A
acromegaly 82
active pharmaceutical ingredient 183
ADME 180
adrenaline 26
adrenoreceptor 26
AIDS. See HIV/AIDS
albuterol 29
Allen & Hanburys 29
Alnylam
Alnylam’s oligomer pipeline 132t
oligomers in development 82, 123, 130–134
start 137
alpha-calcitonin gene-related peptide 59
Alternative splicing example 60f
Amgen 145
AMPA 60
amyloidosis
described 131
oligomers in development 123, 132
amyotrophic lateral sclerosis. See ALS
Anatomical Therapeutic Chemical (ATC) classes 27
anemia
oligomers in development 124, 132
prevalence 131
thalassemia 133
Animal Rule 116
animal toxicology studies 179–182
anthrax
about 95
diagnosis 104
vaccine 97
antibacterial treatments 97
antibiotics
antisense 103
bacterial resistance 98
first 97
new drugs 100
overuse of 96
antidepressant fluoxetine 65
antimigraine triptan drugs 27
antisense
antibiotics 103
antiviral (first) 121
table of antisense oligomers 123–124
targeting pre-mRNA 57
technology developed by ISIS 129
aspirin 21
atrial fibrillation 49
Ayurvedic medicine 16
B
bacteria
See also bacterial resistance
about 93
as disease pathogen 98
diseases 95
first observation 96
healthy 94
prevalence 95
threat of resistance 93
uses 96
bacterial genome 94
bacterial resistance
deaths from 102
described 98
ESKAPE organisms 100
gene sequencing and 103
geographical prevalence 101
new antibiotics 99
Bai, H. 103
Banting, Frederick 22
basic research phase for drug approval 179
Bauhin, Jean 19
Becker muscular dystrophy 88–89
Beecher, Henry 24
Best, Charles 22
beta-blocker 26
bibliographic references 227–229
BigPharma 138
biomarkers 154
Biomedical Advanced Research and Development Authority 114
bird flu virus 116
blood pressure clinical studies 186
blood tests 205
botulism 114
breast cancer 5
bronchiectasis 71
bugs. See bacteria; viruses
building blocks of life 33
C
calcitonin 59
Canadian Organization for Rare Disorders. See CORD
cancer
about 5
carcinogenicity in animal studies 183
categorizing 121
in chickens 53
gene mutations and 41, 136, 137
oligomers and 136
oligomers in development 123, 124, 132
prevalence in children vs. adults 79
carbonic anhydrase inhibitors 23
carcinogenicity trial 183
Center for Drug Evaluation and Research 74, 169
Center of Biologic Evaluation and Research 74
chemistry, manufacturing, and controls phase for drug approval 183–184
children
cancer in 79
cancer mutations 136
cystic fibrosis 70
death rate from rare disease 76, 78
monogenic disease 55
prevalence of disease 28, 51, 78
St. Vitus Dance 19
cholesterol problems 120, 125, 132
chromosomes 38
chronic obstructive pulmonary disease 121
Church, Professor George 37
cimetidine 29
Clinical Investigator Brochure 190
clinical research
gene database 154
oligomer development 155
clinical studies
Investigational Review Boards 189
pediatric data 170
clinical studies in humans phase for drug approval 184–187
Collip, Bertram 23
colon cancer 5
Committee for Medicinal Products for Human Use in Europe 173
Committee for Proprietary Medicinal Products 171
Conference of Drug Regulatory Authorities 175
CORD 86
coronary heart disease 121, 122, 124, 125
cortisone 22
Coumadin. See warfarin
craniosynostosis 83
Crestor 125
Crick, Francis 63
The Critical Path Initiative 168
Crohn’s disease 123
Crooke, Dr. Stan 130
Cruz, Martin de la 18
Culpeper, Nicholas 20
cystic fibrosis 55, 69–71, 77, 104
cytomegalovirus retinitis 121
D
Dalton, John 3
deCODEme genetics 144
Demonstration report from deCODEme 146f
Dengue 107
deoxyribonucleic acid. See DNA
diabetes
oligomers in development 123, 124
predicting 4
diagnosis errors 158
Disease categories targeted by Designated Orphan Drugs 80f
diseases
See also rare genetic diseases
bacteria 98
chronic and common 119
current treatments 2
gene factor 41
genetics and 119
new tools to treat 1
predisposed 5
protein non-production 55
rare, and targeted drugs 51
rare, definition 28
rare vs. common 76
single-gene defects 55
treatment strategy shift 10
disease traits 144
DNA
antisense 57
bacteria 94
base pairing 36f
binding to RNA 53
storing non-genetic information on 37
DNA testing. See genetic testing
Domagk, Gerhard 23
double-stranded RNA 106
The double strand formation of DNA 37f
