TDP-43 Mouse Model of Amyotrophic Lateral Sclerosis (ALS)

Q: Has disease-modification been shown in the TDP43 transgenic model?

Yes. Here is a nice example of a small molecule resulting in disease modification in this TDP43 mouse model: Young, P.R., DeDuck, K., Bedell, B.J. AIT-101 improves functional deficits in a human TDP-43 animal model of ALS. 22nd Annual Meeting of the Northeast ALS Consortium, 2023; doi:10.1002/mus.27969.

Q: What is a "nuclear localization signal"?

A nuclear localization signal (NLS) is typically a short peptide which facilitates the transport of a protein from the cytoplasm into the nucleus of a cell. A review can be found at doi:10.1186/s12964-021-00741-y.

Q: Are phosphorylated TDP43 aggregates seen in the TDP43 mice?

Yes. We have developed excellent immunohistochemistry (IHC) and immunofluorescence (IF) protocols that nicely demonstrate "punctate" p-TDP-43 (p409/410) aggregates in the cytoplasm of neurons without nuclear TDP-43 staining.

Q: What types of therapeutic agents has Biospective evaluated in this TDP43 transgenic model?

We tested a wide range of therapeutic agents, including antibodies, gene therapy, small molecules, antisense oligonucleotides, and peptides using a variety of different routes of administration in this TDP43 model.

Q: Can Biospective perform oral dosing in the TDP43 transgenic ALS model?

Yes. We routinely perform oral gavage of pharmacological agents in this TDP43 mouse model. We can also deliver via food or drinking water.

Q: How long are Biospective's studies involving the "Low Dox" mouse model of ALS?

Typical in-life study durations range from 3-12 weeks. We can work with you to define the optimal duration to assess disease progression and therapeutic effects based on your particular therapeutic agent.

Q: Are mice readily available for studies?

Yes. As a Preclinical Neuroscience CRO, we maintain a well-established breeding colony of the TDP43 ALS mice so that they are readily available for studies. We would be happy to discuss study timelines with you.

Our TDP-43 (TDP43; TARDBP) transgenic mice have cytoplasmic aggregates, motor dysfunction, neurodegeneration, neuroinflammation, and neuromuscular denervation.

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TDP-43 Model Overview

Cytoplasmic TDP-43 (or TDP43) aggregates are a hallmark of familial and sporadic ALS. While several transgenic (tg) mouse models of amyotrophic lateral sclerosis (ALS; also called motor neuron disease [MND]) with TDP-43 aggregation exist, they each have their respective strengths and weaknesses. Learn more about animal models of ALS in our Resource - ALS Mouse Models for Drug Development.

At Biospective, we use both the original and modified versions of the rNLS8 (or ΔNLS; delta NLS; dNLS) ALS mouse model of TDP-43 proteinopathy ("TDP-43 models"):

Original mouse model ("Off Dox"): rapidly progressing (weeks)
Biospective mouse model ("Low Dox"): slower progressing (months)

Significant advantages of these TDP-43 models for ALS researchers include:

Mislocalization of TDP-43 to the cytoplasm
Progressive motor deficits
Motor neuron degeneration & regional brain atrophy
Neuroinflammation
Brain, spinal cord, and neuromuscular junction pathology

The model time course is predictable and the measures of disease progression are highly reproducible, making it an excellent model for the evaluation of therapeutic agents in preclinical studies. Learn more in our Resource - TDP-43 ΔNLS (rNLS8) Mice for Drug Development.

TDP-43 Mice Generation

rNLS8 (NEFH-hTDP-43-ΔNLS) double transgenic ALS mice ("TDP43 mouse model") are generated by breeding mice having the NEFH-tTA transgene with mice having the tetO-hTDP-43-ΔNLS transgene. This TARDBP model was originally developed and reported by Walker et al. (Acta. Neuropathol., 130: 643-670, 2015). It is a model of amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND). It can also be used as a TDP-43 pathology model of frontotemporal dementia (FTD) or frontotemporal lobar degeneration (FTLD).

These TDP-43 transgenic mice are maintained on a Dox diet during breeding and the initial aging period (typically 5 to 12 weeks-of-age). The mice are then changed from a Dox diet to a standard diet ("Off Dox" model) or an alternate protocol developed by Biospective ("Low Dox" model) to allow for human TDP-43 expression. An interesting feature of this model is that pathologic and functional recovery can be achieved by putting mice back on a Dox diet.

Our Validated TDP-43 Transgenic Mice Measures

Body weight
Motor scoring (hindlimb clasping, tremor, grill agility, paralysis)
Grip strength test
In vivo muscle electrophysiology, including Compound Muscle Action Potential (CMAP) (see ALS Mouse Models & Spinal Motor Neurons)
Muscle atrophy measured by longitudinal, in vivo computerized tomography (CT) (see TDP-43 ΔNLS (rNLS8) Mice for ALS Drug Development)
Neurofilament light chain measures in plasma & CSF
MRI brain atrophy to measure neurodegeneration (Read More in our Presentation - Brain Atrophy Analysis in Mouse Models of Neurodegeneration)
Immunohistochemistry & multiplex immunofluorescence

Change in body weight from baseline for control (On Dox), Off Dox, and Low Dox mice. The control mice gain weight while the Off Dox mice rapidly lose weight over several weeks. The Low Dox mice exhibit a slower disease course compared to Off Dox mice. A key feature of this model is the disease-modification (or "reversibility") that can be realized by putting mice back on a high-dose doxycycline diet. The black line shows the gain in weight for mice that were Off Dox for 3 weeks and then put back on a high-dose doxycycline diet for 3 weeks.

Learn more about our characterization of this model, our validated measures, and our Preclinical Neuroscience CRO services.

FAQs

Has disease-modification been shown in the TDP43 transgenic model?

What is a "nuclear localization signal"?

What is the advantage of Biospective's "Low Dox" mouse model over the conventional model?

The standard rNLS8 (or delta NLS; ΔNLS; dNLS) mouse model is a rapidly progressing model of ALS (also known as motor neuron disease; MND). While this model is very useful, we have found that most of our Sponsors want a less severe, slower progressing model to increase the opportunity to observe a drug effect. The Low Dox TDP-43 mice show a similar phenotype to the standard model, including neurodegeneration, but evolves over a longer period of time.

Are phosphorylated TDP43 aggregates seen in the TDP43 mice?

What types of therapeutic agents has Biospective evaluated in this TDP43 transgenic model?

Can Biospective perform oral dosing in the TDP43 transgenic ALS model?

How long are Biospective's studies involving the "Low Dox" mouse model of ALS?

Are mice readily available for studies?

TDP-43 Mouse Model of Amyotrophic Lateral Sclerosis (ALS)

Our TDP-43 (TDP43; TARDBP) transgenic mice have cytoplasmic aggregates, motor dysfunction, neurodegeneration, neuroinflammation, and neuromuscular denervation.

TDP-43 Model Overview

TDP-43 Mice Generation

Our Validated TDP-43 Transgenic Mice Measures

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