Genetically Engineered Mouse Models for Human-Like Multiple Myeloma
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Solution Overview
Problem
Current experimental models for multiple myeloma (MM) are limited by the inability to properly grow human MM cells in vitro or in immunocompetent mice, and lack the ability to recapitulate the natural history of the disease, hindering pre-clinical studies of immunotherapies and drug combinations.
Innovation Solution
Development of genetically engineered mouse models that reflect key elements of MM pathogenesis, including genetic heterogeneity and tumor-immune microenvironment interactions, using bicistronic gene constructs with conditionally activatable transgenes for IKK2, MYC, BCL2, and MMSET-II proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetically engineered mouse models are developed to recapitulate human MM pathogenesis, then the ability to study MM cell interactions with bone marrow immune cells is improved, but the complexity of the experimental model increases
Solution Approach 1:
The patent divides the complex MM pathogenesis into discrete genetic components by using separate transgenes for IKK2, MYC, BCL2, and MMSET-II. Each transgene can be independently controlled and studied, allowing researchers to examine the contribution of individual genetic alterations to MM development while maintaining the overall complexity of the disease model.
Solution Approach 2:
The patent employs conditionally activatable transgenes that can be induced at specific time points during mouse development. This dynamic control allows researchers to study the temporal sequence of genetic alterations in MM pathogenesis, activating different combinations of transgenes at different stages to recapitulate the progressive nature of the disease.
2Reliability
If human MGUS and MM primary cells are grown in immunocompetent mice, then the functional characterization of MM cells is improved, but the availability of suitable experimental models remains limited
Solution Approach 1:
The patent creates a universal experimental platform using immunocompetent mice that can accommodate multiple different transgene combinations. This single mouse model system can study various aspects of MM pathogenesis by activating different combinations of IKK2, MYC, BCL2, and MMSET-II transgenes, making it versatile for studying different stages and subtypes of MM.
Solution Approach 2:
The patent uses genetically engineered mice as an intermediary system between in vitro cell culture and human clinical studies. The mouse model serves as a living platform that maintains human MM cell characteristics while providing the physiological context of an immunocompetent organism, enabling functional characterization that cannot be achieved in either in vitro systems or direct human studies.
3Manufacturing precision
If multiple transgenes are introduced to reflect genetic heterogeneity of MM, then the accuracy of disease modeling is improved, but the difficulty of model generation increases
Solution Approach 1:
The patent segments the multiple genetic alterations characteristic of MM into separate, modular transgenes. Each transgene represents a discrete genetic event (IKK2 activation, MYC amplification, BCL2 overexpression, MMSET-II alteration) that can be independently introduced and controlled, simplifying the generation of accurate disease models compared to introducing all alterations simultaneously.
Solution Approach 2:
The patent uses conditionally activatable transgenes that can be induced in a controlled temporal sequence. This allows researchers to generate accurate disease models by activating transgenes in the order they typically occur in human MM pathogenesis, while maintaining ease of model generation through controlled induction rather than complex simultaneous introduction of all genetic alterations.
Data Source
AI summary
The invention relates to genetically engineered mouse models for multiple myeloma (MM) and their uses thereof for the development of multiple myeloma models as well as for the screening of compounds suitable for the treatment of multiple myeloma.