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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5423_Библиотеки_им_академика_М_И_Перельмана
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18 Current Regulatory Landscape forGene Therapy Product Development and theRole ofBiomarkers
https://t.me/medicina_free
448
66 Maus, M.V., Haas, A.R., Beatty, G.L. etal. (2013). T cells expressing chimeric
antigen receptors can cause anaphylaxis in humans. Cancer Immunol. Res.
1 (1): 26–31.
67 Khan, A.N., Chowdhury, A., Karulkar, A. etal. (2022). Immunogenicity of CAR‐T
cell therapeutics: evidence, mechanism and mitigation. Front. Immunol.13.
68 Wagner, D.L., Fritsche, E., Pulsipher, M.A. etal. (2021). Immunogenicity of CAR
T cells in cancer therapy. Nat. Rev. Clin. Oncol. 18 (6): 379–393.
Index
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449
a
AAV-based invivo gene therapy 63–64
advantages of
biomarkers
cDNA replacement
cell entry and transduction
process 12–13
challenges of
clinical trials
CNS
19
developments in
durability
effectiveness of
genome editing
hemophilia A 20–21
immunogenicity
liver 19
malignancy 24
market assessment 24–26
muscular dystrophies 19
patient advocacy groups 25
scalability issues
serotypes and tissue affinity 18–19
technology platforms of 14–15
toxicity 14
vector structure 11–12
13
19–20, 23
15
14, 22–23
9–10
10
23–24
13
15–17
24
22
AAV data analysis methods 328
clonality analysis
genome rearrangements 332
genotoxic integration
impurity analysis 332
integration site analysis
library preparation methods 328, 330
primary analysis
safety analysis
AAV delivery
challenges and opportunities
nuclease-mediated gene
disruption
AAV8 empty capsids 72
AAV germline transmission risk 73
AAV integration
biologic relevance of 335–337
carcinogenicity 324–325
HCC development 318–324
mechanism of 318
nonclinical studies 325
vectors 318
AAV vector-mediated insertional
mutagenesis risk 72–73
Abecma 6
Achromatopsia 41
333–334
334–335
332–333
331–332
328, 329
56
54–55
Drug Development for Gene Therapy: Translational Biomarkers, Bioanalysis, and Companion
Diagnostics, First Edition. Edited by Yanmei Lu and Boris Gorovits.
© 2024 John Wiley & Sons, Inc. Published 2024 by John Wiley & Sons, Inc.
450
https://t.me/medicina_free
Index
Adaptive immune response
AAV-mediated activation of
animal models for assessing
Adeno-associated viruses (AAVs)
antibodies
discovery of
dose selection
recombinant
replication-deficient
serotypes
vector structure
wild-type 12, 72, 74, 317, 318, 324
Adenosine deaminase deficiency
Adstiladrin
Advocacy groups
Afferent transvenular retrograde
Albumin
Alpha-fetoprotein (AFP)
American Society of Gene & Cell
Amplicon sequencing
Amplification efficiency
AMP-seq
AMT-130, 103
Animal models
adaptive immunity assessment
innate immunity assessment 122
Annual distribution number
Anti-AAV capsid antibodies
preexisting
treatment-induced
Antibody-dependent cellular cytotoxicity
Antibody-dependent cellular
Anti-Cas9 immunity 301–304
Antigen-capture assay format 139–140
20
3, 11
101–103
11
18–19, 63, 90, 120, 323
11–12
437
(ADA)
6
25, 26
extravasation (ATVRX)
51
Therapy (ASGCT)
359–361
371, 374, 375
122–123
(ADN) 415
123–124
124
(ADCC) 124, 125
phagocytosis (ADCP) 124, 125
118–119
122–123
64
292
322
25
255
Antigen-specific ELISPOT assay 279, 285
Anti-retroviral therapy (ART) 55
Anti-transgene protein responses 291
administration route 291–292
analytical methods 294–295
assay development
Bethesda assay 296
biodistribution 293
dose 293
electrochemiluminescence
assay 295–297
ELISA 295, 296
expression level 293
extracellularly vs. intracellularly
297–298
immune status
immunoassay 295
response induction vs. boosting 294
serotype 293
Arginase 3
Artificial intelligence 247
Askbio 25
295–297
293–294
b
Baculovirus-infected insect system
12, 22
Barisoni Lipid Inclusion Scoring System
(BLISS) 247
Base editing
Basic local alignment search tool for
Bethesda assay 296
Biochemical methods
Biodistribution (BD) 66–67
clinical 96–99
data 87
definition of 88
gaps and challenges 99–100
global regulatory guidance on 88–89
modeling and simulation of 106
nonclinical 89–96
17
protein (BLASTP) 243
354
Index 451
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Biomarkers 19
categories 65–66
concept of 65
definition 432–433
diagnostic 80–82
functional 20
gene therapy 434–438
genotoxicity
immune-mediated toxicity 74–78
immunogenicity 23
nonimmune organ-specific toxicity
PD 66–71
PK 65–71
