Evaluate MAPT-Targeted Drugs with Humanized Tau Models
Article Preview-Cyagen Introduces Humanized Tau Mouse Models for Alzheimer's Research:
Alzheimer’s disease (AD) drug development continues to face challenges in 2024, with recent failures highlighting the need for new approaches targeting Tau protein. Cyagen’s proprietary humanized Tau mouse models (e.g., B6-htau, B6-htau*P301L/P301S) provide tools for studying AD mechanisms and testing therapies, including siRNA and gene editing. These models express human MAPT genes with disease-relevant mutations, enabling breakthroughs in drug discovery. Cyagen also offers comprehensive neurodegenerative CRO services. Explore our advanced platforms for AD and other CNS diseases.
Challenges in Alzheimer’s Drug Development
In 2024, Alzheimer’s disease (AD) drug development remains highly challenging. At the beginning of the year, Roche returned two antibody drugs to AC Immune due to poor clinical results for therapeutic intervention of AD.[1] Biogen also stopped the development and commercialization of the Aβ monoclonal antibody Aduhelm, shifting its focus to Tau-targeting antisense oligonucleotide (ASO) and small molecule therapies.[2] Recently, Genentech abandoned the Tau antibody drug Bepranemab, developed by UCB, and pivoted to a collaboration with Sangamo Therapeutics to explore gene therapies targeting the Tau protein-encoding gene MAPT.[3]
Despite Eli Lilly’s approval of Donanemab, an Aβ antibody therapy, its high cost and limited efficacy excluded it from coverage by the UK’s National Health Service (NHS), hindering widespread commercialization.[4] Additionally, companies like AbbVie and Johnson & Johnson have also stopped certain AD research projects.[5-6] These challenges highlight the need for innovative therapeutic approaches for AD drug development, particularly in areas such as transferrin receptor (TFRC) antibody conjugates to cross the blood-brain barrier, Tau protein targeting, as well as small RNA and gene editing therapies.
1. Pathogenic Hypotheses of Alzheimer’s Disease
Alzheimer’s disease (AD) is a common neurodegenerative disorder and a leading cause of dementia, affecting over 55 million people worldwide and incurring an annual economic burden nearing $1 trillion.[8] Symptoms of AD include memory loss, cognitive decline, and behavioral changes, significantly impacting both patients and their caregivers. With the aging population, the incidence of AD continues to rise, and the global number of AD patients is projected to reach 140 million by 2050.[9]
Therapeutic Approaches to Alzheimer’s Disease
Current approved treatments for AD are limited, mainly consisting of cholinesterase inhibitors and NMDA receptor antagonists, which only provide short-term cognitive symptom relief and cannot halt disease progression.[10] Although the exact mechanisms of AD pathogenesis remain unclear, there are several leading hypotheses, such as the amyloid-beta (Aβ) cascade, Tau hypothesis, and cholinergic hypothesis. Additionally, there are a number of likely contributors to the etiology of AD, including disturbances in metal ions, neuroinflammation, compromised blood-brain barrier (BBB), infectious agents, immune system dysfunction, and mitochondrial dysfunction. [11]
2. Role of Tau Protein in Pathogenesis of Alzheimer’s Disease
The Tau hypothesis suggests that Tau, a microtubule-associated protein, plays a critical role in the progression of Alzheimer’s disease (AD). Under normal conditions, Tau stabilizes the microtubule structure within neurons, but in patients with AD, Tau becomes hyperphosphorylated and forms insoluble neurofibrillary tangles (NFTs) that compromise the integrity of the cell structure, disrupting cellular processes and accelerating neurodegenerative damage. These NFTs gradually accumulate, obstructing intracellular transport and signal transduction, ultimately leading to neuronal dysfunction and cell death. Tau pathology is widespread in AD, with NFTs considered one of the hallmark features of the disease.[12-13] Tau also interacts with amyloid-beta (Aβ) protein, exacerbating neurodegeneration. Tau dysfunction is also implicated in other neurodegenerative diseases collectively known as "Tauopathies," including frontotemporal dementia (FTD) and progressive supranuclear palsy.
Tau-Targeted Therapeutic Strategies for Neurodegenerative Diseases
Current therapeutic strategies targeting Tau include inhibiting Tau hyperphosphorylation, preventing Tau aggregation, and promoting Tau clearance.[11, 14] Several Tau-targeted therapies are currently in clinical development that could potentially delay disease progression in AD and other Tauopathies, if successful.
