The discovery of a unique, inheritable resistance to Ebola infection has inspired the development of therapeutics that may not only be effective against Ebola but against COVID-19, as well.
While the introduction and spread of deadly viruses is a recurrent industry topic that remains under the constant surveillance of expert medical researchers and administrative bodies worldwide, the COVID-19 pandemic is still certainly a once-in-a-lifetime experience.
No reasonably compassionate human would hold anyone in harsh regard for momentarily forgetting the viral epidemics of the relatively recent past, such as the bird flu or the swine flu.
However, the Ebola scare of 2016 is certain to ring a few bells. While short-lived, the swiftly contained outbreak remains a staple reference in modern pop culture memory because of the exotic and lethal nature of the disease. Now, interest is beginning to resurface thanks to the discovery of a unique, inheritable resistance to Ebola infection and the subsequently inspired development of therapeutics that may not only be effective against Ebola, but against COVID-19, as well.
The anomalous gene in question contains the erroneous blueprints for a protein found in the membranes of endosomes and lysosomes called Neimann-Pick type 1 C1, or NPC1. While some of the finer details are still limited, researchers do know that NPC1 is involved in the transport of cholesterol and glycosphingolipids. A patient in possession of two mutated copies of the NPC1 gene will develop a lysosomal storage disorder, but the expression of the disease itself is so varied that it may prove lethal before they reach their first birthday, or go undiscovered for decades.
Additionally, researchers know that the Ebola virus is dependent on the courier activity of the NPC1 protein in order to pass through the endosomal membrane and induct the infective cycle. Animal cell and HeLa cell models that were either heterozygous for the mutation, or in which the gene was knocked down or missing altogether, have NPC1 proteins that were less likely to bind to the glycoproteins on the viral surface, and therefore, more resistant to Ebola infection.
The search for a pharmacological means of targeting and exploiting this particularly weak link in Ebola’s chain of infection caused researchers to look for other viral diseases whose infection could be curbed by preempting molecular dialogue between the NPC1 protein and the viral surface. Further exploration revealed the NPC1 protein as an advantageous chink in the armor of several viruses that span across multiple taxonomic classes, including HIV, Hepatitis C, the ZIKA virus and most notably, COVID-19.
Over the past two years, researchers have been piecing together the various cellular mechanisms employed by the SARS-CoV-2 virus, and their results strongly implicate NPC1 as one such stepping stone to viral proliferation. Unlike the Ebola virus, though, SARS-CoV-2 appears to interact with NPC1 via nucleotide-binding proteins that are usually busy keeping the viral RNA in stable, nucleocapsid form. While the exact purpose of this interference is still unclear, further interactions between other viral proteins and additional protein facets of the late endosome suggest that this infection strategy may be as reliant on NPC1 as those used by Ebola and other coronaviruses.
Among the compounds shown to have a moderate-to-high degree of effectiveness in various exploratory studies are imipramine (Tofranil), an antidepressant and occasional treatment for childhood enuresis, as well as cepharanthine and its analogues, an anti-inflammatory compound derived from the tubers of the southeast-Asian plant Stephania cephalantha. While no novel pharmaceuticals or new applications have been examined by clinical trial yet, the development of NPC1-targeting therapeutics seems to only be a matter of time.
Overgrown Bones Lead to Osteoporosis Preventative
If you’ve ever wondered why a reanimated skeleton is supposed to be scary, then you’ve probably forgotten that your bones are alive. They change so slowly that you would only notice over the course of a decade how your skeleton has completely remodeled itself.
This considerate adaptation allows your skeletal structure to reinforce areas of high stress and reallocate resources from areas that need less support–under normal circumstances, that is. Disruption of this balance can result in conditions like excess bone growth and osteoporosis.
But located on the eleventh chromosome, there’s one gene capable of disrupting the balance: LRP5, which contains the details for drafting LDL receptor-related protein 5. When constructed properly, this protein is known to interact with another protein called sclerostin, which has been implicated in the process of bone degradation.
Minor changes to this protein associated with decreased sclerostin interaction are linked to increased bone density without necessarily causing bone overgrowth, making it a prime pharmaceutical target for the treatment of bone diseases like osteoporosis that are caused by a deficiency of bone tissue.
The biggest name in the game so far has been Amgen, with its anti-sclerostin monoclonal antibody therapy, romosozumab (Evenity). Presenting data and study results on the potential of romosozumab to the American Society of Bone and Mineral Research as early as 2013, Amgen and UCB worked tirelessly to develop this treatment and get it into the hands of patients. Then in 2019, the U.S. Food and Drug Administration (FDA) approved EVENITY as a treatment for postmenopausal women with a high risk of bone fractures due to osteoporosis.
More recent, however, is the development of another anti-sclerostin monoclonal antibody by the clinical-stage biopharmaceutical company Transcenta Holding Ltd. Currently using the moniker ‘TST002’, its drug blosozumab is proposed to encourage the rebuilding of bones while simultaneously discouraging their degradation.
While Phase II clinical studies were completed by Eli Lilly in the U.S. and Japan, Transcenta in-licensed the new therapy for development and approval in China.
“Osteoporosis poses a significant burden to China’s health system due to the increasingly growing aging population,” projected Trancenta Head of Global R&D, EVP and CMO Dr. Michael Shi in a press release. The announcement came in September of last year and addressed the reception of an Investigational New Drug clearance from the National Medical Products Administration of China.
Indeed, as the population growth rates of countries across the world begin to mark a notable decline, treatments and maintenance therapies that address age-related conditions like osteoporosis will only become increasingly more relevant.
