Advertisements
Feeds:
Posts
Comments

Posts Tagged ‘immune activation’


The Vibrant Philly Biotech Scene: Focus on Vaccines and Philimmune, LLC

Curator: Stephen J. Williams, Ph.D

I am intending to do a series of posts highlighting interviews with Philadelphia area biotech startup CEO’s and show how a vibrant biotech startup scene is evolving in the city as well as the Delaware Valley area. Philadelphia has been home to some of the nation’s oldest biotechs including Cephalon, Centocor, hundreds of spinouts from a multitude of universities as well as home of the first cloned animal (a frog), the first transgenic mouse, and Nobel laureates in the field of molecular biology and genetics. Although some recent disheartening news about the fall in rankings of Philadelphia as a biotech hub and recent remarks by CEO’s of former area companies has dominated the news, biotech incubators like the University City Science Center and Bucks County Biotechnology Center as well as a reinvigorated investment community (like PCCI and MABA) are bringing Philadelphia back. And although much work is needed to bring the Philadelphia area back to its former glory days (including political will at the state level) there are many bright spots such as the innovative young companies as outlined in these posts.

First up I got to talk with Florian Schodel, M.D., Ph.D., CEO of Philimmune, which provides expertise in medicine, clinical and regulatory development and analytical sciences to support successful development and registration of vaccines and biologics. Before founding Philimmune, Dr. Schodel was VP in Vaccines Clinical Research of Merck Research Laboratories and has led EU vaccine clinical trials and the clinical development of rotavirus, measles, mumps, hepatitis B, and rubella vaccines. In addition Dr. Schodel and Philimmune consult on several vaccine development efforts at numerous biotech companies including:

 

\His specialties and services include: vaccines and biologics development strategy, clinical development, clinical operations, strategic planning and alliances, international collaborations, analytical and assay development, project and portfolio integration and leadership.

Successful development of vaccines and biologics poses some unique challenges: including sterile manufacturing and substantial early capital investment before initiated clinical trials, assay development for clinical trial support, and unique trail design. Therefore vaccines and biologics development is a highly collaborative process between several disciplines.

The Philadelphia area has a rich history in vaccine development including the discovery and development of the rubella, cytomegaolovirus, a rabies, and the oral polio vaccine at the Wistar Institute. Dr. Schodel answered a few questions on the state of vaccine development and current efforts in the Philadelphia area, including recent efforts by companies such as GSK’s efforts and Inovio’s efforts developing an Ebola vaccine.

In his opinion, Dr. Schodel believes our biggest hurdle in vaccine development in a societal issue, not a preclinic development issue. Great advances have been made to speed the discovery process and enhance quality assurance of manufacture capabilities like

however there has not been a great history or support for developing vaccines for the plethora of infectious diseases seen in the developing world. As Dr. Schodel pointed out, there are relatively few players in the field, and tough to get those few players excited for investing in new targets.

 

However, some companies are rapidly expanding their vaccine portfolios including

 

 

Why haven’t 3rd world countries developed their own vaccine programs?

 

  1. Hard to find partners willing to invest and support development
  2. Developing nations don’t have the money or infrastructure to support health programs
  3. Doctors in these countries need to be educated on how to conduct trials, conduct vaccine programs like Gates Foundation does. For more information see Nature paper on obstacles to vaccine introduction in third world countries.

 

Lastly, Dr. Schodel touched on a growing area, cancer vaccine development. Recent advances in bladder cancer vaccine, cervical, and promising results in an early phase metastatic breast cancer vaccine trial and phase I oral cancer vaccine trial have reinvigorated this field of cancer vaccinology.

 

Historic Timeline of Vaccine Development

vaccine development timeline

Graphic from http://en.pedaily.cn/Item.aspx?id=194125

 

Other posts on this site related to Biotech Startups in Philadelphia and some additional posts on infectious disease include:

 

RAbD Biotech Presents at 1st Pitch Life Sciences-Philadelphia

LytPhage Presents at 1st Pitch Life Sciences-Philadelphia

Hastke Inc. Presents at 1st Pitch Life Sciences-Philadelphia

1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

 

 

 

Advertisements

Read Full Post »


Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/6/7/2014/Immune activation, immunity, antibacterial activity

This segment is an update on activation of innate immunity, which has had a great amount of basic science resurgence in the last several decades.  It also addresses the issue of antibiotic resistance, which shall be covered more fully in later segments. Antimicrobial resistance is a growing threat, and a challenge to the pharmaceutical industry.  Moreover, worldwide travel increases the possibility of transfer of strains of virus and microbiota to distant communities.

