H.H. Chartrand
April 2002
Exhibit 1
Biotech Pharmacological Glossary
Martin, C. J., Biotech Trends, Btech Investors, http://www.btechnews.com/sample_reports/BiotechTrends.pdf,
A B C D E F G H I J K L M N O P Q R S T U V X Y Z
Adeno Associated Virus (AAV) - A gene therapy vector which has been gaining
popularity recently in the medical community for its excellent safety profile.
Targeted Genetics and Avigen are
leaders in the use of AAV.
Adenovirus - A
family of naturally occurring DNA viruses which can cause flu-like symptoms in
people. The most popular gene
delivery system until the death of an adenovirus trial participant last year.
Now out of favor but still actively
pursued by several companies including Onyx and Introgen.
Adverse Effect Profile - Inventory of characteristic adverse effects, often
evaluated along a spectrum from low to high corresponding with a small to large
inventory.
Alzheimer Disease – A degenerative brain disorder that primarily effects
the elderly. Symptoms include
cognitive and memory decline, confusion, language disturbances, personality and
behavior changes, and impaired judgment.
Amyloid - Any
of a group of proteins that appears homogeneous under the light microscope but
is actually composed of specifically arranged aggregated fibrils when seen under
the electron microscope. Stained
with the agent congo red and visualized under planepolarized light, amyloid
proteins usually produce an “apple-green birefringency” pattern. Pathological deposition of amyloid is the
defining feature of Alzheimer disease, systemic amyloidosis, and amyloidosis
associated with the failure of virtually every organ/organ system, and can be a
feature of multiple myeloma, monoclonal B-cell tumors, the chronic kidney
failure associated with hemodialysis, medullary thyroid carcinoma, renal
osteodystrophy, carpal tunnel syndrome, and other diseases.
Angiogenesis -
Establishment of new blood vessels from preexisting ones. Also called
neovascularization. Preventing
angiogenesis is being investigated as a treatment for cancer.
Antibody - A
protein produced by immune system B cells. Antibodies defend against invasion by
foreign agents like viruses, bacteria or cancer cells. They work by binding to a marker called
an antigen.
Antisense - (1)
An engineered oligonucleotide whose sequence is complementary to a specific
gene, and thus has the ability to block protein production from that gene when
introduced into cells. (2) The name
of the strand of naturally occurring DNA that is subject to transcription—
making mRNA. The other strand, the “sense” strand has the same sequence as the
initially formed mRNA.
Apoptosis -
Programmed cell death through activation of an internally controlled, genetic
suicide program.
Avonex (Biogen) - An interferon β1-a formulation. To treat multiple sclerosis it attempts to reduce the risk of disability progression, decrease the number of exacerbations, and reduce the number and size of active lesions in the brain (as shown on MRI).
βamyloid Plaques - Protein deposits made out of
amyloid peptide that form on the brain of AD patients.
Bcl-2 - A
protein that protects cells from apoptosis (cell suicide). Tumor cells often turn on expression of
Bcl-2 to avoid cell death, and blocking activity of Bcl-2 is being explored as a
cancer therapeutic.
Betabloc - A
drug being developed by Élan that has been shown to have anti-βamyloid activity
in specific mice as both a treatment and a prophylactic. Also known as AN-1792.
Bioinformatics - The use of computer technology to process, analyze,
store, and retrieve biological data. Bioinformatics applies technology in
information management and mathematics to process the avalanche of data produced
in biological research, particularly in genomics and proteomics. An example of bioinformatics is the use
of computers to analyze information gained from DNA microarray experiments.
Bi-Specific Monoclonal Antibody - A chimeric monoclonal antibody whose two variable
regions each recognize a different antigen.
Cancer - One of
a group of disorders characterized by abnormal growth and proliferation of
cells. Cancers are labeled according to the tissue in which they began to grow.
All begin as a single, genetically
dysregulated cell. In the
Cell Therapy -
Using cells as a therapeutic. Many
cell therapies involve giving the patient their own cells which have been
removed, modified, expanded, and then reinjected. Lymphocytes, monocytes, and stem cells
are some of the cell types used in cell therapies.
