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Organoids Making Their US Clinical Debut with CIDP Drug

The use of organoids in preclinical research has reached a tipping point, with U.S. FDA approval of the first drug to enter clinical trials on the basis of efficacy data derived only from these advanced cell models.

The study started recruiting just over a year ago, but the details have just been made public following publication of a peer-reviewed paper describing the use of a human-on-a-chip system to mimic disease mechanisms of rare autoimmune neuropathies that cannot be replicated in animal models.

The FDA’s decision to allow an existing drug, for which there are safety data, to be repurposed on efficacy data generated in microphysiological systems (MPS), is both a breakthrough in validating the utility of these systems and an important advance in finding treatments for rare diseases.

“There’s 7,000 rare diseases and only 400 research programs in them, because there are no animal models. In some cases, these systems fill a void where animal models don’t exist,” said James Hickman, CEO of Hesperos Inc., the company that generated the MPS model.

The paper published in April, describes testing a murine antibody that inhibits C1s, a key protease in the classical complement pathway, in an MPS designed to mimic key features of chronic inflammatory demyelinating polyneuropathy (CIDP).

CIDP is a rare autoimmune disease that causes muscle weakness that impairs walking and hand function. It is characterized by immune system hyperactivity sparked by autoantibody production, leading to peripheral nerve demyelination and reduction in nerve conduction velocity.

Orlando, Fla.-based Hesperos showed that exposing its model of peripheral motor neuron conduction velocity to serum from CIDP patients led to increased antibody binding and the activation of the complement cascade.

The addition of the murine antibody, TNT-005, rescued neuronal function and restored spontaneous frequency and conduction velocity.

The data generated provided the rationale for testing Sanofi SA’s sutimlimab (SAR-445088; formerly BIVV-020), a humanized anti-C1s monoclonal antibody, in treating CIDP. The product received U.S. FDA approval under the brand name Enjaymo in February 2022 for the treatment of cold agglutin disease [CAD], in which activation of the complement cascade leads the immune system to destroy healthy red blood cells.

“[Sanofi] took that [CAD] safety data, combined with the [MPS CIDP] efficacy data, and that was the only data that was presented to FDA for a new indication,” said Hickman. “That’s the first time this has happened.”

Hesperos aims to replicate that success in other rare diseases for which there are no animal models. Hickman said demonstrating the value of MPS as efficacy models in rare diseases is the route to making regulators more willing to accept MPS efficacy data in common diseases.

Scientific revolution in the making

This is but one of the examples that illustrate how the whole field of bioengineering human organs can now be characterized as a scientific revolution in the making, said Thomas Hartung, professor of public health and director of Johns Hopkins University Center for Alternatives to Animal Testing.

“Revolutionary change has a beginning somewhere, but there’s always milestones and highlights, and we feel that at this moment this field is reaching one of these highlights,” Hartung told attendees of the Euroscience Open Forum meeting in Leiden, the Netherlands, on July 14.

Hartung has been involved in the field for some time and drew more widespread attention to its potential in 2016, when he announced the first mass produced ‘mini brains.’ These show the architecture and functionality of the brain and can be cultured from different genetic backgrounds.

A potent example of the organoids’ utility was in determining how SARS-CoV-2 impacts the brain. It was not possible to investigate that in animal models because the virus does not infect rodents, while macaques, hamsters and ferrets can be infected but develop only mild disease.

“What makes [COVID-19] a really severe disease in humans is very difficult to study in animal models,” Hartung said. He and his colleagues used brain organoids to generate the first image of a human neuron infected with SARS-CoV-2 and showed that the ACE2 receptor, via which the virus enters human host cells, was expressed by the organoids. The data were published in May 2020, just three months after the pandemic took hold.

“This shows that [MPS] are an enabling technology that can really allow us very quickly to move forward,” said Hartung. Since then, a number of other groups have reproduced his findings, generating data that are very much in line with what has been observed in COVID-19 patients.

That illustrates how MPS are poised to overcome the worst of what Hartung refers to as the “reproducibility crisis” in biomedical research. In earlier toxicology research, he found that immortalized breast cancer cells from the same lot reacted differently to the same chemicals. It was subsequently shown that cells from this same cell line had been used in research reported in more than 23,000 papers.

Cell culture is a pillar of biomedical research, but it comes with a lot of flaws. “We have to assume 25% of the cells people are working on are misidentified, not the species we think, not the organ we think, not the gender we think,” said Hartung. “Ten percent to 25% of cells are infected with [antibiotic-resistant] mycoplasma; there’s a lot of genetic instability, and we don’t like to talk about the fact that some are missing entire chromosomes and there are terrible cultural artefacts.”

MPS are beginning to overcome some of these problems and it is an “extremely dynamic” area with scope for further progress.

Work to standardize and validate the capabilities of microphysiological systems has moved into a new phase. A revised version of the Good Cell and Tissue Culture Practice (GCCP) guidance, originally drawn up in 2005, was published in January of this year. Almost 100 experts were involved, with input from 350 stakeholders.

GCCP 2.0 is intended to reflect the way in which cell models have advanced to more complex culture systems and now need more comprehensive quality management to ensure reproducibility.

“It is extremely important that we now have the 2.0 version which embraces these new technologies and gives guidance on how to do this at high quality,” Hartung said. “This technology is new and there are engineers coming into the field who have never seen cell culture before.”

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