Small animal models are still a mainstay of preclinical research. The most significant current trend in model generation focuses on immune system humanization of these models to improve efficiency and translational benefits, along with expanded offerings for neurodegenerative diseases.
As genetic-engineering tools mature, vendors are providing additional flexibility for select applications with custom model generation and preclinical services for in-depth characterization.
Another major evolution in the preclinical tools landscape is the growing acknowledgement and acceptance of NAM (non-animal models). The use of NAM is often a first-line testing strategy to confirm or uncover new findings before moving on to the relatively more expensive small animal models. This approach also facilitates adherence to the 3Rs (Replacement, Reduction, and Refinement).
As the NAM industry matures, vendors offering a range of preclinical in vivo tools are learning how to work hand-in-hand to provide exponential value to drug developers. This next-generation biology will likely shape drug development in the next few years, highlighted by the April announcement by the FDA to phase out animal testing requirements for monoclonal antibodies and other drugs.
According to Sierra Kent, PhD, associate director at The Jackson Laboratory (JAX), JAX pushes the edges of possibilities for humanized mice. A prime example is the NSG-FLT3-IL15 mouse, the world’s most advanced model for cellular humanization with CD34+ human hematopoietic stem cells (HSCs).
This strain carries a knock-out of the mouse Flt3 receptor with transgenes expressing human FLT3 ligand and human IL15. When engrafted with HSCs, the NSG-FLT3-IL15 mouse produces a cellular-diverse human immune system, including development of myeloid cells, mature natural killer (NK) cells, functional dendritic cells, and T cells. JAX provides this strain pre-humanized with HSCs along with preclinical services.
The genetically humanized FcRn mice provide translational pharmacokinetics (PK) and pharmacodynamics (PD) data for antibody-based therapeutics. The Tg32 hALB mouse, lacking the mouse Fc gamma receptor (Fcgrt) and albumin (Alb) while expressing the human counterparts, expands this collection. Tg32 hALB mice are the first of their kind for studying the PK and PD of human albumin therapeutics as well as human IgG and Fc-domain based therapeutics. Preclinical services using these models are available.
This year, JAX expects to make available mouse models with functional human B cells, models for studying autoimmunity, and a variety of pre-characterized human PBMC humanized models.
The over 500-line human iPSC repository also continues to grow at JAX, with engineered iPSC lines carrying disease-relevant mutations associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, ALS, and frontotemporal dementia. In partnership with the iPSC Neurodegenerative Disease Initiative (iNDI), JAX is engineering additional iPSC lines to enable reproducibility studies by introducing the same variants across genetically distinct backgrounds.
“We believe that advanced cellular models, such as iPSC-based platforms, serve as powerful complements to traditional in vivo models,” said Kent. “While some findings are consistent across systems, others uncover unique biology, underscoring that no single model fits all research questions.”
New supply chains and mouse propagation locations fuel a global expansion. JAX Mice® are currently propagated outside of the U.S., in Japan at JAX Japan, in India via ATNT Laboratories, and in multiple European and Asian countries. Soon, production of humanized JAX mice will begin in Australia, eliminating the need to meet current requirements for long quarantine periods.
Taconic is also responding to the growing demand for scientific accuracy, customization, and immunology-ready platforms by focusing on enhancing precision and flexibility in preclinical research.
The FcResolv® NOG portfolio lack FcyRs, which reduces murine immune cell interactions with antibody-based drugs. In addition, Taconic’s huSelect
Custom Immune Cell Engraftment Services, a suite of custom humanization capabilities, are suitable for use with any of their CD34+ humanized immune system models to reduce donor-to-donor variability.
A growing number of mouse and rat models is available for the study of Parkinson’s disease through Taconic Biosciences’ fifteen-year partnership with the Michael J. Fox Foundation.
“To provide more effective translational tools in oncology, immuno-oncology, and neurodegenerative research, new offerings will include advanced flow cytometry panels and additional Parkinson’s disease models,” said Mike Garrett, CEO of Taconic Biosciences.
The flow cytometry panels were developed to provide reproducible, high-content immune data in order to streamline study design and support deeper and more standardized immune profiling. The panels are specifically optimized for Taconic’s humanized immune system mice models to characterize key immune cell subsets—including T cells, B cells, NK cells, and myeloid populations—across blood, spleen, and bone marrow.
