alternative Toxicological Methods.

“If we can get to a place where we really have a fully human-relevant model,” she said, “then we don’t need the animal black box anymore.”

Animal rights groups have been lobbying for a reduction in animal testing for decades, and they have found an increasingly receptive public. In a 2022 Gallup poll, 43 percent of Americans said medical testing on animals was “morally wrong,” up from 26 percent in 2001.

Reducing animal testing “makes sense to so many people for so many different reasons,” says Elizabeth Baker, director of research policy at the Physicians Committee for Responsible Medicine, a nonprofit group that advocates for alternatives to animal testing. does. “Animal ethics is actually quite a big driver.”

But it is not alone. Animal testing is also time-consuming, expensive and vulnerable to shortages. Drug development, in particular, is riddled with failures, and many drugs that appear promising in animals do not extrapolate to humans. “We are not 70-kilogram rats,” said Dr. Thomas Hartung, who directs the Johns Hopkins Center for Alternatives to Animal Testing.

In addition, some cutting-edge new therapies are based on biological products, such as antibodies or fragments of DNA, which may have targets that are specific to humans.

“There is a lot of pressure, not only for ethical reasons, but also for these economic reasons and to really close the security gaps that are more modern and humanitarian,” Dr. Hartung said.

(Dr. Hartung is the named inventor on a Johns Hopkins University patent on the production of brain organoids. He receives royalty shares from that company, and consults for the company that has licensed the technology.)

In recent years, scientists have developed more sophisticated methods to replicate human physiology in the laboratory.

They have learned how to coax human stem cells to assemble themselves into a tiny, three-dimensional clump, known as an organoid, that forms the core of a specific human organ, such as the brain, lung or kidney. Shows some of the same basic characteristics. ,

Scientists can use these miniaturized organs to study the basis of disease or test treatments, even on individual patients. In a 2016 study, researchers created mini-guts from cell samples from patients with cystic fibrosis and then used the organoids to predict which patients would respond to new drugs.

Scientists are also using 3-D printers to create organoids on a large scale and to print strips of other types of human tissue, such as skin.

Another approach relies on an “organ on a chip”. These devices, which are roughly the size of an AA battery, have tiny channels that can be lined with different types of human cells. Researchers can pump drugs through channels to simulate how they might travel through a particular part of the body.

In a recent study, the biotech company Amulet, which makes organs on chips, used liver-on-a-chip to test 27 well-studied drugs. All of the drugs passed initial animal testing, but some were later shown to cause liver toxicity in humans. Researchers reported last December in Communications Medicine that the liver-on-a-chip successfully flagged 87 percent of toxic compounds.

Researchers can link different systems together, from a heart-on-a-chip to a lung-on-a-chip to a liver-on-a-chip, to study how a drug interacts with the whole body. How can it affect interconnected systems? “That’s where I think the future lies,” Dr. Kleinstreur said.

Not all new devices require an actual cell. There are also computational models that can predict whether a compound with certain chemical characteristics is likely to be toxic, how much of it will reach various organs and how quickly it will be metabolized.

The model can be adjusted to represent different types of patients. For example, a drug developer may test whether a drug that works in younger adults will be safe and effective in older adults, who often have reduced kidney function.

“If you can identify problems as early as possible by using a computational model that saves you from going down the wrong path with these chemicals,” said Judith Madden, an “in silico” or computer-based, Liverpool Johns Chemical Testing Moores University. (Dr. Madden is also editor-in-chief of the journal Alternatives to Laboratory Animals.)

Some approaches have existed for years, but advances in computing technology and artificial intelligence are making them increasingly powerful and sophisticated, Dr. Madden said.

Virtual cells have also shown promise. For example, researchers “can model individual human heart cells using a set of equations that describe everything that goes on in the cell,” said Elisa Pasini, director of the National Center for the Replacement, Refinement and Reduction of Heart Disease. Program Manager for Drug Development in Animals. in research, or NC3Rs, in the UK.

In a 2017 study, Dr. Pasini, then a researcher at the University of Oxford, and his colleagues concluded that these digital cells were better than animal models in predicting whether dozens of known drugs would cause heart problems in humans.

Scientists are now building entire virtual limbs that could eventually be joined together into a kind of virtual human, Dr. Pasini said, although some of the work is in early stages.

In the short term, a virtual lab animal may be more achievable, said Cathy Vickers, head of innovation at NC3Rs, which is working with scientists and pharmaceutical companies to develop a digital model of a dog that can be used to study drug toxicity. can be done for testing.

“It’s still a big push to develop a virtual dog,” Dr. Vickers said. “But it’s about building that capability, building that momentum.”

Experts said many potential animal alternatives will require more investment and development before they can be widely used. They too have their limits. For example, computer models are only as good as the ones they are built on, and there is more data available on some types of compounds, cells and outcomes than others.

For now, these alternative methods are better at predicting relatively simple, short-term consequences, such as acute toxicity, than complex, long-term ones, such as whether a chemical will increase cancer risk when used over months or years. Maybe, said the scientist.

And experts disagreed about the extent to which these alternative approaches could replace animal models. “We’re absolutely working toward a future where we want to be able to completely replace them,” Dr. Kleinstreuer said, although he acknowledged that it could take decades, “if not centuries.”

But others said these techniques should be viewed as a complement to, rather than a replacement for, animal testing. Matthew Bailey, president of the National Association for Biomedical Research, a nonprofit group, said drugs that prove promising in organoids or computer models still need to be tested in animals.

“Researchers still need to be able to see everything happening in a complex mammalian organism before they are allowed to move into human clinical trials,” he said.

Still, this more conservative approach could have benefits, said Nicole zur Nieden, a developmental toxicologist at the University of California, Riverside, who said she thought a wholesale replacement of animal testing was unrealistic.

In particular, she said, the new approach could help scientists screen for a greater number of ineffective and unsafe compounds before testing them on animals. By reducing the number of animal studies researchers need to conduct and highlighting the limits of chemical laboratory animals are exposed to, he added, “we will be able to substantially reduce the suffering of test animals. “

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