Animal models are a cornerstone of preclinical research, essential for understanding disease biology and testing potential therapeutics before moving into clinical trials.
Yet many companies and labs either lack animal facilities, face challenges licensing and breeding existing ALS mouse models or do not have in-house expertise to carry out in vivo studies to evaluate their drugs.
How our Animal Models Core is changing ALS research
The Target ALS Animal Models Core addresses these barriers by providing no-strings-attached access to models and data through three mechanisms:
In vivo study support: Funding studies at Target ALS accredited contract research organizations (CROs) for groups without in-house capacity and/or expertise.
Model development and distribution: Supporting the creation and distribution of new mouse models.
Data generation: Producing and integrating multi-omic datasets from animal models into the Target ALS Data Engine.
Available animal models
Target ALS sponsors competitive in vivo target validation grants for in-kind funds to test new potential therapeutics in animal models of ALS/FTD. A competitive funding call is typically held once a year. We are currently not funding the generation of new models, but continue to expand access through licensing and data integration.
Models available for grant application include:
Biospective, a CRO based in Montreal, has established a well-characterized “low dox” model. 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.
It is a model of 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)
Motor neuron degeneration & regional brain atrophy
Neuroinflammation
Brain, spinal cord, and neuromuscular junction (NMJ) 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.
C9 545 KI model is A knock-in model in which the pathogenic G4C2 hexanucleotide repeat expansion is inserted directly into the native mouse C9orf72 locus.
Unlike overexpression or BAC transgenic lines, this approach preserves physiological gene regulation and dosage, enabling more accurate modeling of both gain- and loss-of-function mechanisms implicated in ALS/FTD.
The C9 KI model exhibits hallmark molecular features of C9-related disease, such as RNA foci and dipeptide repeat proteins and pTDP43 accumulation, while providing a genetically stable, translational platform for testing therapeutics that target endogenous C9orf72 expression or repeat-mediated toxicity.
Why our Animal Models Core matters
By pooling resources, licensing models, and generating datasets centrally, our Animal Models Core helps researchers:
Access well-characterized in vivo models without restrictive licensing.
Test potential therapeutics at accredited CROs with Target ALS support.
Leverage integrated multi-omic datasets to connect animal model findings with human biology.
Resources
For additional resources, many animal models of ALS are available for purchase or for in vivo pharmacology studies at The Jackson Laboratory. The Jackson Laboratory has over 138 mouse models for ALS research. These additional ALS mice can be found here.
ALS Mouse Models at The Jackson Laboratory
Below is a list of some of the new and most commonly used ALS models at the Jackson Laboratory:
These mice express a G93A mutant form of human SOD1 in a mixed background of C57BL/6J and SJL/J. Hemizygotes become paralyzed in one or more limbs with paralysis due to loss of motor neurons from the spinal cord. These mice have a slightly shorter survival compared to the B6 background, with a mean survival of 160 days.
These mice express a G93A mutant form of human SOD1 in a C57BL/6J congenic background. Hemizygotes become paralyzed in one or more limbs with paralysis due to loss of motor neurons from the spinal cord. Motor neuron degeneration has been associated with the function and/or degeneration of astrocytes. These mice have a slightly longer survival compared to the B6SJL background, with a mean survival of 120 days.
These mice have the mouse Thy1 promoter driving expression of the human TAR DNA binding protein (TARDBP or TDP-43) gene in neurons throughout the central nervous system. Homozygous mice display an aggressive disease progression and survive an average of 28 days.
These mice have expression of a myc-tagged, human TAR DNA binding protein carrying the ALS-linked Q331K mutation (huTDP-43*Q331K) directed to the brain and spinal cord by the mouse prion protein promoter. Homozygous mice display deficits in CMAP, rotarod and grip strength detectable by 3 months of age with no progression of phenotypes after 6 months of age.
This regulatable NLS (rNLS8) double transgenic line recapitulates cytoplasmic TDP-43 pathology reminiscent of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in brain and spinal cord, accompanied by a progressive neurodegenerative ALS-like phenotype. The phenotype is controllable/reversible by the tetracycline analog, doxycycline (dox).
These mice possess loxP sites flanking exon 3 of the Tardbp gene. When bred to mice that express Cre recombinase, resulting offspring will have exon 3 deleted in the cre-expressing tissues. Ubiquitously deletion of Tardbp results in death of animals ~ 12 days after depletion and is often paired with neuronal and tissue specific core lines.
These mice carry a single BAC insertion carrying the human C9orf72 gene with ~500 hexanucleotide repeats. Hemizygous mice exhibit dinucleotide repeat pathology, with polyGP detected in the brain and spinal cord, long with RNA foci.
These mice have a 3,261 bp human STMN2 gene sequence (containing a modified human-specific exon 2a sequence with ~1500 nt flanking DNA on each side) inserted into intron 1 of the mouse Stmn2 locus. The STMN2 sequence is modified to include the human MS2 stem-loop sequence and replace the TDP43 binding element. The resulting allele renders STMN2 in a cryptically spliced state. This line may be useful in the application of splice correcting therapeutics. This allele also exists on a FVB; B6 genetic background to improve viability.
These mice have a CRISPR/Cas9 generated mutant of the stathmin-like 2 (Stmn2) gene carrying 394 nt of human STMN2 intron 1 replacing 479 nt of murine Stmn2 intron 1. The effect of this substitution is to introduce a functional exon 2a present in human but absent in mouse into the mouse genome as exon 2a utilization is predicted to be TDP43 protein dependent.
The Jackson Laboratory does not distribute double transgenic mice. Instead, the individual transgenic lines can be purchased live