“Our 15-year partnership with The Michael J. Fox Foundation is making available a growing number of mouse and rat models for the study of Parkinson’s disease,” added Garrett. “New models include the aSyn KI/KO Rat, PINK1KO Rat, and the LRRK2 KO Rat.”
A strategic shift in several integrated services should enhance early-stage drug development. Transgene characterization enables rapid, in-depth validation of gene insertion and expression in custom genetically engineered models, while CRISPR off-target analysis helps detect unintended genome edits.
Tiered Custom Model Generation Solutions complement these tools, offering a variety of advanced model generation services tailored to project timelines, budget, and health standards requirements.
“To support customers, we are also investing in comprehensive phenotypic datasets and partnerships to co-publish preclinical findings and positioning our models to slot seamlessly into tiered workflows integrating AI, animal alternatives, organoids, and animal models,” highlighted Garrett.
Lastly, a new CRO preclinic partnership provides customers with greater access to an end-to-end platform by combining the most relevant animal models, custom model generation, and colony management services with downstream in vivo study capabilities.
The demand for more translational and efficient alternatives to traditional animal models shapes model development. “The need for more predictive preclinical research, particularly in immuno-oncology, infectious diseases, and personalized medicine, continues to drive the advancements in humanized models,” said Steve Bronson, DVM, scientific product manager at Charles River Laboratories.
The Charles River models NCG-hIL2 and NCG-hIL15 are built on the NCG background, which lacks functional/mature T, B, and NK cells, and has reduced macrophage and dendritic cell function. NCG-hIL2 expresses the human IL2 cytokine, and NCG-hIL15 expresses the human IL15 cytokine. When engrafted with human HSC, both strains support the growth and development of NK and T cells. NCG-hIL15 further supports the homeostatic expansion and survival of NK cells, allowing for stable, long-term immune cell function.
The humanized portfolio will add two PBMC humanized models, HuPBMC NCG-B2m-KO and HuPBMC NCG-MHC-dKO, to support studies of immune responses, tumor growth, and infectious diseases. In addition, an exclusive, do-it-yourself PBMC Select Humanization kit gives researchers more time to create humanized mice with validated PBMCs from recallable donors per their study timeline.
Bronson added, “More researchers need flexibility in study design with immunodeficient and humanized mice so that they can mimic human immune interactions. By working with these models, researchers can support the 3Rs by lengthening research times and using fewer animals.”
Microphysiological systems (MPS) address the critical need for better models to understand diseases, find targets, and triage compounds. These technologies fill gaps where current animal models fail, rather than compete head-to-head with them. “The most urgent use for MPS is to meet needs for the development of new molecular entities such as bi- and tri-specific antibodies, antibody-drug conjugates, CAR T cells, and gene therapies, amongst others,” said Paul Vulto, PhD, CEO of MIMETAS.
MIMETAS’s service offering concentrates on the interplay between cell types as primary drivers for disease processes. Their breakthrough liver model, used for assessing gene therapy and toxicity, as well as for fibrosis and MASH modelling, comprises a perfused vascular plexus from liver sinusoidal endothelial cells, stellate cells, hepatocytes, and immune cells. The self-organizing hepatic tissues are indistinguishable from primary liver slices.
The company’s CAR T testing services for solid tumors follow the activity of CAR T cells from the bloodstream to the tumor. The tumor comprises critical tumor microenvironment elements, including vasculature, stroma, and immune cells.
UniFlow technology has extended the services portfolio by allowing perfusion of vasculature under unidirectional flow conditions. As such, the technology provides more relevant cues while still retaining the throughput of the original OrganoPlate® technology, and is applied to liver and tumor modelling. “Another new service offering is our lung modelling work for studying diseases such as pulmonary fibrosis and toxicity,” said Vulto.
To go further, the new OrganoReady® Colon Organoid plates provide 64 colon tubules based on the HUB organoid technology. “Next in line will be a full launch of our OrganoReady HBMEC plates that allow compound testing on blood-brain barrier transport and toxicity,” said Vulto.
Vulto feels that the smooth continuity of the FDA drug approval process is vital, and if flawed during restructuring, it will threaten the entire industry. The market is currently improving now that large pharma restructuring, priority shifts to late-stage development, and redefinition of early-stage R&D focus are complete. Unfortunately, a decline in grant funding, particularly in the U.S., will have yet-to-be-determined negative consequences.
