Vertex Pharmaceuticals/Yale Research Team Uses Gene Knockout Mice To Establish Role Of Caspase-9 In Neuronal Cell Death Pathway

August 07, 1998

Cambridge, MA, August 7, 1998 -- A team of scientists from Vertex Pharmaceuticals, Yale University School of Medicine, Howard Hughes Medical Institute (HHMI) at Yale University, and Tokyo Metropolitan Institute of Medical Science (TMI) reported results with a gene knockout mouse that establishes a key role for the enzyme Caspase-9 in a specific biochemical pathway that results in neuronal cell death. These findings, published in the August 7, 1998 issue of Cell, suggest that blocking Caspase-9 may be a viable strategy for treating a variety of acute and chronic age-related neurological diseases, including Alzheimer's disease, Parkinson's disease and stroke.

Caspases comprise a family of enzymes that are being evaluated for their role in a number of diseases, based on their involvement in biochemical pathways of inflammation and of apoptosis (also known as programmed cell death or cell suicide). Apoptosis is an essential component of numerous biological processes, including tissue remodeling, immune system regulation and embryonic development. Abnormal activation of apoptosis, however, is implicated in the development and progression of a number of different human diseases, and links between specific caspases and specific diseases are beginning to be established. The publication of the Cell paper is the first report describing the in vivo function of Caspase-9, and suggests apparent tissue-selective activity among the eleven reported human caspases.

"When mitochondria -- the energy factory of cells -- are damaged, Caspase-9 is activated leading to cell death," said Dr. Richard A Flavell, an HHMI Investigator and an author of the study. "In cells lacking Caspase-9, this damage did not give rise to cell death."

"Our results also indicate that Caspase-9 is activated early and is essential for apoptosis in neuronal cells, and that deletion of Caspase-9 does not interfere with embryonic development of other non-neuronal tissues," said Dr. Keisuke Kuida, Staff Investigator at Vertex and an author of the study. "This suggests that a therapeutic approach designed to interrupt the apoptotic pathway triggered by Caspase-9 could block unwanted cell death linked to several neurological diseases."

The Vertex, Yale/HHMI and TMI researchers inserted a defective Caspase-9 gene into mice and then bred them to produce offspring with two defective copies of the Caspase-9 gene. Biochemical experiments demonstrated that neuronal apoptosis was specifically blocked in the transgenic mice deficient in Caspase-9. Experiments also suggested that Caspase-9 is active upstream of Caspase-3 (also known CPP32) in the neuronal apoptosis pathway. The Caspase-9 knockout mice showed altered central nervous system development, with more profound alterations than those observed in Caspase-3 knockout mice. Both Caspase-9 and Caspase-3 appear to be selectively active in neuronal tissues during development.

"The balance between cell production and cell death is important for normal brain development," said Dr. Pasko Rakic, Professor of Neurobiology and Neurology at Yale University School of Medicine and an author of the study. "Too much or too little cell death can cause severe malformations leading to disorders such as mental retardation and childhood epilepsy. This study shows that Caspase-9 is essential for cell death and therefore gives new insight into how the brain develops in normal and pathological conditions."

"The results of the transgenic experiment are striking," commented Dr. Michael Su, Senior Research Fellow at Vertex and an author of the Cell paper. "By removing the Caspase-9 enzyme, we prevented brain cells from dying during the early stages of mouse development. We can infer from this that using compounds that block Caspase-9 or another enzyme in this pathway may be a viable strategy for treating neurological diseases that involve apoptosis."

"This is the first report in the scientific literature describing Caspase-9 function through a gene-knockout experiment, and illustrates how Vertex approaches functional genomics as part of an integrated discovery platform," said Dr. Joshua Boger, Chairman, President, and CEO of Vertex. "This research clarifying the relationship between caspases and their activity in body tissues greatly increases our understanding of which caspases are appropriate targets for drug discovery."

Vertex Pharmaceuticals has an established track record of scientific innovation and is a leader in caspase research. Previously, Vertex and Yale/HHMI researchers were the first to describe the biochemical and physiological effects of the ICE (Caspase-1) enzyme through a gene knockout mouse experiment, and Vertex researchers were the first to elucidate the 3-dimensional atomic structure of ICE. Additionally, Dr. Keisuke Kuida, together with colleagues Dr. Richard Flavell and Dr. Pasko Rakic, reported the first Caspase-3 (CPP32) gene knockout mouse, and Vertex researchers have solved the structure of the Caspase-3 enzyme. Vertex and partner Hoechst Marion Roussel plan to begin Phase I clinical trials of VX-740, an inhibitor of ICE targeting inflammatory diseases, later in 1998. Vertex has a research program directed at developing novel, orally administered inhibitors of different targets in the caspase family with potential in the treatment of stroke, Alzheimer's and Parkinson's diseases, myocardial ischemia and other indications.

The contributors to the Cell paper include Dr. Richard Flavell, a Howard Hughes Investigator, and Drs. Pasko Rakic, Tarik Haydar, and Chia-Yi Kuan, all of the Yale University School of Medicine; Drs. Choji Taya and Hajime Karasuyama, both of the Tokyo Metropolitan Institute of Medical Science; and Drs. Keisuke Kuida, Yong Gu and Michael Su, all of Vertex.

Vertex Pharmaceuticals Incorporated (Nasdaq:VRTX) is engaged in the discovery, development and commercialization of novel, small molecule pharmaceuticals for the treatment of diseases for which there are currently limited or no effective treatments. The Company is a leader in the use of structure-based drug design, an approach to drug discovery that integrates advanced biology, biophysics and chemistry. The Company is concentrating on the discovery and development of drugs for the treatment of viral diseases, multidrug resistance in cancer, autoimmune and inflammatory diseases, and neurodegenerative diseases.

There can be no assurance that compounds that are discovered on the basis of this research will be successfully developed into compounds for clinical testing, that clinical trials with compounds will commence or compounds will receive marketing approval from the U.S. Food and Drug Administration or equivalent regulatory authorities, or that drugs, if any, which receive such approval will be marketed successfully. Investors are also directed to consider other risks and uncertainties discussed in documents filed by Vertex with the Securities and Exchange Commission.

Vertex Pharmaceuticals

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