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Assignees
J David Gladstone Institutes • University of California San Diego UCSD
Member
Gladstone InstitutesGladstone Institutes is an independent biomedical research organization dedicated to tackling the biggest challenges in human health. By disrupting traditional scientific methods, Gladstone aims to make groundbreaking discoveries that can transform lives. The organization is renowned for its innovative approaches in research, focusing on conditions with significant medical, economic, and social impacts. Founded in 1979 from a donation by J. David Gladstone, the institute has expanded its research areas to include cardiovascular, neurological, and viral diseases, as well as data science and biotechnology.
Gladstone Institutes is an independent biomedical research organization dedicated to tackling the biggest challenges in human health. By disrupting traditional scientific methods, Gladstone aims to make groundbreaking discoveries that can transform lives. The organization is renowned for its innovative approaches in research, focusing on conditions with significant medical, economic, and social impacts. Founded in 1979 from a donation by J. David Gladstone, the institute has expanded its research areas to include cardiovascular, neurological, and viral diseases, as well as data science and biotechnology.
Publication Number
US-11020463-B2
Publication Date
2021-06-01
Expiration Date
2036-08-08
Abstract
The present invention provides assays and compositions to identify the risk of toxicity in a patient population with genotypic variations in specific proteins and/or protein complexes within the patient population.
Core Innovation
The invention provides assays and compositions to identify the risk of toxicity in patient populations with genotypic variations in specific proteins and/or protein complexes. It particularly focuses on the use of cell populations produced from clonal expansion and differentiation of individual cells that represent genotypes of a gene of interest. These cell populations are contacted with agents, and ex vivo activity associated with toxicity is detected to identify genotypes linked to an increased risk of agent-induced toxicity.
The methods utilize differentiated pluripotent stem cells (PSCs), especially induced pluripotent stem cells (iPSCs), to generate isogenic cell populations reflecting specific genotypic variations, including mutations and polymorphisms in chaperone complex proteins such as BAG3 and its associated proteins. The assay detects toxicity-related functional changes, such as sarcomere disarray and contractility, particularly in muscle cells including cardiomyocytes and their progenitors.
The background describes the problem of inadequate predictive systems for identifying individuals at risk of agent-induced toxicity, notably when protein homeostasis and proteome stability are compromised. Proteotoxicity resulting from overwhelmed chaperone networks and insufficient proteolytic systems leads to serious adverse events and late-stage drug development attrition. The invention solves this problem by providing a method to use isogenic, differentiated PSC-derived cell populations to assess risk of toxicity ex vivo, correlating with in vivo effects.
Claims Coverage
The patent includes one independent claim focused on a method for determining risk of agent-induced toxicity using isogenic cell populations derived from pluripotent stem cells.
Use of isogenic cell populations with BAG3 mutations for toxicity assessment
Providing a panel of isogenic cell populations comprising muscle cells or their progenitors, differentiated from induced pluripotent stem cells, wherein the cells comprise mutations and/or polymorphisms of BAG3.
Contacting with an agent and detection of ex vivo live cellular toxicity
Contacting the panel of isogenic cell populations with an agent and detecting ex vivo live cellular activity associated with toxicity that results from the agent contact, thereby detecting BAG3 genotypes associated with increased risk of agent-induced toxicity.
Inclusion of proteasome inhibitors as agents
Use of proteasome inhibitors as the agent subjected to the assay, with optional consideration of agents that inhibit autophagy in the cell populations.
Utilization of muscle cell types relevant for toxicity detection
The muscle cells or muscle progenitors in the isogenic cell populations comprise skeletal muscle cells or skeletal muscle progenitors, or cardiomyocytes or cardiomyocyte progenitors.
Functional readouts of toxicity over time
The ex vivo cellular activities associated with toxicity are functional measures such as sarcomeric disarray or contractility of muscle cells, with detection performed over time.
The inventive features collectively cover a method utilizing differentiated isogenic PSC-derived muscle cell populations with BAG3 genotypic variations, exposed to agents such as proteasome inhibitors, and functional assessment of live ex vivo cellular activity over time to detect genotypes linked to increased risk of agent-induced toxicity.
Stated Advantages
The toxicity observed in the ex vivo cell-based assays correlates with in vivo effects of agents.
Assays can be performed on live cell populations, allowing measurement of responses not only to agent exposure but also to cessation of the agent.
Documented Applications
Identification of risk of agent-induced toxicity in patient populations based on genotypes of the BAG3 chaperone complex and associated proteins.
Use in pre-clinical safety assessment to predict clinical adverse events and optimize clinical trial design.
Screening and identification of candidate therapeutic agents that improve protein homeostasis in muscle cells, including agents targeting proteasome activity and autophagy pathways.
Companion diagnostic use for assessing individual patient risk for toxicity prior to administration of agents, for example proteasome inhibitors used in cancer therapy.
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