Tiny Virus, Big Problem

YEARS IN THE MAKING, EBOLA BUBBLES TO THE SURFACE

 

Bubbling under the surface for years like a volcano packing heat, Ebola erupts into a stark reality for the world health community.

First appearing in 1976, Ebola is a classified “Category A” potential bioterrorism agent. With an incubation period of up to 21 days—early symptoms mimick the everyday flu—it’s entirely possible infected individuals board planes, unknowingly carrying the virus around the world. Given the threat, developing vaccines and treatments is an urgent priority.

The World Health Organization (WHO) has confirmed 932 deaths through August 6th—mostly in Liberia, Sierra Leone, and Guineain total over 1,700 cases have been reported. WHO has pledged $100 million to help bring the current outbreak under control.

In this issue, we’ll learn how Ebola causes its destruction and the therapeutics and vaccines in development for the virus.

Tiny virus, big problem

 

Seven proteins, a long single strand of RNA, and a lipid envelope-type membrane make up the intelligent, yet calamitous Ebola virus. How does a handful of proteins and genetic material wreak such havoc? 

By infecting white blood cells called macrophages during an integral part of the immune process; Ebola disrupts the body’s defenses against foreign invaders.

Macrophages normally release signaling molecules to alert and activate other white blood cells to help fight infection. Simply put, Ebola inhibits macrophages from doing their job. The virus stealthily evades the immune system and spreads to the lining of blood vessels before moving to liver and kidney tissue.  Infected endothelial cells, the cells that line blood vessels, become “leaky”, giving rise to the gruesome hemorrhaging characteristic of infection.

MARKET WATCH: EBOLA therapeutics

 

Unlicensed antibody therapy Zmapp takes the path less traveled when used to treat two Ebola patients on US soil.

San Diego based Mapp Biopharmaceuticals (partnering with federal housing and defense research projects in the US) developed Zmapp whilst working on antibody cocktails to fight Ebola. The serum has yet to reach even a basic Phase-I human trial, as is the case with all, but one, potential Ebola therapeutic.  The basic idea behind Zmapp is for its antibodies to “neutralize” Ebola by binding to the virus and therefore prevent it from entering the target cells. Therapeutic antibodies are typically produced in Chinese hamster ovary (CHO) cells, but in an interesting twist Zmapp’s antibodies are produced in tobacco plants.

An RNA interference (RNAi) drug developed by Tekmira Pharmaceuticals (Vancouver, British Columbia) is targeting Ebola by silencing its genes. The drug demonstrated efficacy at controlling the virus in non-human primates and began human safety testing in January 2014. A higher than expected inflammatory response to the drug caused the FDA to impose a clinical hold on the TKM-Ebola Phase I study; Tekmira is currently preparing a Complete Response to the Agency. Tekmira hopes to resume testing by Q4 2014.

Duplicating a drug used to treat other viruses, such as herpes and hepatitis, BioCryst (Durham, North Carolina) is developing an inhibitor to an enzyme Ebola uses to make copies of its genetic material. Since the inhibitor has a chemical structure similar to the building blocks that make up RNA, Ebola unknowingly incorporates these inhibitors into its growing RNA strand. The secret—once incorporated the RNA strand cannot grow any longer—thus stopping Ebola replication. BioCryst’s drug is still in preclinical development.
 

COCKTAIL FODDER

Novartis’ blockbuster leukemia drug, Gleevec, just might have crossover potential as an Ebola drug.  Both Gleevec and the related drug Tasigna inhibit an enzyme called Bcr-Abl that is overactive in certain types of leukemia. Ebola uses a related enzyme, cAbl1, to help its reproduction. Gleevec and Tasigna appear to inhibit viral replication of Ebola-infected cells in the lab via the enzyme pathway.

 

market watch: Ebola vaccines

 

The premise behind vaccines is straightforward: induce an immune response by injecting the patient with a killed or weakened virus—both traditional vaccine preparations.

Ebola may necessitate a different strategy: a DNA vaccine. 

How do DNA vaccines work? Inject a viral gene, that provides the recipe to make a particular viral protein, into a patient so that their own cells manufacture that viral protein. The viral protein is unable to cause disease, but is able to elicit an immune response. That response—making memory B-cells which act as sentries watching out for particular pathogens to appear and then quickly wiping them out.

The advantages of DNA vaccines:

  • They likely induce a more robust immune response.
  • They can protect against multiple viral strains at once.
  • They are much more transport stable than protein or virus-based vaccines, which takes acute importance considering their intended deployment in developing countries; they will be less dependent on refrigeration in order to maintain efficacy.

The development of DNA vaccines has been elusive due to inefficient delivery methods. However, Inovio Pharmaceutical’s (Blue Bell, PA, and San Diego, CA) DNA vaccine program contains promise with some demonstrated efficacy in preclinical mice testing models. Inovio has developed an electroporation-based delivery system: injection of a vaccine into skin or muscle followed up with short, controlled electrical pulses which significantly increases the tissue’s abililty to take up the DNA vaccine. Perhaps this delivery method could be employed for an Ebola DNA vaccine?

GlaxoSmithKline’s recent acquisition of Okairos, a Swiss biotech with a DNA-based Ebola vaccine in its preclinical development portfolio, is also jumping on the Ebola bandwagon.