Chemotherapy -
Treatment of disease by chemicals that have a direct effect on the
disease-causing organism or disease cells; widely used in the treatment of
cancer.
Chimeric Protein - A protein created in the laboratory by splicing
together two or more gene segments. Chimeric proteins often combine the
functions of two proteins into one.
Cholesterol -
The most common steroid in the body, it is essential in the formation of many
crucial compounds active in the body: bile acids (which aid in the digestion of
fats), Vitamin D, progesterone, estrogens (estradiol, estrone, estriol),
androgens (androsterone, testosterone), mineralocorticoid hormones (aldosterone,
corticosterone), and glucocorticoid hormones (cortisol). It is also important in preserving normal
architecture and function of the membranes that surround cells. In the bloodstream, cholesterol is
carried in a particle called a “lipoprotein,” as it is encased in proteins.
These aggregates vary in their
densities depending upon their levels are associated with an increased risk of
coronary heart disease. High-density lipoprotein (HDL)
cholesterol is the "good" cholesterol, as high HDL levels are associated with a
decreased risk of coronary heart disease. Very low density lipoproteins (VLDL)
are intermediate, although they tend toward being “bad.” Triglyceride levels correlate with VLDL
levels. Diets high in saturated fats tend to increase blood cholesterol levels
whereas diets high in unsaturated fats tend to lower blood cholesterol levels.
Though dietary cholesterol demands
a lot of attention, most cholesterol is made in the liver and other tissues.
The appropriate treatment of
elevated cholesterol includes diet, weight loss, regular aerobic exercise, and
cholesterol-lowering drugs in a majority of cases.
Chromosome -
Paired structures located in the nucleus of the vast majority of cells, each
contains about 2 inches of wound-up DNA. Each normal human cell contains 46
chromosomes — 22 pairs of autosomes and two sex chromosomes. Each parent contributes one chromosome to
each pair, so children get half of their chromosomes from their mothers and half
from their fathers. Sperm and egg
cells each contain 23 chromosomes — one of each pair and one sex chromosome.
There is also a chromosome in the
mitochondria, whose constituents and behavior are vastly different.
Conjugated Monoclonal Antibody - A monoclonal antibody carrying a payload, such as
radiation or chemotherapy.
Conjugation -
The process of chemically attaching two molecules, such as a monoclonal antibody
and another protein.
Cytokines -
Small proteins secreted by lymphocytes which initiate specific responses from
nearby cells.
Dementia - Mental deterioration often characterized by
disorientation, memory impairment, judgment impairment, and intellectual
decline.
Diabetes Mellitus- Disorder characterized by high levels of glucose in
the blood. Diabetes may be caused
by a failure of the pancreas to produce sufficient insulin or, more commonly, by
resistance of the body to the action of insulin.
DNA (Deoxyribonucleic Acid) - A nucleic acid that constitutes the genetic material
of all cellular organisms and DNA viruses. It is the main component of chromosomes.
A molecule of DNA consists of two
strands arranged in spiral ladder formation with side pieces composed of
phosphate and deoxyribose units and the "rungs" comprised of nucleotide bases
(adenine, cytosine, guanine, and thymine.) The genetic data are encoded in the
sequence of the nucleotides.
DNA Microarrays – A new way of studying how large numbers of genes
interact with each other and how a cell's regulatory network controls vast
batteries of genes simultaneously. The method uses a robot to precisely
apply tiny droplets containing functional DNA to glass slides. Researchers then
attach fluorescent labels to DNA from the cell they are studying. The labeled probes are allowed to bind to
complementary DNA strands on the slides. The slides are put into a scanning device
that can measure the brightness of each fluorescent dot; brightness reveals how
much of a specific DNA fragment is present, an indicator of how active it is.
Drug Targets -
Molecules, parts of molecules, molecular processes, and constituents of
molecular processes that can be affected by a drug. The best targets tend to have the
greatest degrees of specificity.
Ex vivo - Out
of the body. Often refers to manipulations done to a patient’s cells after
they’ve been removed. For example
giving gene therapy to harvested blood cells before re-injection is ex vivo
therapy.