 

8-OH-dG: A novel immune activator.

Innate immunity against viral or pathogenic infection involves sensing of non-self-molecules, otherwise known at pathogen-associated molecular patterns (PAMPs).  This same sensing mechanism can be applied to damaged self-molecules, which are called damage-associated molecular patterns (DAMPs).  One type of molecular pattern, for both groups, is cytosolic or extracellular DNA.  However, there is not an extensive amount of research showing specifically what type of DAMP DNA molecule is best at activating this immune sensing response.  A recent study investigated the mechanism behind how oxidized DNA from UV damage activates an immune sensing response.

A group of researchers found that, compared to a variety of types of cellular damage, damage from UV irradiation created a strong immune response (type I IFN response), seen across different types of immune regulatory cells.  This was compared with freeze/thaw, physical damage and nutritional deprivation, each of which did not produce a noticeable immune response. Additionally, this immune response was seen when DNA was exposed to UV-A and UV-B (the type of radiation produced by our sun) and UV-C radiation.

DNA can be damaged by UV light directly, or through reactive oxygen species (ROS) caused by UV light.  A well-known mark of DNA damaged by ROS is the oxidation of guanine to create 8-hydroxyguanine (8-OH-dG).  These researchers saw an increase in 8-OH-dG dependant on the level of UV dose, and this also correlated with an increase in immune response; showing that DNA damage created by UV light in the form of 8-OH-dG is sufficient to activate an immune response. This study shows that 8-OH-dG can be classified at a DAMP.

Next, this group wanted to place a mechanism to these observations. They found that the ability of oxidation-damaged DNA to activate an immune response was dependant on cGAS and STING.  Free DNA in the cytosol binds cGAS, a cGAMP synthase.  This action produces a messenger molecule which proceeds to bind to and activate STING, an endoplasmic reticulum protein.  STING activation will ultimately stimulate a type I IFN response.

When a cell’s own DNA is damaged, the cell’s machinery does all it can to repair it.  This sometimes involves erasing, or degrading, the DNA that has been damaged.  The enzyme, TREX1 exonuclease, has this job in a cell.  However, this group found that when DNA was modified with an 8-OH-dG, it was resistant to this degradation by TREX1.  This implies that the observed increase in immune response due to the presence of 8-OH-dG occurred because of an accumulation of damaged DNA, because it was not being degraded by TREX1 and could therefore sufficiently activate cGAS and STING.

This type of study has important implications for autoimmune diseases like lupus erythematosus (LE), which is characterized by its abnormally high number of autoantibodies against DNA.  It is possible that this uncontrollable immune response is activated by oxidation-damaged DNA.  Studies in this area, therefore, hold great importance.

– See more at: http://www.stressmarq.com/Blog/November-2013/8-OH-dG-A-novel-immune-activator.aspx#sthash.CvSdK0H1.dpuf

 

Oxidative Damage of DNA Confers Resistance to Cytosolic Nuclease TREX1 Degradation and Potentiates STING-Dependent Immune Sensing

Nadine Gehrke, Christina Mertens, Thomas Zillinger, Jörg Wenzel,…,Winfried Barchet

DOI: http://dx.doi.org/10.1016/j.immuni.2013.08.004

Highlights

  • •UV or ROS damage potentiates immunorecognition of DNA via cGAS and STING
  • •The oxidation product 8-OHG in DNA is sufficient for enhanced immunorecognition
  • •Oxidized self-DNA acts as a DAMP and induces skin lesions in lupus-prone mice
  • •Oxidized DNA is resistant to cytosolic nuclease TREX1-mediated degradation

Summary

Immune sensing of DNA is critical for antiviral immunity but can also trigger autoimmune diseases such as lupus erythematosus (LE). Here we have provided evidence for the involvement of a damage-associated DNA modification in the detection of cytosolic DNA. The oxidized base 8-hydroxyguanosine (8-OHG), a marker of oxidative damage in DNA, potentiated cytosolic immune recognition by decreasing its susceptibility to 3′ repair exonuclease 1 (TREX1)-mediated degradation. Oxidizative modifications arose physiologically in pathogen DNA during lysosomal reactive oxygen species (ROS) exposure, as well as in neutrophil extracellular trap (NET) DNA during the oxidative burst. 8-OHG was also abundant in UV-exposed skin lesions of LE patients and colocalized with type I interferon (IFN). Injection of oxidized DNA in the skin of lupus-prone mice induced lesions that closely matched respective lesions in patients. Thus, oxidized DNA represents a prototypic damage-associated molecular pattern (DAMP) with important implications for infection, sterile inflammation, and autoimmunity.

ribonuclease TREX1 and immunity

ribonuclease TREX1 and immunity

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Immunity 19 Sep 2013;39(3), p482–495,

New Weapon in Fight Against ‘Superbugs’

Some harmful bacteria are increasingly resistant to treatment with antibiotics. A discovery might be able to help the antibiotics treat the disease.