3. Cyagen’s Humanized Tau Mouse Models
To advance research on Alzheimer’s disease and Tauopathies, Cyagen has developed multiple humanized mouse models that express the human Tau protein-encoding gene, MAPT, and its 3' UTR in situ.
Key Tau Mouse Models include:
- B6-htau Mouse (Product Code: C001410): Expresses wild-type human MAPT and Tau protein.
- B6-htau*P301L Mouse (Product Code: I001181): Carries the P301L pathogenic mutation.
- B6-htau*P301S Mouse (Product Code: I001182): Carries the P301S pathogenic mutation.
- B6-hTFRC Mouse (Product Code: I001189): In situ humanized transferrin receptor (hTFRC), enabling BBB-related research and development (R&D).
- B6-hTFRC/htau Mouse (Product Code: I001209): Combines TFRC and MAPT humanization, enabling R&D of Tau-targeted drugs that can cross the BBB.
Applications
These humanized Tau models are tailored for:
- Studying Tau’s role in AD and Tauopathy pathogenesis.
- Evaluating small RNAs, gene-editing therapies, antibodies, and small molecules targeting MAPT or Tau protein.
Model Validation
- Expression of Human MAPT Gene: Quantitative RT-PCR confirmed significant human MAPT expression with no endogenous mouse Mapt detected.
- Human Tau Protein Isoforms: Western blot analysis demonstrated multiple human Tau isoforms in the brains of B6-htau mice.
- siRNA Efficacy: Targeted siRNAs significantly reduced human MAPT mRNA levels in the hippocampus and cortex of B6-htau mice.
Below are the detailed phenotype data validating these models.
1. Humanized Tau Models Successfully Express The Human MAPT Gene
RT-qPCR analysis of the expression of the human MAPT gene in the mice showed that significant expression of the human MAPT gene was detected in the B6-htau, B6-htau*P301L, and B6-htau*P301S mice. Additionally, the expression of the endogenous mouse Mapt gene was not detected in these models, confirming successful expression of the human MAPT gene.
2. Humanized Tau Mice Express Multiple Isoforms Of The Human Tau Protein
Western blot analysis using human-specific Tau protein antibodies detected the expression of human Tau protein in the B6-htau mouse brains. The results showed that the B6-htau mice successfully expressed human Tau protein, and multiple distinct human Tau protein isoforms were detectable.
3. Efficacy Evaluation of Human MAPT-targeting Small Interfering RNA (siRNA)
After treatment with two human MAPT-targeting siRNAs (AD-1637701 and Conjugate 31), the expression levels of human MAPT mRNA in the hippocampus and cerebral cortex of B6-htau mice were significantly reduced.
Summary
Cyagen has developed several in situ humanized mouse models to advance neurodegenerative research of AD and tauopathies. The B6-htau mouse (Catalog number: C001410), B6-htau*P301L mouse (Catalog number: I001181), B6-htau*P301S mouse (Catalog number: I001182), B6-hTFRC mouse (Catalog number: I001189), and B6-hTFRC/htau mouse (Catalog number: I001209) are humanized mouse models developed by Cyagen specifically for Alzheimer’s disease (AD) research.
The B6-htau mouse successfully expresses the human MAPT gene without expressing the endogenous mouse Mapt gene, and generates multiple human Tau protein isoforms. This model has been successfully used for testing human MAPT-targeting small interfering RNA (siRNA) therapies.
The B6-htau*P301L and B6-htau*P301S mice successfully express human MAPT and respectively carry the pathogenic mutations P301L and P301S in the MAPT gene. These models not only express the full human MAPT gene but also retain the complete splicing patterns of the human MAPT Pre-mRNA, generating various Tau protein isoforms. They are suitable for studying the critical role of Tau protein in the pathogenesis of AD and for evaluating the efficacy of therapies targeting the MAPT gene or Tau protein, including small nucleic acids, gene editing, antibodies, and small molecule treatments.
Cyagen offers comprehensive custom genetically modified mouse models for neurodegenerative diseases, as well as target-humanized and full-genome humanized models, to meet the needs of researchers in various disease studies and therapeutic development. Go beyond custom animal modeling with our specialized neuroscience CRO platform services, including behavioral analysis and drug efficacy evaluations for preclinical R&D.
