SOCRATECH
On the forefront of Alzheimer's research

Socratech L.L.C. is a biotechnology company with the primary focus on discovery and development of therapeutics for the treatment of neurodegenerative disorders such as Alzheimers disease and stroke.  Alzheimer's disease is the fourth leading cause of death. Alzheimers Disease is a devastating brain disorder associated with fatal cognitive impairment, mental disability and progressive degeneration of brain cells in elderly population. Stroke is the third leading cause of death associated with degeneration of brain cells and neurological disabilities.

The major thrust in Socratech is the novel concept that vascular system plays a key role in initiating the pathology of brain cells and therefore represents a primary therapeutic target. The Nobel Prize Winner 2000, Dr Arvid Carlsson, the world-renowned neuroscientist, has commented on Socratech’s concept:  “The role of vascular system in brain disorders has not been studied enough, and it would be of great importance to pursue these studies”.

Vascular system controls cerebral blood flow, transport of molecules across the blood-brain barrier including removal of critical toxins, and formation of new blood vessels during aging and neurodegenerative disorders.  Socratech has strong expertise in studying vascular pathogenic mechanisms in Alzheimer’s disease and stroke, and is a pioneer in developing vascularly-based diagnostic tests and therapeutic strategies for brain disorders.  Socratech’s portfolio comprises of new therapeutic approaches for vascular and brain cell protection, removal of Alzheimer’s toxin, diagnostic tests for Alzheimer’s disease, and identification of new diagnostic markers and molecular targets for treatment of Alzheimer’s disease.

As evidence of its quality programs, Socratech’s portfolio is based on research projects that have been awarded financial support from several leading organizations in the U.S.; the National Institute on Aging, the National Institute for Neurological Disorders & Stroke, the National Institute for Heart, Blood and Lung, and the MSZ Investments, Inc.  Socratech has its own research group working on “Vascular Gene Discovery in Alzheimer’s Disease” sponsored by MSZ Investors. The company’s R & D center is in Rochester New York.  Socratech has established collaborations with the University of Rochester Medical Center New York, the Scripps Research Institute La Jolla, the Keck School of Medicine University of Southern California Los Angeles, the College of Physicians and Surgeons of Columbia University New York, the School of Medicine at the SUNY Stony Brook and the Iowa University School of Medicine. 

The fields in which Socratech is currently working are divided as follows:

(1) Activated protein C (APC) to treat neurodegenerative brain disorders,

(2) Protein S for protection of the nervous system from cell injury,

(3) New vascular gene targets for treatment and diagnosis of        

brain disorders and cognitive impairments and development of new drugs

Recent discussions of work done by Dr. Zlokovic, the chief scientific officer of Socratech as stated in University of Rochester Medical Center Newsletter:

Dr. Zlokovic investigates vascular mechanisms in two neurological diseases of enormous clinical and public health significance: Alzheimer's Disease and stroke. His work on Alzheimer's Disease earned him the MERIT award (pending an official award notice from NIH.) Betsa is pursuing an etiologic theory that has substantial therapeutic potential. This theory holds that accumulation of amyloid peptide (which I will call "amyloid"), the primary pathologic event in Alzheimer's Disease, is the result of disordered equilibrium in the flux of amyloid across the blood-brain barrier. Although there are skeptics who favor alternative views, Dr. Zlokovic has now developed many lines of experimental support for his case, leading to a growing consensus about the fundamental importance in Alzheimer's Disease of the amyloid-clearing phenomenon through the blood-brain barrier.

The overarching questions that Dr. Zlokovic and his collaborators are asking about Alzheimer's Disease are the most fundamental ones that one can ask about any disease: "What causes it?" and "If we can know the cause, does this lead to effective treatment?" To understand Betsa's approach, let me recount a few fundamental observations about Alzheimer's Disease: deposition of amyloid in the central nervous system is accelerated in Alzheimer's Disease; amyloid is neurotoxic, inducing oxidant stress in endothelial cells and causing synaptic dysfunction in the brains of AD patients and in AD animal models; transport of amyloid across the blood-brain barrier (BBB) plays a central role in determining concentrations of amyloid in the central nervous system (CNS); and finally, the BBB regulates entry of amyloid from the bloodstream into the CNS and clears brain-derived amyloid through specific receptors or carrier-mediated mechanisms.

If Alzheimer's Disease is etiologically linked to over-accumulation of amyloid in the CNS, how might this occur? The answer lies in either overproduction or inadequate clearance of amyloid. In his grant proposal, Dr. Zlokovic draws from extensive literature to argue that increased amyloid production can explain only a small number of AD cases that are due to specific inherited mutations in the amyloid precursor gene. Inadequate clearance may be due to inefficient degradation of amyloid by a variety of protease enzymes. An alternative hypothesis, however, and the one investigated by Dr. Zlokovic and his collaborators in their recent AD grant, states that amyloid is cleared out of the CNS to blood mainly via transport through the BBB and/or via the interstitial fluid into the cerebrospinal fluid and thence into the bloodstream. The innovative aspect of Beta's proposal that attracted such enthusiasm from reviewers is the hypothesis that two "scavenger" proteins might regulate amyloid transport back and forth across the BBB, and that defects in this regulation represent both an etiologic explanation and an opportunity for effective treatment. Betsa and his team had developed novel transgenic mouse models to test central aspects of this hypothesis and had published key data on the two "scavenger proteins" (LDL receptor-related protein-1 and RAGE) in highly cited reports (JCI 2000;106:1489-1499; Nature Medicine 2003;9:907-913). As one of the reviewers noted, "identifying LRP-1 as the major source of amyloid efflux from the CNS represents a major advance, and the fact that the LRP-1 levels go down in the AD brain represents a potentially important site for targeting therapeutic interventions."

A second major line of research in Dr. Zlokovic's laboratory relates to stroke. Ischemic strokes are due to thrombotic or thromboembolic vascular occlusions. This area of investigation focuses on the role endogenous activated protein C (APC), which is part of the systemic anticoagulant and anti-inflammatory surveillance system. The risk of stroke goes up when circulating APC is reduced; furthermore, resistance to the anticoagulant effect of APC is a potential risk factor for stroke. Using a mouse model of stroke, Drs. Zlokovic and his colleagues demonstrated that exogenously administered APC exerts anti-inflammatory, antithrombotic, and neuroprotective effects in stroke (Circulation 2001; 103:1799-1805). More recently, Dr. Zlokovic's and his team (first co-authors Tong Cheng, Ph.D. and Dong Liu, Ph.D.) have reported that APC protects the brain from ischemic injury by specific and direct actions on brain cells (Nature Medicine 2003; 9:338-342), and that APC protects mouse cortical neurons from two different inducers of apoptosis (first author Huang Guo, Ph.D.) (Neuron 2004; 41:563-572). This work in mice has clear and exciting potential for translation to the treatment of human stroke. Indeed, Curt Benesch, MD, in the Department of Neurology, has recently submitted a proposal to NHLBI for a pilot clinical trial, involving Rochester and four other institutions, to conduct phase I/II studies in 40 human subjects. In this trial, stroke patients who are seen within 6 hours of the onset of symptoms will be administered APC in 3 doses (on admission, and at 1 and 2 hours after admission) to study the safety and efficacy of APC in the early treatment of stroke.

Link to press about the work by Dr. Zlokovic