The post New Translational Models for Drug Development Forge Ahead appeared first on GEN - Genetic Engineering and Biotechnology News.
As genetic-engineering tools mature, vendors are providing additional flexibility for select applications with custom model generation and preclinical services for in-depth characterization.
Another major evolution in the preclinical tools landscape is the growing acknowledgement and acceptance of NAM (non-animal models). The use of NAM is often a first-line testing strategy to confirm or uncover new findings before moving on to the relatively more expensive small animal models. This approach also facilitates adherence to the 3Rs (Replacement, Reduction, and Refinement).
As the NAM industry matures, vendors offering a range of preclinical in vivo tools are learning how to work hand-in-hand to provide exponential value to drug developers. This next-generation biology will likely shape drug development in the next few years, highlighted by the April announcement by the FDA to phase out animal testing requirements for monoclonal antibodies and other drugs.
Pushing the boundaries
According to Sierra Kent, PhD, associate director at The Jackson Laboratory (JAX), JAX pushes the edges of possibilities for humanized mice. A prime example is the NSG-FLT3-IL15 mouse, the world’s most advanced model for cellular humanization with CD34+ human hematopoietic stem cells (HSCs).
This strain carries a knock-out of the mouse Flt3 receptor with transgenes expressing human FLT3 ligand and human IL15. When engrafted with HSCs, the NSG-FLT3-IL15 mouse produces a cellular-diverse human immune system, including development of myeloid cells, mature natural killer (NK) cells, functional dendritic cells, and T cells. JAX provides this strain pre-humanized with HSCs along with preclinical services.
The genetically humanized FcRn mice provide translational pharmacokinetics (PK) and pharmacodynamics (PD) data for antibody-based therapeutics. The Tg32 hALB mouse, lacking the mouse Fc gamma receptor (Fcgrt) and albumin (Alb) while expressing the human counterparts, expands this collection. Tg32 hALB mice are the first of their kind for studying the PK and PD of human albumin therapeutics as well as human IgG and Fc-domain based therapeutics. Preclinical services using these models are available.
This year, JAX expects to make available mouse models with functional human B cells, models for studying autoimmunity, and a variety of pre-characterized human PBMC humanized models.
The over 500-line human iPSC repository also continues to grow at JAX, with engineered iPSC lines carrying disease-relevant mutations associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, ALS, and frontotemporal dementia. In partnership with the iPSC Neurodegenerative Disease Initiative (iNDI), JAX is engineering additional iPSC lines to enable reproducibility studies by introducing the same variants across genetically distinct backgrounds.
“We believe that advanced cellular models, such as iPSC-based platforms, serve as powerful complements to traditional in vivo models,” said Kent. “While some findings are consistent across systems, others uncover unique biology, underscoring that no single model fits all research questions.”
New supply chains and mouse propagation locations fuel a global expansion. JAX Mice® are currently propagated outside of the U.S., in Japan at JAX Japan, in India via ATNT Laboratories, and in multiple European and Asian countries. Soon, production of humanized JAX mice will begin in Australia, eliminating the need to meet current requirements for long quarantine periods.
Enhancing precision and flexibility
Taconic is also responding to the growing demand for scientific accuracy, customization, and immunology-ready platforms by focusing on enhancing precision and flexibility in preclinical research.
The FcResolv® NOG portfolio lack FcyRs, which reduces murine immune cell interactions with antibody-based drugs. In addition, Taconic’s huSelect
A growing number of mouse and rat models is available for the study of Parkinson’s disease through Taconic Biosciences’ fifteen-year partnership with the Michael J. Fox Foundation.
“To provide more effective translational tools in oncology, immuno-oncology, and neurodegenerative research, new offerings will include advanced flow cytometry panels and additional Parkinson’s disease models,” said Mike Garrett, CEO of Taconic Biosciences.
The flow cytometry panels were developed to provide reproducible, high-content immune data in order to streamline study design and support deeper and more standardized immune profiling. The panels are specifically optimized for Taconic’s humanized immune system mice models to characterize key immune cell subsets—including T cells, B cells, NK cells, and myeloid populations—across blood, spleen, and bone marrow.
“Our 15-year partnership with The Michael J. Fox Foundation is making available a growing number of mouse and rat models for the study of Parkinson’s disease,” added Garrett. “New models include the aSyn KI/KO Rat, PINK1KO Rat, and the LRRK2 KO Rat.”
