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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5943_Библиотеки_им_академика_М_И_Перельмана
.pdf
458
https://t.me/medicina_free
Index
Liver 126
Liver toxicity
LogicBio
Long-term risks
Lower limit of detection (LLOD)
Lower limit of quantification
Low-quality control (LQC) 232–233
Luminex
Luxturna 7, 26, 36, 38–40, 47, 64, 218,
Lysophosphatidic acids (LPAs)
Lysosomal storage disorders (LSDs)
Lysosomal storage enzyme
74–76
51
442
178, 232–233
(LLOQ)
249, 251
219, 323, 325, 431
activity
228, 233
280
242
70
m
Machine-learning 247
Maci 7
Manufacturing-related risk factors 120
Mass spectrometry (MS) 71,
216, 222–223
Matrix interference
Maximum tolerated dose (MTD) 102
Medicines and Healthcare products
Regulatory Agency
(MHRA)
Meganucleases 348
Messenger RNA (mRNA) 194
Metabolic diseases, AAV-mediated gene
replacement therapy 49–50
Methylmalonic acidemia (MMA) 51
4-Methylumbelliferone
(4MU) 226–227, 232
Mice, rAAV integration studies
in 318–322
Michaelis–Menten kinetics 224–225
MicroRNAs (miRNAs) 194
Middle-quality control (MQC) 232–233
Minimum required dilution
(MRD) 231
231
410, 420–421
MiSeq
359
Modeling gene therapy
Morphological factor
MPS I/MPS II/MPS IIIA/MPS VI
mRNA expression
MSD S600, 249, 250
Multiple reaction monitoring (MRM)
transition
Multiplexed epitope mapping 277
Multiplicity of infection
145, 146
(MOI)
Muscle toxicity 77
Muscular dystrophies 19
105–106
104
50
68
244
n
Nanodrop 200
Nanostring technology 260–261
National Cancer Institute (NCI) 434
National Institutes of Health
432–434
(NIH)
National Medical Products
Administration
(NMDA)
Natural tissue tropism
Neoplasia 318–324
Nephrotoxicity 79
Neurodegenerative diseases 9
Neurofilament light chain (NFL) 79
Neuromuscular diseases 273
Neutralizing antibodies (NAbs)
150–151, 271, 295, 396, 397
Neutralizing antibodies (NAb)
assay 137–138
Next-generation sequencing (NGS)
background 362
indel detection 359
bioanalytical characterization
of 364–369
sensitivity of 362–364
insertions and deletions 358
large genomic rearrangements 371
410, 421
90
Index 459
https://t.me/medicina_free
NextSeq 359
No-adverse event level (NOAEL)
dose
101
Nonclinical biodistribution
Nonclinical immunogenicity
assessment
Nonclinical shedding
Non-droplet digital PCR
Non-homologous end joining
(NHEJ)
Non-human primates (NHP)
123, 323
Nonimmune organ-specific toxicity
DRG toxicity 78–79
safety biomarkers for
target organ toxicity
Non-secreted proteins
Novartis
Nuclease-mediated gene disruption
Nuclease-mediated HDR
44
54–55
121
348, 349, 356
89–96
89–96
203
121,
78–79
79
218–220
52–54
o
Off-target gene editing 73–74
251
Olink
Onasemnogene abeparvovec
Ordinary differential equations
106
(ODE)
Ornithine transcarbamylase (OTC)
deficiency 50
103, 105
p
Parallelism 231
Parkinson’s disease 45
Pathogen-associated molecular patterns
(PAMPs) 439
Patient-related risk factors 120–121
Performance evaluation application
(PEA) 390
Peripheral blood mononuclear cells
(PBMC) 435
Pfaffl model
Pharmaceuticals and Medical Devices
Pharmacodynamic (PD)
functional protein activity
gene expression analysis 253–254
histology 246–248
immunoassays 249
LC-MS/MS
single-cell analysis 263, 265
Pharmacokinetic (PK)
Pharmacokinetic/pharmacodynamic
AAV dosing 101–102
clinical pharmacology
dose scaling 102, 104–105
dose selection 100–104
gaps and challenges in 108
259
Agency (PMDA) 386, 410, 421
biomarkers
nanostring technology 260–262
