Figure 5. 15 disease genes of broad impact. A representative set of human disease genes were selected for use in the construction of RediMODEL kits containing gene specific KOs, KIs and clinical variants (CV). * indicates null of C. elegans ortholog that are non-viable.
Disease types. The 15 disease genes of Figure 5 range in human relevance. Disease fields such as cancer, neurology, cardiology, and early aging are well represented. It has become clear that a given disease gene will have multiple associations to various disease types.18 The average disease type association for the 15 disease genes are 345 diseases/gene. As a result, the RediMODEL kits are expected to have a broad impact across a variety of NIH agencies, such as cancer (NCI), cardiomyopathies (NHLBI, NINDS) aging (NIA), psychiatric (NIAAA, NIDA, NIMH, NINDS), muscular degeneration (NIAMS), metabolic disorders (NIDDK), toxicity (NIEHS), and other disease (NIGMS).
Rare Disease. A focus on the discovery of pathogenic variants in disease genes inherently addresses a form of personalized medicine for diseases that are rare. Therapeutics developed to restore normal function (ie. CRISPR/Cas9 or antisense DNA) are therapies that serve a rare disease population when prevalence threshold does not exceed 200,000 persons.19 The variants in disease genes contribute to the expanding number of rare diseases, which, under the European system, are now approaching 20,000 disease categories.20 Therapeutics developed on rare disease genes are eligible at the FDA for expedited development activities via the Orphan Drug Act.21 The speed of animal model development in C. elegans, and its ease-of-use brings to many researchers an affordable platform for fast phenotyping of rare disease alleles.
Competing technologies. Various technologies ranging from bacterial-yeast expression systems to mammalian animal models are used to gain insight into the pathological effects of clinical variants. For instance, expressing disease genes in bacteria is a classic way to detect pathological phenotypes when the disease gene is an enzyme whose catalytic capacity can be measured.22 Yet, for disease genes with complex interaction phenotype, expression in bacteria removes the gene from native context and prevents the full exploration of the pathological profile of a genetic variant. A mouse or rat animal model is the “gold standard” for finding clear phenotypes from a clinical variant, yet the cost and amount of time spent are high, and results can be challenging to interpret from a drug development standpoint.23 Disease modeling with Induced Pluripotent Stem Cells (iPSC) offers an exciting platform to study clinical variants,24 but the removal of the cells from their native context of the intact animal regrettably removes the important effect of a tissue-based environment. 3D cell culturing techniques and organs-on-a-chip can be useful in restoring proper microenvironment context,25 but the ease of use for routine analysis clinical variant phenotypes has yet to evolve.
Simple Model Organisms
. The depth of genetic understanding in Drosophila and C. elegans
have made these model organisms powerful surrogates to deploy in clinical variant understanding and drug discovery. For instance, insertion of human p53 in replacement of the Drosophila homolog was recently done for a variety of clinical variants of the TP53 gene.26
Foci defect phenotypes were observed that were consistent with similar defects in pathogenic p53 cancer tissues. In C. elegans
, similar humanization of the dopamine transporter (DAT) was performed.27
The authors demonstrate two pathogenic alleles of DAT (399delG and 941C>T) gave significant defect phenotypes. The 399delG, which is known to be more pathogenic in humans, also gave a more significant LOF phenotype, when inserted as a homolog replacement into the C. elegans
genome. These results demonstrate the humanization of small animal models can be used as a powerful system for detecting pathogenic phenotypes in the clinically-relevant SNPs that are associated with human disease.
RediMODEL kits bring the power of a simple model organism into the hands of researchers worldwide. With hundreds planned, soon a RediMODEL kit will be available for your favorite gene. Explore the current RediMODEL kits at the following link.
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