Drosophila melanogaster. See fruit fly
drug development
agencies that oversee 161
animals 25
animal testing 179
attributes for developing oligomers 129–130
bioterrorism counter measures 115
changes needed 11
companies testing oligomers 134
company partnering 128
confirming potential drug 24
container materials 183
discovery and licensing 25
Duchenne muscular dystrophy 90
efficacy requirements 166
FDA approval process 167
FDA Orphan Drug Approvals in First Nine Months of 2010 212
Japan 174
large vs. small companies 138
measuring results 186
new drug, approval process 178
oligomer development 162
oligomer review 169
OSWG consensus guidelines 163
Big Pharma partnerships 138
patent protection 129
post-approval monitoring 190
regulations for rare disease drugs 177
regulatory agencies 162
risks vs. benefits 194
safety regulation deficiencies 169
safety requirements 166
side effects 63
speed of development 194
therapeutic oligomers 176, 198
treatment INDs 168
drug discovery phase 178
drug manufacturing
costs 195
FDA inspection 165
regulating 161
drug patents 167
drug regulation
oligomers, obstacles 177
safety review 165
drugs
Anatomical Therapeutic Chemical (ATC) classes 27
bacteria for antibiotic production 96
classes 26
first biologic 22
future of 28
implanted devices 202
inhalation 201
insulin 22
microbe resistance 26
misbranding 164
number by beginning of 21st century 27
placebo effect 24
platform technologies 31
slow delivery 202
targeting faulty DNA messages 10
Top 20 Drugs in 2010 in the U.S. by Annual Sales 211t
drug testing 24
Duchenne, Guillame xiii
Duchenne muscular dystrophy (DMD)
about xii
case of xi–xiv
causes 55
converting to BMD 89
mechanisms 88
mutation data storage 87
oligomers in development 82, 87, 123, 124
PRO051 188
treating 208
TreatNMD meeting 176
variants and drug development 208
E
E. coli 104
Ebola
cause 106
described 112
outbreak in Uganda 117
Ebola virus
accidental infection 113
bioterrorism threat 114
oligomers in development for 123
Ehlers-Danlos Syndrome Type IV 83
Ehrenberg, Christian Gottfried 97
electronic medical records 199, 203
Encyclopedia of DNA Elements Consortium 41
enzyme replacement strategies 51
epilepsy 60
errors in diagnosis 158
ESKAPE organisms 100
ethics committees 189
eukaryotes 94
European Medicines Agency 161, 171–174
European Organization for Rare Diseases. See EURORDIS
EURORDIS
described 83
patient stories 84
scope 73
F
familial hypercholesterolemia 126–127
farnesyl transferase inhibitor 78
FDA Orphan Drug Approvals in First Nine Months of 2010 212t
filoviruses
Fleming, Alexander, Sir 25
Fluoroquinolone-resistant Pseudomonas aeruginosa 99
fluoxetine 30
fluvoxamine 30
folk medicine 14
Food, Drug, and Cosmetic Act 165
Food and Drug Act 164
Food and Drug Administration
bioterrorism 116
drug development regulations 161
Food and Drug Administration Act 169
Food and Drug Administration Modernization Act 170
Food and Drug Administration structure OOPD vs. OND 75–76
Four-base pairing in DNA 36f
Franklin, Rosalind 34
Friedman, Theodore 56
fruit fly
alternative splicing 61
genetics 43
Fuchs, Leonhart 19
future hospitals
small vs. huge 204
specialists 198
future of medical care
cost of new therapies 193
doctor involvement 207
doctor-patient relationships 12
doctors as genetic scientists 141
doctors’ role 157
drug testing 155
gate keepers 153
hospital facilities 11
knowledge required of doctors 156
specialized hospitals 197
future of surgery 204
future pharmacies
funding 193
new gene therapies, supply chain for 195–197
special pharmacies 196
G
Gaucher’s disease 51
gene database 154
gene mutations
in frame vs. out of frame 88–89
single gene defects 51
variations of diseases 208
genes
described 33
faulty 5
fruit fly 43
largest 39
mutations 4
protein production 38
gene therapy
camouflaging the RNA message 57–62
cell penetration 9
costs of manufacturing 195
distribution 145
first use of oligomer 54
future administration 197
oligomers 87
overcoming bacterial resistance 103
patch vs. gene replacement 206
replacing defective DNA 56
resurrecting abandoned drugs 67
safety 49
side effects 145
timing of giving 209
geneticists
botanists and 61
current medical care 141
oncologists and 142
