Researchers create 3D model for rare neuromuscular disorders, setting
stage for clinical trial
Tissue chip platform shows potential uses for developing treatments for
rare diseases

Date:
April 19, 2022
Source:
NIH/National Center for Advancing Translational Sciences (NCATS)
Summary:
Scientists have created a bioengineered 3-D model that mimics
the biology of two rare diseases. The researchers used the 'tissue
chip' model to show how a drug could potentially treat the diseases,
providing data for a drug company's FDA submission for authorization
for clinical testing.

This is one of the first examples of using primarily tissue chip
data for an FDA application to test the efficacy of a candidate
drug for rare diseases.



FULL STORY ==========================================================================
A scientific team supported by the National Institutes of Health has
created a tiny, bioengineered 3-D model that mimics the biology of chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy,
a pair of rare, devastating neuromuscular diseases. The researchers used
the organ-on-a-chip, or "tissue chip," model to show how a drug could potentially treat the diseases. They provided key preclinical data for
a drug company to submit to the U.S. Food and Drug Administration to
get authorization for testing in a clinical trial.


==========================================================================
This work provides one of the first examples of scientists using primarily tissue chip data for an FDA Investigational New Drug application to test
the efficacy of a candidate drug in people with rare diseases. The drug
company Sanofi started recruiting participants into a Phase 2 clinical
trial in April 2021. The drug was tested for safety previously and
approved by the FDA for a different indication.

The tissue chip research was led by Hesperos, Inc., an Orlando-based
company partially funded by a Small Business Innovation Research
grant from NIH's National Center for Advancing Translational Sciences
(NCATS). This study could open the door to studying and developing
new therapies for other rare diseases by establishing a new avenue for repurposing existing drugs for rare diseases.

Most of the known 7,000 rare diseases do not have effective treatments.

Researchers often lack animal models for studying rare disease biology
and testing potential drugs.

"This marks an important milestone in the evolution of the use of tissue chips," said Lucie Low, Ph.D., scientific program manager for the NCATS
Tissue Chip for Drug Screening initiative. "We know that pharmaceutical companies are using tissue chips internally. Submitting data to regulatory agencies generated from tissue chip platforms is a powerful indicator
of their growing promise." James Hickman, Ph.D., chief scientist at
Hesperos, and his colleagues described the development of the model and
their research results in Advanced Therapeutics. In these diseases,
the immune system makes proteins called antibodies that damage nerve
cells and slow down messages moving from the brain to the muscles. This
can make it hard for people to move their arms, hands and legs. Current treatments can help, but often are inconsistent.

The researchers developed a tissue chip model consisting of two cell
types: motoneurons and Schwann cells. Motoneurons transmit messages
from the brain to muscles. Schwann cells help the signals move more
quickly. The model could mimic functional characteristics of the diseases, allowing the scientists to see how a drug was working by determining
whether the brain's messages to muscles were slowing down or not.

The researchers showed that exposing the cells to blood serum from
people with these rare diseases caused a shower of immune system
antibodies against the cells. This made the motoneuron signals move more slowly. After treatment with TNT005, a drug that blocks the immune system reaction, the cells and the message speed returned to normal.

"We're confident that our system can reproduce what happens to a
patient, including the disease symptoms and disease progression," said
Hickman. "It's important to create functionally relevant patient models
that will mimic what is seen in clinical trials." Approximately 90% of promising therapies fail in clinical trials because animal models used in preclinical testing are not good at predicting how people will respond. To improve that success rate and help get more treatments to people who
have few options, scientists are exploring the uses of tissue chips.

Designed to support living human tissues and cells, tissue chips mimic the structure and function of human organs and systems, such as the lungs,
heart and liver. Researchers are studying their uses in many areas,
including for testing the safety and effectiveness of candidate drugs
and modeling diseases.

The potential clinical uses of tissue chip data are growing. Recently,
an NIH- supported research team at Harvard University's Wyss Institute
reported using a tissue chip model to generate data on the effectiveness
of a repurposed drug for treating lung damage from COVID-19 infection. In
the NCATS-funded Clinical Trials on a Chip program, several projects
examine how tissue chip data can help researchers design more useful
clinical trials. This might include using such data to predict which
patients in a trial are most likely to respond to a therapy.

"Creating a platform that can predict human responses to a drug in a
rare disease could lead to exciting new opportunities in research," said
Low. "If tissue chip data can be generated that inform the decisions made before early human trials, this could reduce the risks to vulnerable populations." Funding for this research was provided by True North Therapeutics (now Sanofi), NCATS (SBIR 2R44TR001326-03) and internal
Hesperos development funds.


========================================================================== Story Source: Materials provided by NIH/National_Center_for_Advancing_Translational_Sciences_ (NCATS). Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. John W. Rumsey, Case Lorance, Max Jackson, Trevor Sasserath,
Christopher
W. McAleer, Christopher J. Long, Arindom Goswami, Melissa
A. Russo, Shruti M. Raja, Karissa L. Gable, Doug Emmett, Lisa
D. Hobson‐Webb, Manisha Chopra, James F. Howard, Jeffrey
T. Guptill, Michael J. Storek, Miguel Alonso‐Alonso,
Nazem Atassi, Sandip Panicker, Graham Parry, Timothy Hammond,
James J. Hickman. Classical Complement Pathway Inhibition
in a "Human‐On‐A‐Chip" Model of Autoimmune
Demyelinating Neuropathies. Advanced Therapeutics, 2022; 2200030
DOI: 10.1002/adtp.202200030 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220419103240.htm

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