regulatory considerations 261–263
RNA-seq
RT-qPCR-based relative
quantitation 254–259
high sensitivity 249
multiplexing 249
technologies and
platforms 249–251
validation 249, 252–253
immunoassays vs. 244–245
lack of analyte-free matrices 242
method development 241–245
method validation 245–246
small molecule biomarker
quantitation 241
stability issues 241–242
surrogate matrix/analyte
approach 242–244
biomarkers 65–71
(PK/PD)
considerations 106–108
66–71, 239–241
248–249
259–260
241
460
https://t.me/medicina_free
Index
Pharmacokinetic/pharmacodynamic
(PK/PD)
availability of clinical samples and
bioanalytical assays
availability of long-term follow-up
data
interspecies differences 108–109
modeling gene therapy 105–106
recombinant AAV
Phenylketonuria (PKU) 49, 52
Physiologically-based PK (PBPK)
model
Polymerase chain reaction (PCR)
acceptance criteria 185–187
accuracy 181
amplification 170, 324
back-calculation formula
colinearity 181
DART-PCR 255
data reporting formats 184
ddPCR 166–171, 356, 358,
360, 365–366
digital PCR
efficiency 180
extraction efficiency assessment
172, 174–177
immunocapture qPCR
insertions and deletions 359–361
LAM-PCR 326–327
locus-specific 359
matrix interference
method development 168–171
precision
publications on 164
qPCR 164–168, 185–187, 435
quality control 185
rAAV integration 326–327, 331
regulatory guidance 163–164
RT-ddPCR 167, 196–204, 206–207
RT-qPCR 194, 196–204, 206–207,
254–259, 262–264
(continued)
109
109
100
106
22
172–175
164–168, 201, 203, 435
187–189
181–182
181
selectivity
sensitivity 177–179
specificity 163, 179–180
stability 182–184
standard curve performance
Pompe disease 50
Predictive biomarker 80–82
Preexisting anti-AAV capsid
Preexisting anti-capsid antibody 80–81
Preexisting anti-transgene protein
Premarket approval (PMA) 414–416
Prime editing 17
Prime editing gRNA (pegRNA) 17, 350
Primer extension-mediated sequencing
Process-related risk factors 120
Product/process-related impurity
Product-related risk factors 119–120
Proliferation assays 276
Provenge
181–182
180–181, 185
antibodies 123–124
antibody
(PEM-seq) 372, 374, 375
126–127
81–82
7
q
Q-Submission program 394
Quality control (QC) 185, 232–233,
243, 364
Quality management system
(QMS) 388, 419
Quansys Q-view imaging
system 249, 250
Quantitative polymerase chain reaction
(qPCR) 67, 94, 164–168, 185–187,
435. See also Immunocapture qPCR
r
rAAV-cDNA replacement therapies 35
approved 36
in clinical development 46–48
Index 461
https://t.me/medicina_free
Glybera 36–38
Luxturna
Zolgensma
rAAV integration
analysis
biologic relevance of
HCC development
in large animal species
mechanism of
in mice
PCR methods
TE 327, 331
Rapamycin
Rare disease, CDx for 423–424
Recombinant AAV (rAAV)
dose selection
innate immune response
invivo gene editing
Reflectance in situ hybridization
Regulation of CDx
Canada
China
European Union
global regulatory strategy
Japan 421
United Kingdom 420–421
US FDA
Relative quantitation, RT-qPCR-based
38–40
40, 43–45
326–328
335–337
72–73, 318–324
321, 323
318
318–322
326–327, 331
128
11, 63, 72
100, 104
118
48, 51–54
52. See also In situ
(RISH)
hybridization (ISH)
409, 410
421
421
clinical trials
IVDR 416–419
marketing authorization 418–420
510(k) process 413, 415–416
guidance documents 410
HDE process
IDE 410–412
marketing authorization 413–416
premarket approval 414–416
pre-submission feedback 416
255–259
416–418
421–422
409–410
414–415
Rep (replication) 63, 64, 318