Gerard, John 19
Gerhardt, Charles 21
germ theory 97
glanders 114
GlaxoSmithKline 29, 90, 135, 188, 190, 211
glioma 82
government agencies for rare diseases 74–76
G-protein coupled receptors 4
Groom, Colin 4
H
Harvey, William 79
Hatch-Waxman Act 167
heart attack and erythromycin 66
heart disease 41
hemophilia 132
hepatitis B 108
hepatitis C 106
herbalism
China 14
Egypt 15
Muslim 17
Sumeria 15
hereditary transthyretin amyloidosis 82
H5N1 bird flu virus 116
Hippocrates 16
Hippocratic Oath 156
Hirschsprung disease 83
histamine H receptor antagonists 27
History of medicinal use from primates to the present 16f
history of medicine
first millennium 17
second millennium 17
third millennium 27
China 14
Europe 16
France 21
Germany 21
India 16
Italy 21
prescriptions 15
primates and non-humans 13
Sumeria 15
home intravenous antibiotic therapy 70
Honore, Tage 60
Hopkins, Andrew 4
hospital facilities in the future 11
human genome
diagnosing diseases 157
drug development and 3
Encyclopedia of DNA Elements Consortium 41
future specificity 153
impact 1
interpreting sequencing results 6–7
personal sequencing and clinical trials 67
sequencing COX-2 inhibitors 65
sequencing impact 120
sequencing individuals 6
spit swabs at birth 205
Human Microbiome Project 93
human papilloma virus 108
Hunt, John 46
Huntington’s disease 131
Hutchinson-Gilford progeria syndrome 77–79
hydrofluoroalkane 29
hypertension 186
I
Incidence of infection by MRSA, VRE, FQRP 99f
Incidence of MRSA 101f
indalpine 30
infectious diseases 206
inflammatory bowel disease 123, 124
influenza, oligomers in development for 107, 123
influenza virus 116
information exchange 195
Ingram, Vernon 45
inhalation drug delivery 201
insulin 22
International Conference on Harmonization 162, 174–176
Isis Pharmaceuticals
fomiversen 121
mipomersen development 124, 126
start 137
J
Jenner, Edward 107
Journal of RNAi and Gene Splicing 52
junin virus 114
K
Keilin, David 23
Kendall, Edward 22
kidney cancer 124
kinases 4
Kole, Ryszard 134
Kraut, Karl-Johann 21
Kynamro. See mipomersen
L
Leeuwenhoek, Antonie van 96
Life Technologies 144
Lilly, Eli 23
Lipitor 125
liver cancer 131
Location of CRE in the United States 101f
Loeffler, Friedrich 105
lonafarnib 78
Lou Gehrig’s disease. See ALS
lysozyme 25
M
macrolide antibiotics 65
malaria 133
Mann, Thaddeus 23
Marburg virus
described 109
hemorrhagic fevers 106
post 109
sources 108
transmission 109
maximum tolerated dose 181
Mayo Clinic 22
MDR anthrax 114
measles 108
medical care
See also future of medical care
physicians’ skills 11
today 2
medical education 11
medical records
availability 156
MedWatch program 190
melioidosis 114
Memorial Sloan-Kettering Cancer Center 5
Mendel, Gregor Johann 62
meningitis production contamination case 161
messenger RNA. See mRNA
measuring results of drugs 186
Methicillin-resistant Staphylococcus Aureus 99
Miescher, Friedrich 34
Ministry of Health, Labor, and Welfare in Japan 174
mipomersen
familial hypercholesterolemia 126–127
monoclonal antibodies 3
mRNA
production questions 46
multicystic dysplastic kidney 72
multi-drug resistant TB 102
mumps 108
myotonic dystrophy 176
N
National Organization for Rare Disorders 80–83
Navigenics 144
New Molecular Entities 73
no adverse effect level 181
non-arteritic ischemic optic neuropathy 82
nuclear hormone receptors 4
O
obesity 41
Office of Orphan Product Development 74, 177
oligomer development
attributes for successful development 129
to combat bioterrorism 115
to combat Ebola and Marburg 113–114
companies doing testing 134–136
currently in development 122
FDA approval process 169
regulatory review 194
oligomers
as antibiotics 103
antiviral 107
APO B blockers 125
cancers and 136
cancer stopping 57
cell penetration 139
for cholesterol problems 125
described 183
exon splicing 61
first active 53
gene mutations and 137
lab vs. live animal cells 139
purpose 87
target 119
as therapy for common diseases 120
Translation Suppressing Oligomer 122, 130
Oligomers currently in clinical development 82t
Oligonucleotide Safety Working Group 163, 185
Oligonucleotide Therapeutic Society 195
Oliver, George 26
oncologists and geneticists 142
ovarian cancer 5
P