By  ANN LUKITS  June 30, 2014 8:47 p.m. ET

 

Some harmful bacteria are increasingly resistant to treatment with antibiotics. This common fungus found in soil might be able to help the antibiotics combat diseases. Corbis

A soil sample from a national park in eastern Canada has produced a compound that appears to reverse antibiotic resistance in dangerous bacteria.

fungus with antimicrobial activity

 

 

 

 

 

 

 

 

 

 

 

 

Scientists at McMaster University in Ontario discovered that the compound almost instantly turned off a gene in several harmful bacteria that makes them highly resistant to treatment with a class of antibiotics used to fight so-called superbug infections. The compound, called aspergillomarasmine A, or AMA, was extracted from a common fungus found in soil and mold.

Antibiotic resistance is a growing public-health threat. Common germs such asEscherichia coli, or E. coli, are becoming harder to treat because they increasingly don’t respond to antibiotics. Some two million people in the U.S. are infected each year by antibiotic-resistant bacteria and 23,000 die as a result, according to the Centers for Disease Control and Prevention. The World Health Organization has called antibiotic resistance a threat to global public health.

The Canadian team was able to disarm a gene—New Delhi Metallo-beta-Lactamase-1, or NDM-1—that has become “public enemy No. 1” since its discovery in 2009, says Gerard Wright, director of McMaster’s Michael G. DeGroote Institute for Infectious Disease Research and lead researcher on the study. The report appears on the cover of this week’s issue of the journal Nature.

“Discovery of a fungus capable of rendering these multidrug-resistant organisms incapable of further infection is huge,” says Irena Kenneley, a microbiologist and infectious disease specialist at Frances Payne Bolton School of Nursing at Cleveland’s Case Western Reserve University. “The availability of more treatment options will ultimately save many more lives,” says Dr. Kenneley, who wasn’t involved in the McMaster research.

The McMaster team plans further experiments to determine the safety and effective dosage of AMA. It could take as long as a decade to complete clinical trials on people with superbug infections, Dr. Wright says.

The researchers found that AMA, extracted from a strain of Aspergillus versicolor and combined with a carbapenem antibiotic, inactivated the NDM-1 gene in three drug-resistant superbugs—Enterobacteriaceae, a group of bacteria that includes E. coli;Acenitobacter, which can cause pneumonia and blood infections; and Pseudomonas, which often infect patients in hospitals and nursing homes. The NDM-1 gene encodes an enzyme that helps bacteria become resistant to antibiotics and that requires zinc to survive. AMA works by removing zinc from the enzyme, freeing the antibiotic to do its job, Dr. Wright says. Although AMA was only tested on carbapenem-resistant bacteria, he expects the compound would have a similar effect when combined with other antibiotics.

AMA was first identified in the 1960s in connection with leaf wilt in plants and later investigated as a potential drug for treating high blood pressure. The compound turned up in Dr. Wright’s lab a few years ago during a random screening of organisms derived from 10,000 soil samples stored at McMaster. The sample that produced AMA was collected by one of Dr. Wright’s graduate students during a visit to a Nova Scotia park. It was the only sample of 500 tested that inhibited NDM-1 in cell cultures.

“It was a lucky hit,” says Dr. Wright. “It tells us that going back to those environmental organisms, where we got antibiotics in the first place, is a really good idea.”

The McMaster team developed a purified form of AMA for experiments on mice injected with a lethal form of drug-resistant pneumonia. Treatment with either AMA or a carbapenem antibiotic alone proved ineffective. But combining the substances resulted in more than 95% of the mice still being alive after five days. The combination was also tested on 229 cell cultures from human patients infected with resistant superbugs. The treatment resensitized 88% of the samples to carbapenem.

Still, bacteria could someday find a way to outwit AMA. “I can’t imagine anything we could make where resistance would never be an issue,” he says. “At the end of the day, this is evolution and you can’t fight evolution.”

Read Full Post »