Battling Zika: A Biotechnological Approach

By Glenn Petrie, Ph.D.
Senior Scientific Advisor
ABC Laboratories

www.abclabs.com

Zika is a disease caused by the Zika virus which is spread to humans primarily through the bite of an infected Aedes species mosquito. The disease can also be by transmitted through sex with an infected partner. The symptoms of Zika are fever, rash, joint pain, and conjunctivitis. The illness is usually mild with symptoms lasting for several days to a week and rarely requires hospitalization. There is no vaccine or specific treatment for Zika virus infection. Treatment is symptomatic and supportive, including rest and the use of acetaminophen to relieve fever.

Federal health officials recently confirmed that the Zika virus causes a rare birth defect and other severe fetal abnormalities, typically, abnormally small heads and severe brain defects. There is also limited evidence of Guillian-Barre’ syndrome and multiple sclerosis being related to Zika infection. The greatest risk is to pregnant women; however the Center for Disease control has recommended that men and women should wait a minimum of 8 weeks after possible exposure before trying to conceive. This period may increase based on the latest findings regarding the latency of the virus.

In a recent article in The New England Journal of Medicine it was noted that Zika is the fourth mosquito-borne illness to infiltrate the Western Hemisphere over the past 20 years, following dengue, West Nile, and chikungunya. There is currently no available vaccines for any of these diseases. According to the World Health Organization (WHO), more than 60 research institutes and companies are working on products to combat the spread of the Zika virus, but a vaccine is likely to take years to develop.

The disease can alternatively be attacked by control of the vector, Aedes aegypti. WHO states that traditional insecticide spraying methods have had no significant impact in decreasing the spread of dengue, implying that these classical methods for battling mosquito borne disease may be equally ineffective for Zika.

There is another possibility for eradicating the Aedes species mosquito over large areas. This involves modification of the mosquitos themselves. This approach has been used successfully in the past for eradication of the screwworm, an insect that was a major cause for livestock deaths in the mid- 20^th century. The screwworms were irradiated, sterilizing the male flies. Only the male flies were released, typically sprayed from small planes. The sterile males could not produce progeny, gradually eradicating the species. The technique was an unmitigated success.  The last cases of screwworm in the United States were reported in 1982, followed by eradication in Mexico and Central America.

Now, the world is focused not only on the Zika virus, but dengue, chikungunya and yellow fever, all transmitted by Aedes aegypti .  A British company, Oxitec, has approached the problem utilizing genetic engineering and inserting a gene that kills the insect. Male mosquitoes containing the gene are released to mate with wild females. The released male mosquitoes have no effect on people because males don’t bite. Offspring die before they reach adulthood, in that way suppressing the population of wild mosquitoes. Small-scale tests conducted in the Cayman Islands, Panama and Brazil since 2009 reduced local mosquito populations by as much as 99 percent.

Last month the federal government tentatively approved a field test (Florida Keys) of genetically engineered mosquitoes that might help slow the spread of the Zika virus. A final approval for the trial will not be made until the FDA receives and assesses comments from the public, which is likely to take months and the plan has faced fierce opposition from some residents in the state.

Information for this article was obtained from The Washington Post, The New York Times, The New England Journal of Medicine, CDC website and WHO website.

Download ABC's 3 Presentations from AAPS 2015

Below are recent presentations by ABC at this year's AAPS in October.

Don’t Leave Method Transfers to Chance

When planning your development strategy, you probably didn’t give much thought to method transfers. But when an analytical method doesn’t perform as expected, it can take precious days of investigative work to find the problem, and even more to resolve it. Learn about common pitfalls that cause method transfer failures, how to decide what type of method transfer makes sense for your study, and how to implement a fail-safe communication plan that will help put your outsourcing relationship on the right course.

To download this presentation, click here.

 

The Critical Role of CMC in your IND Submission

Early stage drug developers generally have their sights firmly set on the initiation of clinical trials, focusing on toxicological and pharmacological studies. Often, the importance of Chemistry, Manufacturing and Control (CMC) data is underestimated. But the CMC package is critical to IND approval, and meeting all FDA requirements demands careful planning and sound execution. This discussion will cover the risk/reward criteria for determining the level and degree of method validation, reference standard characterization and formulation; as well as potential pitfalls and ways to streamline the entire development process.

To download this presentation, click here.

Are Extractables & Leachables Going Phase-Appropriate?

Not long ago, it was more or less conventional wisdom that E&L studies should be performed late in the development cycle—even after the final container/closure system is known. But current regulatory trends suggest that, like many things GxP, expectations for early E&L data are on the rise. In recent years, many drug sponsors have been required to address E&L questions as early as phase I/II. It isn’t just CTM containers causing concern; questions often involve the equipment used in manufacturing and dosing devices. Phase-appropriate E&L program design can help you avoid related clinical holds and unplanned expense.

To download this presentation, click here.