Replication-competent virus 434–435
Rethymic 7
Retinitis pigmentosa (RP) 38, 42
Retinoschisis 42
Retroviral gene therapy
Reverse transcription ddPCR
(RT-ddPCR) 167,
196–204, 206–207
Reverse transcription qPCR
(RT-qPCR)
206–207, 254–259, 262–264
rhAmpSeq 361
Riboprobes 208
Rituximab
RNA interference (RNAi) 17–18
RNA-ISH
for discovery studies 204–205
hybridization and detection
probe preparation 208
signal quantification 210
steps in 205, 209
tissue section preparation
transgene expression
RNA quality number (RQN) 200
RNAscope 204, 265
RNA-seq 254, 259–260, 262
Roctavian 36
RPE65, 218–220
128
209–210
analysis 204–205, 208–210
3
68, 194, 196–204,
208
s
SABER-FISH technology 205, 208
Safety analysis 328, 329
Sanger sequencing 368
Sanger sequencing combined with
sequence trace decomposition
360, 368–369
Secreted proteins 220
Self-complementary AAV (scAAV) 68
462
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Index
Sequence alignment map (SAM)
format
332, 333
Sequencing
amplicon
CAST-seq
hybrid capture-based
next-generation sequencing
PEM-seq
whole genome sequencing
Serotype-specific TAb assay
Severe combined immune deficiency
Shedding 67–68
clinical
data
definition of
gaps and challenges
global regulatory guidance on
nonclinical
Shope papillomavirus
Short interfering RNAs (siRNAs)
Significant Risk Determination
SIMOA HD-X analyzer
Single-cell analysis
Single-stranded AAV (ssAAV) 68
SITE-seq 355–356
Skeletal muscle disease
Skysona 8
Small interference RNAs (siRNAs) 194
SMCxPRO
Spatial RNA integrity number
Spinal muscular atrophy (SMA)
Spinal muscular atrophy-type 1
Stable isotope-labeled internal standard
Standard curve method 259
359
359–361
372–375
372, 374, 375
333, 359
437
(SCID)
96–99
87
88
89–96
3
(SRD)
389
263, 265
251
200
(sRIN)
40, 43–45, 64, 217
323
(SMA1)
(SIL-IS) 243
360–362
358, 359
327, 328,
142–143
99–100
88–89
18
249, 250
48, 51
19, 29,
Staphylococcus aureus (S. aureus) 299
Statistical cut-points 148
Stratagraft 8
Streptococcus pyogenes
(S. pyogenes) 299
Substantial equivalence (SE)
Summary of technical documentation
(STED) 420
Surfactants 230, 242
Surrogate matrix/analyte 242–244
Survival motor neuron (SMN)
protein 36, 40, 217–218, 220
Synthetic DNA 365
413
t
Tagmentation 372
Target enrichment (TE) 327, 331, 333
Target organ toxicity 79
Target protein, activity and
concentration
T-cell-mediated immune
response 272–274
cytokine bead array 276–277
ELISPOT assay 274–276
gene expression profiling 277
ICS 276
multiplexed epitope mapping
proliferation assays 276
tetramer staining 276
Tecartus
Tetramer staining 276
Thrombotic microangiopathy
Total antibodies (TAbs)
Total antibody (TAb) assay 127, 137–138
8
(TMA) 52, 76–77, 440
analyte 138–139
antigen-capture format 139–140
bridging assay format 139, 140
cut-point 143–144
data interpretation 144
parameters 142–144
68–70
277
396
Index 463
https://t.me/medicina_free
precision 143
reagent considerations
capture and detection
negative control
positive control
sample testing strategy
selectivity/matrix interference 143
sensitivity 142
serotype specificity
standardization 156
Toxicity
biomarkers
genotoxicity
hepatotoxicity 74–76
immune-mediated toxicity 74–78
muscle 77
nonimmune organ-specific toxicity
Tracking of indels by decomposition
Transcription 253
Transcription activator-like effector
Transduction inhibition (TI)
cell-based 145
clinical relevance 146–147
cut-point
data interpretation 152–155
development 146–147
limit of detection