A strategic shift in several integrated services should enhance early-stage drug development. Transgene characterization enables rapid, in-depth validation of gene insertion and expression in custom genetically engineered models, while CRISPR off-target analysis helps detect unintended genome edits.
Tiered Custom Model Generation Solutions complement these tools, offering a variety of advanced model generation services tailored to project timelines, budget, and health standards requirements.
“To support customers, we are also investing in comprehensive phenotypic datasets and partnerships to co-publish preclinical findings and positioning our models to slot seamlessly into tiered workflows integrating AI, animal alternatives, organoids, and animal models,” highlighted Garrett.
Lastly, a new CRO preclinic partnership provides customers with greater access to an end-to-end platform by combining the most relevant animal models, custom model generation, and colony management services with downstream in vivo study capabilities.
Efficient translational options
The demand for more translational and efficient alternatives to traditional animal models shapes model development. “The need for more predictive preclinical research, particularly in immuno-oncology, infectious diseases, and personalized medicine, continues to drive the advancements in humanized models,” said Steve Bronson, DVM, scientific product manager at Charles River Laboratories.
The Charles River models NCG-hIL2 and NCG-hIL15 are built on the NCG background, which lacks functional/mature T, B, and NK cells, and has reduced macrophage and dendritic cell function. NCG-hIL2 expresses the human IL2 cytokine, and NCG-hIL15 expresses the human IL15 cytokine. When engrafted with human HSC, both strains support the growth and development of NK and T cells. NCG-hIL15 further supports the homeostatic expansion and survival of NK cells, allowing for stable, long-term immune cell function.
The humanized portfolio will add two PBMC humanized models, HuPBMC NCG-B2m-KO and HuPBMC NCG-MHC-dKO, to support studies of immune responses, tumor growth, and infectious diseases. In addition, an exclusive, do-it-yourself PBMC Select Humanization kit gives researchers more time to create humanized mice with validated PBMCs from recallable donors per their study timeline.
Bronson added, “More researchers need flexibility in study design with immunodeficient and humanized mice so that they can mimic human immune interactions. By working with these models, researchers can support the 3Rs by lengthening research times and using fewer animals.”
Alternative translational models
Microphysiological systems (MPS) address the critical need for better models to understand diseases, find targets, and triage compounds. These technologies fill gaps where current animal models fail, rather than compete head-to-head with them. “The most urgent use for MPS is to meet needs for the development of new molecular entities such as bi- and tri-specific antibodies, antibody-drug conjugates, CAR T cells, and gene therapies, amongst others,” said Paul Vulto, PhD, CEO of MIMETAS.
MIMETAS’s service offering concentrates on the interplay between cell types as primary drivers for disease processes. Their breakthrough liver model, used for assessing gene therapy and toxicity, as well as for fibrosis and MASH modelling, comprises a perfused vascular plexus from liver sinusoidal endothelial cells, stellate cells, hepatocytes, and immune cells. The self-organizing hepatic tissues are indistinguishable from primary liver slices.
The company’s CAR T testing services for solid tumors follow the activity of CAR T cells from the bloodstream to the tumor. The tumor comprises critical tumor microenvironment elements, including vasculature, stroma, and immune cells.
UniFlow technology has extended the services portfolio by allowing perfusion of vasculature under unidirectional flow conditions. As such, the technology provides more relevant cues while still retaining the throughput of the original OrganoPlate® technology, and is applied to liver and tumor modelling. “Another new service offering is our lung modelling work for studying diseases such as pulmonary fibrosis and toxicity,” said Vulto.
To go further, the new OrganoReady® Colon Organoid plates provide 64 colon tubules based on the HUB organoid technology. “Next in line will be a full launch of our OrganoReady HBMEC plates that allow compound testing on blood-brain barrier transport and toxicity,” said Vulto.
Vulto feels that the smooth continuity of the FDA drug approval process is vital, and if flawed during restructuring, it will threaten the entire industry. The market is currently improving now that large pharma restructuring, priority shifts to late-stage development, and redefinition of early-stage R&D focus are complete. Unfortunately, a decline in grant funding, particularly in the U.S., will have yet-to-be-determined negative consequences.
The post New Translational Models for Drug Development Forge Ahead appeared first on GEN - Genetic Engineering and Biotechnology News.