Expanded Label Use - The use of a drug in a way both approved by the FDA
and permitted to be put on its label and advertised as its intended purpose.
Indications added to the label
identified as expanded label uses imply (1) that they were not on the label
prior to (2) acceptance of and approval for a supplemental biologic license
application (sBLA).
Fully Human Antibody - A monoclonal antibody derived from human genes. These
antibodies avoid the immune reaction against antibodies derived from mouse
genes.
Gene - The
functional and physical unit of heredity passed from parent to offspring. Genes are segments of DNA and most genes
contain the information for making a specific protein.
Gene Expression – A gene is expressed when its sequence is transcribed
into RNA. Most frequently, that RNA is an mRNA which is later translated into
protein. Although all genes of an organism are present in each cell, not all
genes are active in each. Some
genes are activated only in certain tissues; others are activated only in
response to certain environmental stressors. Studies of gene expression patterns are a
source of information about gene function.
Gene Therapy -
Treatment of a disease or condition by adding to or replacing a patient’s DNA.
GeneChip –
Affymetrix brand name for its DNA microarrays.
Genetic Marker - A polymorphic sequence of DNA with an identifiable
physical location on a chromosome and whose inheritance can be followed. A marker can be a gene, or it can be some
section of DNA with no known function. Because DNA segments that lie near each
other on a chromosome tend to be inherited together, markers are often used as
indirect ways of tracking the inheritance pattern of a gene that has not yet
been identified, but whose approximate location is known. Markers can also be exploited for
mapping.
Genetic Predisposition – Susceptibility to disease, conditions or traits due,
at least in part, to the characteristics of an individual’s or family’s DNA.
Genetic Screening - Testing a population group to identify a subset of
individuals at high risk for having or transmitting a specific genetic disorder.
Genetic Variation - Differences in genetic composition at any given level:
total genome, sub-genomic, chromosomal, genic/allelic, or nucleotide. Most often, the biotechnology industry
uses differences at the level of the DNA sequence, specifically at the level of
the allele or single nucleotide. Variation at these levels gives rise to
polymorphisms, DNA spellings
along analogous stretches (loci) of DNA, the differences of which may be
associated with disease, freedom from disease, drug response, lack of drug
response, adverse effects, and other human traits. The origins of genetic variation are
direct consequences of sexual reproduction: (1) mutations (altering DNA by
changing base pairs), (2) segregation (random distribution of one of each
chromosome pair into sperm or egg), and (3) recombination (an event in sperm and
egg cell development [meiosis] during which specific DNA is “shuffled”). These processes make each
sexually produced individual unique and provide the basis of genetic variation.
Genetics - The
science of biological inheritance.
Genome - All
the DNA contained in an organism or a cell, which includes both the chromosomes
within the nucleus and the DNA in mitochondria.
Genomics -
Study of the genome, the complete complement of DNA in an organism.
Growth Factor - Any of an array of molecules that are known to mediate
cell growth, often also associated with cell differentiation, locomotion, and
contractility. Many are involved in
essential developmental processes, fundamental cell and tissue repair processes,
and wound healing. Growth factors
are peptides, similar in structure to hormones.
HER2 Gene - A
gene overexpressed in approximately 30% of metastatic breast cancers. Its
overexpression is associated with poor clinical outcomes such as metastasis,
resistance to chemotherapy, and short survival. This gene also tends to be overexpressed
in a substantial proportion of patients with poor-outcome ovarian cancer and non
small cell lung cancer. Its expression in normal, healthy adult tissue is low.
The gene encodes a specific
receptor in the epidermal growth factor receptor (EGFR) family, a cadre of
receptors known to be overexpressed in cancers of the head and neck, kidney,
bladder, prostate, and colon.
Herceptin -
Genentech’s monoclonal antibody formulation directed against the HER 2 gene, for
the treatment of breast cancer.
Hormone - A
substance secreted in the body and carried through the bloodstream to various
tissues, where it serves a regulatory function.
