QC inhibition to be discussed at Alzheimer’s Association International Conference on Alzheimer’s Disease (ICAD) 2008
Halle (Saale) //
Probiodrug AG (Probiodrug), a developer of small molecule inhibitors for the treatment of inflammatory and neurodegenerative diseases, announced today that the company has been invited to present its findings that inhibition of the enzyme Glutam(in)yl Cyclase in vivo can be considered as a potentially causative new treatment of neurodegeneration in Alzheimer’s Disease (AD).
On July 29, Hans-Ulrich Demuth, CSO of Probiodrug will present an overview of the results supporting the company’s hypothesis, that the enzyme Glutam(in)yl Cyclase (QC) plays a major role in initiation and progression of Alzheimer’s disease and may therefore represent a promising target for a causative treatment of AD.
“Today, there are only treatment options available to temporarily slow down progression of Alzheimer’s disease”, Demuth said, “and so far all efforts to come up with a disease modifying treatment have failed. There are a lot of approaches aiming at the plaques and tangles found in brains of AD-patients, but no attempt to break down these structures or to prevent their formation has been successful.”
Probiodrug believes that it has identified a causal mechanism explaining plaque formation as well as neurotoxicity and neuron loss in the brain of AD patients, thereby providing a starting point to stop or prevent plaque formation and neurodegeneration. “We have compelling evidence suggesting that a certain variation of the beta amyloid peptide, i. e. a pyroglutamyl-modified beta amyloid plays a major role in Alzheimer’s disease”, Demuth added. “The variation is caused by a cyclization of an N-terminal glutamate residue of the peptide. As a result, the modified peptide is uncharged, and thus hydrophobic and degradation resistant and it exhibits a very strong tendency to aggregate.”
In addition, its occurrence correlates with dementia in AD patients and neuron loss in animal models. While plaques frequently present in the brain of non-demented elderly consist primarily of full-length amyloid beta, the plaques of AD patients mainly consist of pyroglutamated amyloid beta peptides. Moreover, the modified peptide unfolds profound seeding capacity, thus forming the core of plaques found in AD patients’ brains.
“We have elucidated the molecular mechanism that leads to the formation of the pyroglutamated amyloid beta”, Demuth said, “and found that an enzyme called Glutam(in)yl Cyclase, or QC performs the glutamyl cyclization activity. Since then, we have conducted several studies applying QC inhibitors to murine models of AD and found that the treatment reduced not only the pyroglutamated variety but concomitantly also the full-length peptides in the plaques and that it led to profound cognitive improvement.”
ICAD is the world’s leading forum on dementia research. The 2008 conference will take place July 26-31, 2008 in Chicago and will be joined by more than 5,000 world-renowned researchers.
Probiodrug is a biopharmaceutical company specialized on the development of innovative small molecule drugs for the treatment of neuronal, inflammatory, and autoimmune diseases. In these areas, Probiodrug is focusing on innovative targets with the prospect of first and best in class therapeutics.
The Company has a dominant position in the area of glutaminyl cyclase inhibition, an enzyme central for the pathogenesis of AD. In this field, Probiodrug is pioneering a completely novel therapeutic approach. In addition, the company is pursuing further novel approaches in the area of inflammatory diseases.
Probiodrug has generated evidence that glutaminyl cyclase, an enzyme that cyclizes N-terminal glutamine of peptides to pyroglutamate (pGlu), is massively overexpressed in the brain of patients with Alzheimer’s disease (AD). The company has also demonstrated that pyroglutamated derivatives of the amyloid beta (Aß) peptide are much more toxic and degradation-resistant than unmodified Aß peptides and that they form the very seeds of the typical Aß aggregates like AD plaques seen in the brain of AD patients. Moreover in animal models of AD, inhibitors of QC reduce both pGlu-Aß and total Aß, and improve memory.
Probiodrug`s core expertise is based on its long-standing, unique experience with the structure and function elucidation of enzymes central for the maturation of hormones. The company has pioneered the field of DP4-inhibition for the treatment of type 2 diabetes. Compounds and technology patents of its DP4 (dipeptidyl peptidase 4) program in diabetes were licensed to various pharmaceutical companies. In 2004, all metabolic assets were sold to (OSI) Prosidion. The first drug based on Probiodrug`s technologies reached the market in late 2006. The proceeds of these transactions have been reinvested to fund the novel approach for the treatment of AD.
The Company was founded in 1997 by Dr Konrad Glund and Prof Dr Hans-Ulrich Demuth and has raised a total of $52 million. In 2007, it acquired Ingenium Pharmaceuticals AG. The company is located in Halle (Saale), Germany, and operates a subsidiary in Martinsried/Munich, Germany. For more information, please visit www.probiodrug.de.
Dr Konrad Glund, CEO
D-06120 Halle (Saale)
Tel.: +49 345 55599-00
Fax: +49 345 55599-01
Dr Ludger Weß
Saseler Loge 6b
Tel.: +49 40 88 16 59 64
Fax: +49 40 88 16 59 65