The project, called Dynamic Ensemble-to-Rescue: Decoding and Controlling the IDR Molecular Grammar at Scale (DETR), will initially study Parkinson’s disease and Ewing sarcoma, a rare cancer of bone and soft tissue in children and young adults. Its investigators plan to develop three tools and resources: a cerebrospinal fluid test for the shape of alpha-synuclein, molecules designed to bind harmful forms of disordered proteins, and an open foundation model for studying thousands of disease proteins that do not have proven drug therapies.

Neurologist Xiaobo Mao, Ph.D., a professor of neurology at the Johns Hopkins University School of Medicine, created the project’s scientific vision and is serving as principal investigator. He assembled 21 investigators from 12 institutions in the United States and Europe. DETR is one of several efforts in ARPA-H’s BIOmolecular Grammar for protein Aggregation Modulation and Intervention program, which is intended to support earlier detection of protein misfolding and intervention before disease advances, particularly in neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease. Shannon Greene, Ph.D., leads the ARPA-H program.

The central problem is that a protein’s amino-acid sequence can be read quickly but may not reveal which three-dimensional shape a protein will adopt or whether that shape is harmful. Mao said that predicting a protein’s shape could support the design of drugs that recognize a harmful form while leaving a healthy form alone. This is the program’s scientific premise; the funded work has not yet established that such predictions, diagnostic tests or targeted molecules will work in patients.

DETR is organized around two technical areas spanning two 24-month phases. The first will seek to establish the molecular grammar of intrinsically disordered regions by examining how primary sequence, structural features and environmental conditions govern their behavior. The investigators plan to build a foundational model that integrates computational and experimental work, with high-throughput laboratory platforms producing measurements used to train and test it. These are proposed methods and development objectives, not findings from a completed experiment.

The second technical area will focus on detecting and controlling protein misfolding. For early detection, the investigators aim to identify misfolding that could function as a biomarker in diagnostic tests. The planned cerebrospinal fluid assay is intended to read the shape of alpha-synuclein, the protein associated with the deposits that define Parkinson’s disease, and could potentially identify the disease years before symptoms occur. That timing is a project goal rather than a demonstrated result of the award announcement.

For therapeutic development, the program’s stated aim is to restore a protein’s function or prevent aggregation and misfolding from beginning while leaving a working form untouched. A second intended resource is a class of molecules designed to bind harmful forms of disordered proteins while sparing healthy forms. The third is an open foundation model intended to allow laboratories to ask consistent questions about disease proteins that currently lack proven drug therapies. These outputs remain to be developed and evaluated.

Although the first studies will focus on Parkinson’s disease and Ewing sarcoma, the project is designed to produce foundational resources that may support research into other conditions. The announcement identifies possible applications including Alzheimer’s disease, cancer, heart disease, type 2 diabetes and infections that may remain dormant before reappearing years later. These are intended areas of future use; the protocol has not demonstrated detection or treatment for those conditions.

Johns Hopkins Medicine will serve as the prime institution guiding DETR, with eight additional Johns Hopkins laboratories taking part. The institutional partners also include Columbia University, the Gladstone Institutes, the Massachusetts Institute of Technology, the University of Michigan at Ann Arbor, Emory University, the University of Copenhagen, the Institute for Research in Biomedicine in Barcelona, the University of Texas at Austin, Arizona State University, the University of Texas at Dallas, and the University of Washington with the Seattle Institute for Biomedical and Clinical Research. Project outputs are planned for public sharing through open-access resources, but the award does not yet establish the accuracy, safety or clinical usefulness of the proposed tools.

Subject of Research: A planned multicenter research protocol on detecting and controlling disease-associated protein misfolding

Article Title: Johns Hopkins Medicine leads up to $52 million federal effort to study protein shapes and folding

Article References: Johns Hopkins Medicine leads up to $52 million federal effort to study protein shapes and folding. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: protein misfolding, ARPA-H, Johns Hopkins Medicine, Parkinson’s disease, Ewing sarcoma, alpha-synuclein, biomarker, foundation model, intrinsically disordered proteins, research protocol, Johns, Hopkins