methodology of 145–146
MOI 145, 146
neutralizing antibodies
parameters 147–152
performance 152
precision 150
preexisting TI titer and clinical
438–442
72–74
78–79
(TIDE)
368–369
nucleases (TALENs)
298–299, 348
137–138
assay
147–148
detection 150–151
efficacy 152–155
140
141–142
141
140–141
142
142–143
15, 16,
148–149
principle of 145–146
sample testing strategy
selectivity/matrix interference
specificity
stability
standardization
Transgene
Transgene mRNA expression
ISH 204
purpose of measurement 193–196
RT-qPCR/RT-ddPCR 196–197
Transgene product
durability 107–108
modeling 106
variability in levels/treatment
Transgene protein 124–125
Transgene protein activity
method development
150
151–152
68–70
quantification
for discovery studies 204–205
hybridization and
detection
probe preparation 208
signal quantification 210
205, 209
steps in
tissue section preparation 208
assay qualification
co-extraction of DNA
and RNA
comparative overview of 202
extraction/purification 197, 199
quantification and quality
200–201
check
reporting 203–204
schematic of 198
validation 201, 206–207
response 106–107
determination 224
buffer 230
dynamic range 231
initial rate of reaction 225
152
151
156
68
209–210
201
199
464
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Index
Transgene protein activity
determination (continued)
matrix interference 231
Michaelis–Menten kinetics
224–225
231
MRD
parallelism 231
QCs 232–233
reference standard
sample processing 229
selectivity 232
specificity 232
substrate concentration 225–226
method validation
Transgene protein expression
quantification
assay format 221–222
immunoassays 222
222–223
MS
semiquantitative 223
human transgene
expressed therapeutics
intracellular proteins 216–218
non-secreted proteins
in preclinical species 216
secreted proteins 220
Transgene protein, humoral immune
response to 291
administration route 291–292
analytical methods 294–295
assay development 295–297
Bethesda assay 296
biodistribution 293
dose 293
electrochemiluminescence
assay 295–297
ELISA 295, 296
expression level 293
extracellularly vs.
intracellularly 297–298
immune status 293–294
226–228
234
215–216
221
218–220
immunoassay
response induction vs. boosting
294
serotype
Translocations
Trastuzumab
Treatment-emergent adverse events
(TEAEs)
Treatment-emergent serious adverse
events (TESAEs)
Treatment-induced anti-AAV capsid
antibodies
Triton X-100, 230
Tropisms, of AAV serotypes
Tumor-infiltrating lymphocytes
(TIL)
295
293
348–349, 370
385, 387
438
437
124
90, 120
437
u
UDiTaS 372, 374, 375
Unique molecular identifiers
361
(UMIs)
uniQure 36–38, 103
United Kingdom, CDx regulation
410, 420–421
Upper limit of detection (ULOD)
280–281
Upper limit of quantitation (ULOQ)
232–233, 255
Upstaza 36
v
Valoctocogene roxaparvovec 103, 105
Viral shedding. See Shedding
Virica Biotech 38
VirusBreakend 328
Virus-clip 328
VirusFinder 328
w
Western blot analysis 218–219, 223
Whole genome sequencing (WGS) 327,
328, 333, 359
Index 465
https://t.me/medicina_free
Whole transcriptome sequencing
(WTS) 328
Wild-type AAV (wtAAV) 317, 318, 324
Wilson disease 49, 248
World Health Organization (WHO)
433
x
X-linked myotubular myopathy
(XL-MTM)
X-linked RP 42
51
y
Yescarta 8, 431
z
Zinc finger nucleases (ZFNs) 3–4, 15,
16, 53, 298–299, 348, 351
Zinc finger proteins (ZFPs)
Zinc fingers
Zolgensma
Zynteglo
3–4
8, 36, 40, 43–45, 64, 75, 76,
217, 218, 323
8
349
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