Papyrus Ebers 15
Parkinson, John 19
pasteurization 97
Pediatric Committee in Europe (PDCO) 173
Pediatric Research Equity Act 171
pegaptanib 137
Pfizer 4, 125, 132, 135, 138, 211
Pharmaceutical Research and Manufacturers of America 27
Pharmaceuticals and Medical Devices Agency 161
Pharmaceuticals and Medical Devices Agency in Japan 174
Phase I clinical studies 184–186
Phase II clinical studies 186–188
Phase III clinical studies 188
Phase IV trials 191
The phosphate-deoxyribose backbone of DNA 37f
phosphodiesterases 4
phosphorodiamidate morpholino oligomer 104, 123t
physicians and genome information 11
Piria, Raffaele 21
placebo effect 24
plague 114
Pliny the Elder 17
Pokemon gene 5
polio 107
predicting drug behavior in humans 180
pre-mRNA
camouflaging mutations 87
production of mRNA 41
fruit fly example 43
production 39
primates as teachers 13
privacy 155
Project Bioshield 114
propranolol 26
Prosensa 82, 90, 124, 136, 138, 188, 208
proteases 4
protein families 4
proton pump inhibitors 27
Prozac. See fluoxetine
Q
QT interval prolongation 66-67
R
rabies vaccine 97
ranitidine 29
Rare Disease Act 73
Rare Disease Day 86
Rare Disease Program 74
rare genetic diseases
about 72
death rate 76
definition in Japan 76
definition in U.S. 73
drug development focus 77
EURORDIS support 84
legislation 73
rarest 79
raxibacumab 116
Ray, John 19
refractory anemia 132
regenerative medicine 203
reproductive toxicology 182
respiratory syncytial virus 131, 132
Rhazes 17
rheumatiod arthritis 123
riobose-5-phosphate isomerase deficiency 79
risks and benefits of drugs 194
RNA
See also mRNA; viral RNA
binding to DNA 53
described 34
siRNA 135
stranded 106
RNA virus types 106
Roblin, Richard 56
Roosevelt, Franklin D. 165
Rous, Peyton 53
Royal College of Physicians 21
RSV infection 123
rubella 108
S
Salvarsan 22
Sarepta
research 104
start 137
SARS influenza 106
Schafer, Edward 26
schizophrenia 153
selective serotonin receptor antagonists 27
selective serotonin reuptake inhibitor 30
Serturner, Friedrich 21
Shen Nung 15
Shrewsbury, Prof. John F.D. 95
sickle cell anemia 45, 56, 132, 133
The similarities and differences between the FDA’s OOPD and OND RDP 75f
single nucleotide polymorphism 143
single-stranded RNA 106
siRNA 135
small molecule drugs
advantages 50
described 3
smallpox 114
smallpox virus 107
Sohail, Muhammad 52
Spanish Flu (1918) 116
Spinal Muscular Atrophy 176
spinal muscular atrophy 82
spit swabs at birth 205
spliceosomes 61
splicing
alternative, using plants 61
described 41
failure of 55
St. Vitus Dance 19
staphylococcus aureus 104
statins 125
Stephenson, Mary 53
stomach ulcers 29
Stretton, Antony 46
sulfanilamide 23
sulfanilamide elixir tragedy 165
Sushruta Samhita 16
Sydenham, Thomas 19
Sydenham’s Chorea 19
T
thalidomide 166
Thies, Dr. William 4
Top 20 Drugs in 2010 in the U.S. by Annual Sales 211t
Total number of new antibiotic approvals in the U.S. for five year periods 100t
toxicology studies in animals phase for drug approval 179–182
training
continuing medical education requirements 157
genetics and future clinical studies 154
Transcription initiation 40f
translation suppressing oligomers 130
treatment INDs 168
TreatNMD 176
Trefouel, Therese 23
tuberculosis
antibiotic resistance 102
history of 96
shorter oligomers for 104
tularemia 114
The 22 pairs and two sex chromosomes of a human 38f
23andME 142
The 27 EU Member states 173f
typhus 114
U
U.S. Department of Defense 113
Ustinov incident 110
V
vaccination 107
Vancomycin-resistant Enterococci 99
Various oligomers in clinical development 124f
Ventolin. See albuterol
Vioxx
adverse reaction over time 64–65
post-approval monitoring 190
viral RNA
compared to human mRNA 106
treating 107
viruses
See also filoviruses
about 33
cancer and 54
concerns about highly transmissible 112
described 105
how interrelated 106
RNA virus types 106
species jumping 108
volume of 105
Vitravene. See fomivirsen
W
warfarin
about 8
and atrial fibrillation 49
gene variations and response to 50
Wegener’s granulomatosis 83
Wiley, Harvey Washington 164
Wilkins, Maurice 35
World Health Organization 175
Worshipful Society of Apothecaries 19
Wurtzel, Elizabeth 30
Z
Zantac. See ranitidine
zimeldine 30