Discover how Cyagen’s cutting-edge models can support your research goals in Alzheimer’s disease and beyond. Contact Us Today for More Information!
| Product Number | Product | Strain Background | Application |
|---|---|---|---|
| C001427 | B6-hSNCA | C57BL/6N | Parkinson's disease |
| C001504 | B6-hSMN2(SMA) | C57BL/6N | Spinal muscular atrophy (SMA) |
| C001518 | DMD-Q995* | C57BL/6J | Duchenne muscular dystrophy (DMD) |
| C001410 | B6-htau | C57BL/6J | Frontotemporal dementia, Alzheimer's disease, and other neurodegenerative diseases |
| C001437 | B6-hIGHMBP2 | C57BL/6N | Spinal muscular atrophy with respiratory distress type 1 and Charcot-Marie-Tooth disease type 2S |
| C001418 | B6-hTARDBP | C57BL/6J | Amyotrophic lateral sclerosis, frontotemporal dementia, and other neurodegenerative diseases |
| C001398 | B6-hATXN3 | C57BL/6N | Spinocerebellar ataxia type 3 |
| I001128 | B6-hMECP2 | C57BL/6N | Rett syndrome |
| I001124 | B6-hLMNA | C57BL/6N | Progeria syndrome |
| CG0015 | 6-OHDA Rats | - | Parkinson's disease (PD) |
| CG0016 | CUMS Model | C57BL/6JCya | Depression |
References
[1]Roche’s Genentech returns Alzheimer’s assets to AC Immune, cutting 18-year tie. (2024, November 1). Retrieved from https://www.fiercebiotech.com/biotech/roches-genentech-returns-alzheimers-assets-ac-immune-cutting-18-year-tie-biotech
[2]Biogen to Realign Resources for Alzheimer's Disease Franchise. (2024, November 1). Retrieved from https://investors.biogen.com/news-releases/news-release-details/biogen-realign-resources-alzheimers-disease-franchise
[3]Sangamo Therapeutics Announces Global Epigenetic Regulation and Capsid Delivery License Agreement with Genentech to Develop Novel Genomic Medicines for Neurodegenerative Diseases. (2024, November 1). Retrieved from https://investor.sangamo.com/news-releases/news-release-details/sangamo-therapeutics-announces-global-epigenetic-regulation-and
[4]Approval Alert: Eli Lilly’s Kisunla™ (Donanemab-azbt) UK Approved but Not Reimbursed. (2024, November 1). Retrieved from https://www.pearceip.law/2024/10/23/approval-alert-eli-lillys-kisunla-donanemab-azbt-uk-approved-but-not-reimbursed/
[5]AbbVie axes mid-stage Alzheimer’s program amid evolving landscape. (2024, November 1). Retrieved from https://www.fiercebiotech.com/biotech/abbvie-axes-mid-stage-alzheimers-program-amid-evolving-landscape
[6]J&J jettisons several programs, ending seltorexant work for Alzheimer's. (2024, November 1). Retrieved from https://www.fiercebiotech.com/biotech/jj-jettisons-several-programs-ending-seltorexant-work-alzheimers
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[8]Behrman S, Chouliaras L, Ebmeier KP. Considering the senses in the diagnosis and management of dementia. Maturitas. 2014 Apr;77(4):305-10.
[9]2023 Alzheimer's disease facts and figures. Alzheimers Dement. 2023 Apr;19(4):1598-1695.
[10]Liu E, Zhang Y, Wang JZ. Updates in Alzheimer's disease: from basic research to diagnosis and therapies. Transl Neurodegener. 2024 Sep 4;13(1):45.
[11]Abuelezz NZ, Nasr FE, AbdulKader MA, Bassiouny AR, Zaky A. MicroRNAs as Potential Orchestrators of Alzheimer's Disease-Related Pathologies: Insights on Current Status and Future Possibilities. Front Aging Neurosci. 2021 Oct 12;13:743573.
[12]Chen Y, Yu Y. Tau and neuroinflammation in Alzheimer's disease: interplay mechanisms and clinical translation. J Neuroinflammation. 2023 Jul 14;20(1):165.
[13]Yang J, Zhi W, Wang L. Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review. Molecules. 2024 Jun 13;29(12):2812.
[14]Congdon EE, Ji C, Tetlow AM, Jiang Y, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease: current status and future directions. Nat Rev Neurol. 2023 Dec;19(12):715-736.
[15]Frost B. Alzheimer's disease and related tauopathies: disorders of disrupted neuronal identity. Trends Neurosci. 2023 Oct;46(10):797-813.
