Our Approach

Rare disease mouse model development pipeline

Generating precise genetic mutation in mice is a critical step in preclinical drug development. New technologies in genome editing have allowed for the introduction of patient mutations more efficiently than ever before. The Jackson Laboratory works to understand the patient, the disease and the potential therapeutic strategies that can be applied.

Phenotyping: Our wide array of preclinical diagnostic and disease evaluative platforms provide a comprehensive suite of tests to determine which of the clinically relevant disease presentations are common for both the mice and the patients. These outcome measures are used to determine efficacy in the preclinical models.

Preclinical Therapeutics: A number of disease modifying strategies, such as Antisense Oligonucleotides Therapies and Gene Therapy have successfully found their way to the clinic and achieved FDA approval. Other strategies for addressing the urgency of rare diseases include testing of existing FDA approved drugs. Personalized therapies and small individual drug trials are starting to gain momentum. At JAX, we have the ability not only to generate the mouse models but to test new therapeutics in a variety of dosing routes to determine potential efficacy and inform clinical trials.

The addition of CRISPR/Cas9 technologies has dramatically impacted the abilities of researchers around the world to specifically target specific nucleotides within any gene in the genome and introduce specific mutations matching those found in the clinical patients. Although the technology remains relatively new, it is subject to continual improvements to on-target genetic changes verses unwanted random insertion/deletion of nucleotides around the target region and potential off-target mutagenesis elsewhere in the genome. The Jackson Laboratory has embraced this new technology and has generated over 250 new mouse mutant models to date including models with clinical mutations and other conditional expression based model systems to study the biology of the gene and its relative importance in different tissues of the body. The ability of the Jackson Laboratory to distribute these new models worldwide to researchers has produced a new generation of scientists working on diseases and therapies that would be been unattainable for all, except a select few well-funded Scientists, just a few short years ago. Challenges remain. Many models generated in individual laboratories are not distributed widely to the community because of institutional restrictions limiting availability to for-profit pharmaceutical companies or because the originating laboratory wish to conclude ongoing studies. The mission of the Jackson Laboratory is to make these models available for public distribution in the absence of restrictive agreements as soon as practicable, once standardized validation studies have been completed.

Our generalized pipeline for targeted mutagenesis is illustrated below. Animal models, once generated, are screened for effects on the mutation on protein expression or mRNA abundance to help validate the model generated. Breeding metrics, captured during strain development, help guide the ideal breeding strategy with which to maintain the mouse strain. Some models are moved into the in vivo pharmacology area where Rare and Orphan Disease researchers perform a more comprehensive series of tests that are optimized for the model being evaluated. The primary aim of these studies are to determine the efficacy of the mouse model for the clinical disease. Where a strong correlation exists, additional in vivo therapeutic studies can be performed to optimize delivery and dosage of the therapeutic and to determine behavioral outcomes. Models are rapidly moved into the Jackson Laboratory Repository were they are made available for distribution. These activities are supported by the many core services in the laboratory. Those in Yellow are used most heavily but collectively these services provide an ad hoc collection of capabilities with which to perform studies.

We have generated mouse models with clinical knock-in (KI) mutations in the mouse as a preclinical research tool. Other models generated have differing uses; these include conditional KO mice (cKO), loss of exons or small insertions or deletions that cause frameshift mutations in protein translation and generate loss of function (null) mouse mutants. Our transgenic pipeline can place human or mouse cDNAs under the regulation of ubiquitous expressed promoters or regulated promoter systems such as TetO or LoxStopLox (LSL) regulation. Transgene can be expressed via random insertion into the genome or more directed single copy integration into safe harbor sites in the genome such as Rosa26. The transgene itself can be a wild-type copy or carrying a specific engineered mutation. Together these models collectively provide a valuable resource from which to characterize normal and mutant gene function and to pilot critical gene therapy approaches such as using AAV9 virus modified to express a normal copy of the defective gene.