Tag: QC

Company News: Neurodegeneration in Alzheimer’s Disease: The crucial role of QC

Probiodrug provides further insights into the onset of AD in The Journal of Neuroscience

Probiodrug AG (Probiodrug), a biotech company developing novel products for the treatment of neurodegenerative and inflammatory disorders, today announced the publication of data providing key insights into the onset and development of Alzheimer’s disease (AD) in the Journal of Neuroscience (http://redir.ec/jneurosci).

AD is characterized by deposition of amyloid-β (Aβ) plaques in the brain. However, quantitative relationship between plaque deposition and severity of cognitive decline in the affected individuals is still elusive. Often, elderly people carry a large amyloid burden without any signs of cognitive impairments, and many animal models of AD also develop the characteristic hallmarks, such as plaques, but do not demonstrate the cognitive defects and loss of neurons typical of the human disease.

Several years ago, Probiodrug developed the hypothesis that the missing link between Aβ load and prevalence of AD is a certain modification of Aβ, in which the Aβ molecule carries a pyroglutamate residue (pGlu) at its N-terminus. This pGlu-Aβ is neurotoxic and develops a strong tendency to aggregate and to seed aggregation of further pGlu-Aβ as well as unmodified Aβ. The modification of glutamic acid to a pGlu-residue is catalyzed by the so-called QC enzyme (glutaminyl cyclase).

In this week’s The Journal of Neuroscience* Probiodrug researchers (and their collaborators from Friedrich Alexander University, Erlangen, the German Center of Neurodegenerative Diseases, Magdeburg, the Leibniz Institute for Neurobiology, Magdeburg, the Paul Flechsig Institute for Brain Research, Leipzig, and the University of Tennessee, Knoxville/ USA) now describe the generation and characterization of a novel animal model that solely expresses N-truncated human Aβ, which in turn is modified by QC to pGlu-Aβ. As a result, these animals which express the toxic species 1000fold less than other models do with Aβ not only have the typical pathological changes, but also neuronal loss and cognitive impairments.

”We now have animal models that represent the full spectrum of pathological and behavioral changes in AD without overexpressing the Aβ peptides. In addition, we could once again clearly demonstrate that the activity of QC enzymes is starting the chain of events that ultimately leads to the debilitating disease, which already affects millions of people world-wide. The results in this study also demonstrate that lowering the QC-dependent formation of pGlu-Aβ reduces the amount of neurotoxic aggregations, and further strengthens the hypothesis that inhibition of QC is a promising new treatment strategy for AD” commented Hans Ulrich Demuth, CSO of Probiodrug.


Company News: Probiodrug to Host Alzheimer Symposium

Despite considerable efforts to find a cure, Alzheimer’s disease  (AD) at present cannot be treated adequately, as there is no therapy available to significantly slow down disease progression, halt the disease or prevent it.
During the past years, researchers from the German-based biotech company Probiodrug have generated a compelling body of evidence that a particular variant of the notorious A beta peptide, which clumps together in the brain of AD patients to the typical plaques, is the major culprit. This variant is formed through a hitherto unknown reaction of a brain enzyme called glutaminyl cyclase (QC) and carries a pyroglutamic residue at its N-terminus. This renders it much more neurotoxic than the unmodified A-beta and also significantly reduces its solubility so that it starts aggregating.
Today, this hypothesis  is not an outsider opinion any more. On Monday, November 22, well-known Alzheimer researchers from Germany (Christian Haass, Stephan v. Hörsten, Marcus Fändrich, Thomas Bayer, Steffen Roßner, and Stephan Schilling), the U.S. (Cynthia Lemere, Lennart Mucke, Steve Jacobsen), Austria (Reinhold Schmidt), and Japan (Takaomi Saido) will meet at Probiodrug´s Halle (Saale) headquarter to provide the latest findings in the light of this hypothesis and to discuss novel therapeutic strategies. One of the approaches pursued by Probiodrug is inhibiting the formation of the toxic A-beta variant by small molecule inhibitors of the QC enzyme.
The public symposium entitled “Neurodegenerative Disorders During Aging – Contemporary Research and New Therapies” will take place on Weinberg Campus in Halle (Saale) on Monday, November 22, 2010, from 10am to 3pm. The detailed program can be found on Probiodrug‘s website.

Food for Thought: Key to Stopping Alzheimer’s Disease

In Germany, newpapers are widely reporting about a recent paper by a team of researchers led by  Thomas Bayer from Ernst-August University Goettingen, Germany, in which the team reports about an approach able to halt the progress of Alzheimer’s disease in mice.

For a long time, researchers have tried to stop Alzheimer’s disease (AD) by either dissolving the plaques found in the brains of AD patients or by trying to get rid of the so-called Abeta peptide that is believed to aggregate to plaques. However, none of these approaches has been successful so far.

A couple of years ago, researchers from the biotech company Probiodrug AG (Halle, Germany) found that the major culprit for the detrimental aggregation of peptides to plaques is not Abeta as such, but a variation carrying a pyroglutamate residue. This pyroglutamated Abeta peptide (pGlu-Abeta), they found, is generated by a hitherto unknown reaction catalyzed by the brain enzyme glutaminyl cyclase (QC). pGlu-formation leads to stabilization of the peptide and protection against cleavage. Moreover, Probiodrug has been able to demonstrate that pGlu-Abeta peptides show increased neurotoxicity, a prolonged half-life and an increased tendency for aggregation. They also form the seeds of the typical plaques observed in the brain of AD patients.

While Probiodrug is developing small molecule inhibitors of the QC enzyme to halt the disease, Thomas Bayer (who is a member of Probiodrug’s Scientific Advisory Board) and his team generated a monoclonal antibody against pGlu-Abeta. Passive immunization of transgenic mice models of AD  with this monoclonal antibody significantly reduced overall Abeta plaque load and levels of pGlu-Abeta, and also normalized behavioral deficit in the mice.

Later this month during the Neuroscience 2010 conference, Probiodrug will demonstrate that increasing pGlu-Abeta potentiates the behavioral deficits observed with transgenic AD mouse models significantly, and will also presented data showing that inhibitors of QC can reduce the level of pyroglutamated beta-amyloid species and alleviate the observed behavioral changes.

While the approach presented by Thomas Bayer will take a few years to reach the clinic, Probiodrug’s first small molecule QC inhibitor already has reached the regulatory phase.

Company News: Probiodrug Appoints Kumar Srinivasan as Chief Business Officer

Probiodrug (Halle, Germany) has appointed Dr Kumar Srinivasan, previously Vice President, Global Business Development at Wyeth, to Chief Business Officer. Wyeth was acquired by Pfizer in 2009. Probiodrug has a focus on neurodegenerative diseases, in particular Alzheimer’s disease. In this indication, the company pursues a novel target and pathway and is preparing for the start of clinical development of one of its lead candidates, a small molecule inhibitor of the enzyme glutaminyl cyclase (QC). Kumar Srinivasan, MBA, has a background as research chemist and is an experienced pharma / biotech dealmaker. He will be responsible for Probiodrug’s global business development activities and will be based in Philadelphia, PA. The full press release can be found here.