Humanized Models

Genome edited animal models for studying your gene of interest


InVivo Biosystems is a licensed CRISPR/Cas9 gene editing solutions provider. We deliver CRISPR genome edited animal models that allow scientists to study biological processes in simpler contexts without losing the value of in vivo studies.

Using CRISPR and other genome editing methods, we can create genetically engineered animal models for better understanding genetic mutations. Using the power of gene editing, InVivo Biosystems can humanize Zebrafish and C. elegans into powerful animal models for disease biology discovery.

Use the HElio Ortholog Gene Finder to find a usable model for studying your gene of interest.

Disease gene finder: Linking human disease genes and C. elegans genes and their corresponding phenotypes.

Whole Gene Humanization

We have found whole gene humanization can create a platform for highly translatable results in a model organism. The gene humanization method we use replaces the ortholog locus with human cDNA.  The cDNA is sequence-optimized for expression in the animal.

Gene-swap humanization technique.  Ortholog gene is removed from animal (KO) to determine if defective phenotype is present. Ortholog is replaced with human coding sequence to create gene-humanized animal.  Variants are installed in gene-humanized locus create Patient Avatars. Humanized animals in Patient Avatar format are phenotyped for activity defects.

Model Stxbp1a Patient Variants in C. elegans

In this example, the human coding sequence of STXBP1 was able to restore function when inserted as gene replacement of the unc-18 locus. Referenced against a set of known pathogenic and benign variants, we were able to detect pathogenicity in a set of VUS.

Diagnostic curve for VUS assessment. (a) Transgene rescue demonstration by electrophysiology. (b) Transgene rescue demonstration by movement in liquid. (c) Deep phenotyping parameters for movement on solid surface comparis benign (green), pathogenic (red) and VUS (grey). d) diagnostic curve for pathogenicity assessment of VUS where values above harmonic mean indicate possible pathogenicity in the strain.

The video below shows that the human coding sequence of STXBP1 is inserted into the native locus of a C. elegans ortholog gene. The worms version of the gene is replaced with a human coding sequence.
- Left: the gene-swapped STXBP1 sequence functions and shows a significant level of activity.
- Middle: In contrast, the knock-out shows very little activity.
- Right: for the R406H genomic variant, its activity is somewhere in between the “humanized” and “knock-out” strain.

96 point mutations in 1 gene. All 96 mutations were created in the STXBP1 gene (which is associated with epilepsy in humans) via CRISPR. The worm homolog of STXBP1, unc-18, causes uncoordination and near-complete lack of pharyngeal pumping when knocked out. The functionality is restored by replacing the worm gene with the coding sequence for human STXBP1.

Model Stxbp1a Patient Variants in Zebrafish

Illustration of a successful precise point mutation of Stxbp1a in Zebrafish. Stxbp1a is a highly conserved zebrafish ortholog of human STXBP1 (87% identity). Using CRISPR/Cas9 technology, we were able to precisely generate a benign patient mutation at the conserved amino acid residue (CCC>CTG, p.P94L).

Who We Serve

We work with scientists seeking new or alternative ways to approach their research.

  • R&D researchers who need to test their hypotheses before moving to a mammalian system.
  • Pharmaceutical companies who need to quickly understand a compound’s mechanism of action as well as cytotoxic effect, CC50, IC50, SI, and etc.
  • Animal-conscious organizations who need to perform proof-of-concept validation.
  • Researchers studying longevity and senescence who want to eliminate the maintaining and handling of mouse model for months.

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