Gene Editing - A New Frontier

By Glenn Petrie, Ph.D.
Senior Scientific Advisor
ABC Laboratories
www.abclabs.com

A new technology for “editing” genes has scientists excited about an entirely new method for treating disease. The CRISPR technique, along with other gene-editing technologies (TALENS, zinc finger nucleases) allow for the precise deletion of specific DNA sequences. CRISPR involve a Cas9 protein linked to an RNA strand. The RNA sequence serves to target the specific DNA sequence of interest and once bound the Cas9 enzyme cleaves both strands of the DNA.

Above graphic credit (link) to Scitechweb.com 

Since RNA synthesis is relatively cheap and easy this technology has exploded in the last 2 years. Feng Zhang and Eric Lander at MIT have created CRISPR libraries that target essentially the entire human genome. The promise of the technology is to delete genetic mutations and replace them with the correct genes.  Initial targets involve only a single mutation, e.g. sickle-cell anemia, progressing to diseases involving multiple mutations.

As with any new technology there are calls for caution. Chinese scientists reported attempts to repair defective genes in human embryos. This held up the specter of future “designer babies” enhanced in their embryonic stages. Others warn that this technology could be used to “weaponize” bacteria or viruses. Several prominent scientists have proposed a complete moratorium on gene editing until proper safeguards are in place.

Despite these concerns several biotech start-ups have been founded in the last 2 years including Intellia Therapeutics, Editas Medicine and Crispr Therapeutics. Successful in vitro results have been reported for the repair/modification of clinically important genes in hematopoietic stem cells, fibroblasts and T-cells. A quick internet search yields a number of companies offering their services to utilize CRISPR to perform gene editing in both cell lines and whole animals. Based on the extremely rapid advances in this area, gene-editing using CRISPR and other technologies promises to revolutionize our ability to manipulate the genome and attack genetic diseases.

Radiolabeled CTMs in Early Phase Development under GLP

By Wayland Rushing, Ph.D.

Senior Scientific Advisor

ABC Laboratories

www.abclabs.com

Radiolabeled products are used extensively during pre-clinical studies in BA/DMPK studies. The material used for these studies is typically research grade material released under Good Laboratory Practices (GLP’s). However radiolabeled drugs are also used during ADME and bio-availability studies. Since the products are now intended for use in human studies, they now must comply with CGMP regulations in terms of its manufacture and release testing.

While the processes by which CGMP’s are applied to the synthesis, control and testing of non-labeled materials is well understood, we have found there is a fair amount of confusion in terms of the regulatory requirement and how to apply those to radiolabeled products.  Here I want to address one specific aspect of this: Analytical Methods and Testing.

Typically during the point in development that CGMP radiolabeled materials are needed, significant work has been performed on the unlabeled material.  This normally means that analytical methods and testing specifications have already been developed and validated accordingly.  There are two issues which may occur in implementing these analytical methods for testing of the labeled material:

·       Impurity profiles: The impurity profile of the radiolabeled material may be significantly different than the un-labeled material.  This may be the result of the synthetic route having to be altered to prepare the labeled material and/or  radio-induced degradation which can lead to new impurities being formed.  This requires evaluation of the existing methods to ensure that they still properly work for determination of the chemical purity without interferences.

·       Radio-purity determination: One of the key specifications of the labeled material is the radio-purity of the final material.  The existing analytical methods are not able to determine this as it requires the use of a radio-detector (typically in-line with HPLC).

Since the testing of the final material is required to be CGMP compliant then the methods used are required to be developed and phase-appropriately validated for their intended use.  As a result the analytical testing for radio-labeled materials can be a complex process requiring: method transfer (of existing methods), method development and phase appropriate method validation.  Hence it is critical that at the initiation of a CGMP radiolabeling program a thorough plan is designed and implemented to ensure that not only is the material synthesis accordingly to meet the regulatory needs, but also that the analytical methods are also appropriate for use for the testing and release of the final product.

I will expand on this topic at the 12^th International Symposium on the Synthesis and Application of Isotopically Labelled Compounds on the campus of Princeton University June 7-11.  Join me at 10:30 AM June 11 for a podium presentation titled, “CGMP Radiosynthesis for Early Clinical Trials: A Unique Challenge.”

ABC Laboratories: Addressing the Growing Needs of the Biotech Crop Industry

ABC combines more than 45 years' experience analyzing chemical compounds in plant and environmental matrices with expertise in protein analysis to address the growing needs of the biotechnology crop industry. We offer a wide range of techniques required to fully characterize expressed proteins, as well as the various studies required to confirm the food, feed and environmental safety of products that represent the trait.

Some of ABC's Biotech Crop Services include:

• Protein expression analysis


• Feeding and exposure studies


• Ecotoxicological testing


• Environmental Fate Studies


• Compositional Equivalence


• Sample Processing

All work is performed in well managed, modern laboratories equipped to handle most any analytical methodology. And all of our capabilities are wrapped in a stellar regulatory record—a testament to strong quality systems, rigorous GLP compliance and ABC's deeply ingrained culture of continuous improvement.

See the full description of the Biotech Crop services ABC offers here:

http://www.abclabs.com/agriculture_ag-biotech.html