In a play on the adage “the early bird gets the worm”, Newormics describes how Perlara accelerated the search for a repurposed drug to treat an orphan disease using the microscopic soil worm, C. elegans.
Drug repurposing, once thought to be much less desirable than the development of new molecular entities for disease treatment, has seen the pendulum swing to the other side as recognition of high attrition rates, huge expense, and relatively slow regulatory pace and path to commercialization has taken its toll on the patience of investors and Big Pharma (Pushpakom et al. 2019). Drug repurposing even has its own hashtag now following its popularization in works such as that of David Fajgenbaum’s search for therapies for Castleman’s disease described in detail in his memoir, Chasing My Cure (Fajgenbaum, 2019). Hundreds of journal articles in the last two years (and thousands more in the last fifteen years), show the tremendous effort to find novel treatments using drugs already in the pharmacopeia, especially for rare and orphan diseases, including the establishment of drug repurposing taskforces and collective shared databases (Southall et al., 2019; Fajgenbaum, 2019).
As the Covid-19 pandemic crisis pushes the envelope on all existing medical and clinical research development pathways, there is another mechanism now available to further accelerate drug repurposing efforts: the use of microscopic soil worms as “patient avatars”. The traditional development path takes a drug candidate through testing that begins There in vitro (single isolated cells), transiting through in vivo using vertebrate animals (mice/rodents as well as higher order vertebrates such as rabbits, dogs, and monkeys) on its way to human clinical studies. There has long been recognized a non-trivial gap between what can be learned and translated from simple, fast, inexpensive in vitro methods versus longer, complex, and costly in vivo studies in higher order animals. The approach that Newormics has backed to fill this gap is the use of C. elegans as an in vivo, whole organism model system. C. elegans has been demonstrated as a robust and useful model since its establishment as a model organism in the early 1960s, earning to its investigators 3 Nobel prizes (refs 3-15). The use of C. elegans as whole organism model system, has expanded in recent years with the use of CRISPR technology to produce worms with genetic and phenotypic attributes of interest.
Ethan Perstein’s group at Perlara has not only also embraced the promise of C. elegans for filling this gap, they have now used a CRISPR-modified C. elegans model to fast-track screening of repurposed drug candidates for treatment of a congenital disease of glycosylation, PMM2-CDG. Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation and affects over 1000 patients globally. Deficiency of the enzyme phosphomannomutase 2 (PMM2) caused by loss-of-function mutations in the human PMM2 gene. Classical pediatric clinical presentations include developmental delay, severe encephalopathy with axial hypotonia, abnormal eye movements, psychomotor retardation and cerebellar hypoplasia (Matthijs et al., 1997). As patients reach their teenage years and young adulthood, health challenges include hypogonadism, coagulation abnormalities and thrombotic events, retinitis pigmentosa and peripheral neuropathy (Monin et al., 2014) The prognosis for PMM2-CDG patients is poor and there is currently no FDA-approved treatment that alleviates the symptoms of PMM2-CDG or any targeted therapy that safely increases PMM2 enzyme activity.
The Perlara group has demonstrated the utility of screening candidates in C. elegans for these studies. “In order to identify drug repurposing candidates that boost PMM2 enzyme function, we generated and characterized the first worm patient avatar of PMM2-CDG as an intermediate translational model situated between our previously published yeast models and well-established PMM2-CDG patient fibroblasts” (Iyer et al., 2019).
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