Humanized - A
technology that assembles monoclonal antibodies by attaching several small
pieces of the antibody derived from a mouse to the basic framework of a human
antibody. The goal is to decrease
the chance of an adverse immune response.
Hybridoma - An
immortal cell with unique properties made in the laboratory from the fusion of a
tumor cell and a normal cell.
Hypoglycemic -
(1) Relating to a state of hypoglycemia - deficiency of sugar in the blood. (2)
An agent designed to lower blood sugar.
Hypotension - Low blood pressure.
Insulin - A
hormone made by the pancreas or taken by injection that regulates the amount of
sugar (glucose) in the bloodstream.
Knockout Mouse - A strain of mouse engineered to lack the expression of
a specific gene or genes.
Malignant - (1)
Regarding abnormal growths, it implies potential or actual spread to other areas
of the body (potential or actual metastasis), and implies the existence of
cancer. (2) Resistant to treatment or severe, as in malignant hypertension.
Monoclonal Antibody - A laboratory-engineered antibody, derived from a
single cell, that recognizes a specific antigen.
Multiple Sclerosis - A neurodegenerative disease caused by damage to the
brain and spinal cord, particularly to the myelin sheath which surrounds nerves.
Mutation - A
heritable alteration in a DNA sequence or chromosome.
Naked DNA - The
simplest form of gene therapy in which the gene and control regions are injected
without a vector into the patient.
Neurodegenerative Disorders - Disorders characterized by the death of neurons and/or
related cells. Alzheimer disease,
Parkinson disease, Friedreich Ataxia, Multiple Sclerosis, and Amyotrophic
Lateral Sclerosis are the prototypical neurodegenerative disorders.
Neuron - Nerve
cell; cells transmitting electrical signals that make up the brain, spinal cord,
and peripheral nerves.
Neurotransmitter - A chemical that is released by a presynaptic cell that
crosses a synapse to stimulate a postsynaptic cell. Different types of neurons release
different neurotransmitters.
Non-Hodgkin Lymphoma (NHL) - One of two main categories of lymphoma involving
cancerous growth of B or T cells. About 85% of NHL are of B cell origin
compared to about 15% of T cell origin.
Orphan Drug - A
drug targeted to treat an Orphan Disease, which is a condition affecting a
population less than 200,000. The
Orphan Drug Act offers tax credits, protocol assistance, research grants and a
seven-year monopoly on drug sales as incentives to pharmaceutical companies to
develop and manufacture Orphan Drug.
Parkinson Disease - A neurological disorder characterized by shaking and
difficulty with walking, movement, and coordination. The disease is associated with damage to
specific parts of the brain that control muscle movement.
Payload - A
substances attached to a monoclonal antibody to improve its effectiveness. Payloads can be radiation,
chemotherapeutics, enzymes, or other molecules.
Phage Display -
A laboratory technique used to screen for particular proteins produced by
viruses. Phage display can be used
to identify fully human antibodies that bind to a particular target antigen.
Pharmacogenomics - Genome-wide analysis of the genetic determinants of
drug efficacy, toxicity, pharmacokinetics, and pharmacodynamics in order to
correlate genetic variation with drug response.
Plaques –
Patchy area on a body surface or cut surface of an organ, often described by the
constituents of the area. Plaque formation on neurons is associated with
neurodegenerative disease.
Protein - One
of a group of large, complex molecules consisting of chains of amino acids
linked together, containing carbon, hydrogen, oxygen, nitrogen, and (often)
sulfur.
Proteomics -
Molecular characterization of the proteins found in an organism, with an
emphasis on unraveling the systematic interactions of the proteins within the
living cell. The technology involves large scale ("highthroughput") protein
separation and identification. Proteomics will provide the link between
genomics and drug discovery by elucidating the function and interaction of
proteins in vivo and identifying potential therapeutic targets. Proteomic research will depend in part on
the development of sophisticated database and information technology tools.
Radiation - A
stream of particles or electromagnetic waves emitted by the atoms and molecules
of a radioactive substance as a result of nuclear decay. Radiation treatment interferes with
growth and replication of cancer cells by changing the structure of molecules
that make up the cell's DNA.
