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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.

*doi:10.1523/JNEUROSCI.2172-11.2011

Company News: biocrea’s First-in-class PDE2 Inhibitor Demonstrates Strong Potential For The Treatment Of Cognitive Disorders

– Data on novel PDE2 inhibitor BCA909 presented at 24th ECNP Congress in Paris –

biocrea, a biopharmaceutical company focusing on novel treatments for disorders of the central nervous system (CNS), today announced data on its innovative CNS-penetrating PDE2 inhibitor. The compound, which is code-named BCA909, was selected as a candidate for preclinical development  earlier this year. It demonstrates strong potential for the treatment of diseases in which normal learning and memory is impaired, e.g. mild cognitive impairment, Alzheimer’s disease and schizophrenia. Details on the compound were presented at the 24th ECNP Congress of the European College of Neuropharmacology in Paris, France (Sept. 3-7, 2011).

To date, few PDE2 inhibitors have been pharmacologically characterized. While initial findings have been encouraging, suggesting pro-cognitive and anxiolytic efficacy, the compounds did not enter the brain in sufficient quantities. With BCA909, biocrea has developed a novel, potent and selective PDE2 inhibitor with excellent CNS penetration and an efficacy and safety profile suitable for further development for multiple disease indications.

During the ECNP congress, biocrea presented data from extensive preclinical studies in vitro and in animal models of learning and memory. The key findings demonstrate that BCA909 delivers significant pro-cognitive activity in models of cognitive impairment resulting from either disruption of cholinergic or glutamatergic neurotransmission. Furthermore, BCA909 does not induce tolerance, indicating that maintained pro-cognitive efficacy, achieved through modulation of multiple neurotransmitter systems, can be delivered by the novel PDE2 mechanism of action.

Preclinical development of BCA909 is ongoing.

Company News: Aleva Neurotherapeutics Closes EUR 9.5 Million Series A Financing Round

– Novel Products for Deep Brain Stimulation (DBS) to Be Advanced Into the Clinic –

Aleva Neurotherapeutics, a company developing next-generation implants for Deep Brain Stimulation (DBS) in major neurological indications such as Parkinson´s disease or depression, today announced the closing of a Series A financing round totaling EUR 9.5 million. Aleva was founded in 2008 as a spin-off from the Ecole Polytechnique Fédérale de Lausanne (EPFL) Microsystems Laboratory.

The round was funded by a group of seasoned industry specialists and co-led by BioMedInvest AG (managed by BioMedPartners AG, Basel, Switzerland) and BB BIOTECH VENTURES III, L.P. (advised by Bellevue Asset Management AG, Kuesnacht, Switzerland). Initiative Capital Romandie (Lausanne, Switzerland) and renowned private investors also participated in the financing.

The proceeds will be used to support the development of Aleva’s pioneering product pipeline for neurostimulation, which is based on the company’s proprietary microDBS™ technology. microDBS™ is a next-generation technology addressing Deep Brain Stimulation therapy, currently a US$ 450 million market with strong double-digit growth rates.

Aleva’s microDBS™ technology for target-specific stimulation has been developed to significantly reduce the side effects and potential complications as well as the costs of DBS therapy. Moreover, its features allow for expanding the existing DBS market to new indications which cannot be addressed by currently available technologies.

The company is developing three products based on its microDBS™ technology: directSTIM™, an intelligent electrode compatible with existing DBS platforms; spiderSTIM™, a full solution for both intra-surgical and long-term therapeutic use; and the cortiSTIM™ device for cortical stimulation. All products will be compatible with marketed pulse generators. Clinical trials of the lead product, directSTIM™, are scheduled to start later this year.

Food for Thought: Weekly Wrap-Up

Joining the recent denunciation of personalized medicine in Süddeutsche Zeitung (SZ), Der Spiegel this week follows suit. Markus Grill and Veronika Hackenbroch cite Dr. Baerbel Huesing, Coordinator of Business Unit Biotechnology and Life Sciences of Fraunhofer ISI, as saying that the concept of personalized medicine is a “battle cry” of public relations: “Whoever invented it needs to be congratulated.” She added: “It is not a paradigm change. There is not that much in it. However, it is very well suited to justify to Jane Doe the enormous investments made in genomics – similar to the teflon-coated frying pan which was used as an excuse for manned space research.” As an example, Grill and Hackenbroch cite a study from 2009 in colon cancer patients, stating that adding Erbitux to the treatment scheme of patients selected by a concomitant Qiagen test resulted in a survival improvement of 4 months: “Is this a medical breakthrough? Is this what  progress looks like, bought by spending billions?” Instead, Grill and Hackenbroch recommend spending money on better care at home and better palliative treatment. The article ends with a quote from Wolf-Dieter Ludwig, head of the clinic for hematology, oncology and tumor immunology at Robert-Roessle-Klinik in Berlin: “Up to date, the concept of personalized medicine is an empty promise in the first place.”

Harro Albrecht and Sven Stockrahm in Die Zeit feature the suspicion expressed by medical doctors and competent authorities in the EU that the flu vaccine Pandemrix might cause narcolepsy, in particular in children and young adults. Already, EMEA issued a recommendation to use Pandemrix in children and adults under 20 in exceptional cases only. While there were only two reported cases of narcolepsy among children in the US, there were more than 300 in the EU, with 70% of those cases coming from Scandinavia. Narcolepsy is an autoimmune disease, predominantly in humans with a certain genetic modification, and the authors feature the theory that the adjuvant used in the vaccine might have induced the disease in these patients. However, the genetic variant known does not have a bigger frequency in Scandinavia.

Sven Stockrahm, also in Die Zeit, features miniature, flexible electronic devices that stick to the skin by physical means. They can be hid by a tattoo motif and are able to measure and transmit physiological data for medical purposes. One company developing these devices is mc10 Inc. in Cambridge, Mass.

Martina Lenzen-Schulte in Frankfurter Allgemeine Zeitung (FAZ) gives an overview on the arrival of maggot therapy as a means to clean wounds, stating it has become standard therapy in many German clinics already. Maggots not only remove dead tissue and eschar, they also kill bacteria. Therefore, they are increasingly being used in infections with bacteria carrying multiple resistance to antibiotics. However, maggot therapy is not yet approved in Germany (in contrast to the US).

Sebastian Matthes in Wirtschaftswoche interviews Jackie Fenn, analyst at Gartner and co-author of Gartner’s Hype Cycle Report. Fenn forecasts computers with the ability to understand spoken questions and to put out spoken answers as well as printing of organs and arteries.

Roland Fischer in Neue Zürcher Zeitung (NZZ) looks back at 50 years of the influential Science Citation Index SCI. Originally founded to make the identification of relevant scientific papers easier, it soon became a tool for sociologists of science and led to the birth of scientometry as a new discipline. However, SCI also was used to take quantity for quality, measuring quality of science as number of citations, and it is a well-known episode that in the UK funding of clinical research was cut because preclinical research generates more citations. While this controversy is still ongoing, the taking of quantity for quality is already spilling over into search engines, Fischer describes.

Alex Knapp in Forbes describes a novel approach to broad spectrum antivirals. It is based on a bi-specific drug: one arm binds to double-stranded RNA which is specific for viruses. Once bound, a second arm triggers a mechanism that leads to the destruction of the cell it is in. The experimental drug named DRACO has been successful at eliminating cells infected by 15 different viruses from the common cold to polio in vitro and in vivo (mice).

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