Rh System – A
series of antigens on red blood cells whose combinations define an individual as
Rh-positive or Rh-negative. Rh-positive individuals express the Rh- D antigen on
their red blood cells and Rh-negative individuals do not. The major clinical significance of this
is that Rh-negative persons can form anti-Rh antibodies after exposure to
Rh-positive red blood cells. When
an Rh negative pregnant woman carries an Rh positive fetus, then, the fetus is
at risk for “hemolytic disease of the newborn” as small amounts of fetal blood
cross the placental barrier and reach the maternal circulation. When the mother forms antibodies that
return to the fetal circulation to damage the fetus’s red cells, the cells can
break apart with potentially fatal consequences. Now that genotyping and phenotyping can
reveal this clinical potential, and intervention (including Ortho- Clinical’s
RhoGam and Bayer Biological and Nabi’s Rh Immune globulin) can be established,
the disorder has gone from the most common human genetic disorder to a
relatively rare entity. Rh-related transfusion disorders are rare.
RNA (Ribonucleic Acid) - A nucleic acid found in cells that have nuclei. RNA
serves as a messenger between different structures in the cell and plays a key
role in the synthesis of proteins based on the "instructions" received from DNA.
In some viruses RNA serves as the
genome.
Single Nucleotide Polymorphism (SNP) - Variations in a single nucleotide base that occur in
DNA. In humans, these variations
occur at a frequency of one every 1,000 bases. These variations can be used to track
inheritance in families. SNP is
commonly pronounced "snip. " SNP discovery refers to the identification of a
specific location within a DNA sequence where there is variation in a single
nucleotide base across a population. SNP scoring refers to the measurement of
the presence or absence of a particular SNP in the DNA sequence of a particular
individual. Used in
pharmacogenomics as a tool for diagnostics, drug discovery, clinical trials, and
for anticipating drug responses.
SNP - See
single nucleotide polymorphism.
Statin - The
colloquial name for a one of a class of drugs that lowers cholesterol,
especially the low density lipoprotein (LDL) fraction. Statins inhibit HMG- CoA reductase, an
enzyme that controls the rate of cholesterol production in the body. They lower cholesterol by both slowing
down cholesterol production and increasing the liver's ability to remove
LDL-cholesterol already in the blood. The clinical value of cholesterol
reduction is large reductions in the rates of heart attacks (myocardial
infarction) and heart disease-related deaths. Statins, in certain individuals, produce
a modest increase in HDL-cholesterol (the “good” cholesterol) and reduce
elevated triglyceride levels. Statins may also strengthen bone tissue,
inhibit the accumulation of the β-amyloid found in Alzheimer disease plaques,
and target proteins in blood vessel walls such as to improve certain aspects of
vascular integrity.
Stem Cells -
Undifferentiated cells with the capacity to be both self-renewing and to
differentiate into multiple cell types.
Target -
Molecules, parts of molecules, molecular processes, and constituents of
molecular processes that can be affected by a drug. The best targets tend to have the
greatest degrees of specificity.
Target Validation - The process of demonstrating, by a variety of
techniques, that a drug interacting with a given target could have a therapeutic
effect.
Telomerase -
The enzyme that lengthens telomeres.
Telomeres -
Repeating sequences of DNA at the ends of each choromosome that shorten every
time a cell divides. When a
telomere is completely eroded, the cell dies. Self-renewing cells, including tumors,
must activate an enzyme called telomerase to maintain telomeres.
Transdermal -
Relating to, being, or delivering a medication in a manner for absorption
through skin into the subcutaneous tissue and/or bloodstream.
Transgenic - A
genetically modified organism that contains a modified or novel gene. Transgenic technology is different from
gene therapy because the genetic change is made early during embryonic
development, therefore occurring in every cell and inherited by offspring of the
transgenic organism. Transgenic
technology has been applied to both plants and animals.
Validated Target - A drug target, usually a protein, that has been
demonstrated by any of a variety of methods to have therapeutic potential.
Vector - A gene delivery system. Vectors can be modified viruses or artificial constructs such as liposomes.