predictive 80–82
safety 23
structural
toxicity 438–442
translational 20, 23
tumorigenesis 20
Biomolecules 241
Breyanzi 6
Bridging assay format 139, 140
Buffer 230, 242
72–74
78–79
20
c
Canada, CDx regulation 410, 421
Canavan disease
Cap (capsid) 63, 64, 318
Carboxyfluorescein succinimidyl ester
(CFSE) 276
Cardiac troponins
Carvykti 6
CAST-seq 372–375
cDNA replacement 15
Cellular assays
challenges of 277–278
T-cell responses 272–274
cytokine bead array 276–277
ELISPOT assay 274–276
gene expression profiling 277
45
79
ICS
276
multiplexed epitope mapping 277
proliferation assays
tetramer staining
validation of
Cellular immune responses
440
Cellular methods
Center for Devices and Radiological
Health (CDRH)
Center for International Blood and
Marrow Transplant Research
(CBMTR)
Centers for Biologics Evaluation &
Research (CBER)
Centers for Device & Radiological
Health (CDRH)
Centers for Medicare and Medicaid
Services (CMS)
Central nervous system
(CNS)
Cerebrospinal fluid (CSF)
Ceroid lipofuscinoses (CLN)
CHANGE-seq
Chimeric antigen receptor (CAR) T
cells
China, CDx regulation
Chondroitin sulfate (CS) 244
Chorioretinal atrophy
Choroideremia 41
CIRCLE-seq
Class I device 413
Class II device 413
Class III device
Clinical and Laboratory Standards
Institute (CLSI)
403, 406
Clinical biodistribution 96–99
Clinical Laboratory Improvement
Amendments
(CLIA) 388, 406–407
278–285
19, 125–126
355–356
442
355–356
414
276
276
271–272,
354, 355
409
435
406
406
388
67, 78
45
410, 421
39
389, 395,
452
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Index
Clinical shedding 96–99
Clinical trial assay (CTA), in GTx clinical
trials
397
CLIA validation of
design considerations
regulatory risk determination
398–400
stratification vs. selection
validation
Clonality analysis
Clustered regularly interspaced short
College of American Pathologists
Companion diagnostics (CDx)
bridging studies
categories of
co-development process
commercial assay
commercialization
concept of
design considerations
development of
final version of 407
future proofing 425–426
genetic disorders
GTx CDx 395–396, 406
investigational device
modifications of 426
partner relationship 424–425
rare disease
regulatory guidance 386 (see also
role in gene therapy 386–387
single-site vs. distributable kit 402
validation of
401
palindromic repeats
(CRISPR) 15, 23
(CAP)
also Clinical trial assay (CTA)
422–423
385
exemption 389, 395, 396
Regulation of CDx)
for commercial use 401–402
406–407
400–401
397–398
333–334
388
81. See
404–405
396
387,
423
390–391, 425–426
402–404
387–390, 396
396
423–424
FDA submission
requirements
Comparative Ct method
Complementary diagnostics
Complementary DNA (cDNA)
Complement-dependent cytotoxicity
(CDC) 125, 294
Corticosteroids 44, 128
Cost of gene therapies 26–27
COVID-19, 22
Crigler-Najjar syndrome 49
CRISPR/Cas9, 16–17, 299–301
Cut-point
statistical 148
TAb assay 143–144
TI assay 147–148
Cytokine bead array 276–277
Cytotoxicity 440
403–404
402–404
259
386
68
d
Danon disease 47
Data analysis for real-time PCR
(DART-PCR) 255
Dermatan sulfate (DS) 244
Diagnostic biomarker 80–82
Digital PCR (dPCR) 67, 201, 203, 435
Digital polymerase chain reaction
164–168
DNA 3, 431
DNA microarray technology 254
Dorsal root ganglia (DRG) 44,
67, 78–79
Dose scaling 102, 104–105
Dose selection 100–104
Double-stranded break (DSB) 348–349
Double-stranded RNA (dsRNA) 18
Droplet digital PCR (ddPCR) 94,
166–171, 203, 356, 358,
360, 365–366
Duchenne muscular dystrophy (DMD)
51, 75, 124, 126, 194, 273, 439
Index 453
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e
Ecrulizumab 76
Eladocagene exuparvovec
Electrochemiluminescence (ECL)
assay
217, 295–297
Ella 249, 250
Empty capsids 72, 127
Endonuclease mismatch cleavage (EMC)
assays
356, 358, 360, 366–367
Engineered nucleases
Enzyme activity
assays
219, 224, 228, 229
defined 224
4MU and
lysosomal storage 228, 233
QC levels 232–233
RPE65, 219–220
sample processing
time course of 226
Enzyme-linked immunosorbent assay
Enzyme-linked immunosorbent spot
antigen concentration 285
antigen-specific 279, 285
challenges in 278
FluoroSpot vs., 276
number of replicates 285
PBMC sample handling 282–285
principle of 275
T-cell responses 274–276, 278
validation of 278–279
Etranacogene dezaparvovec 103, 105
EtranaDez 220
227, 228
(ELISA)
295, 296
(ELISPOT) assay
accuracy 281
limit of detection and
range
linearity 281–282
precision 279
specificity 279–280
215, 222, 249, 251,
280–281
103, 105
352–353
229
European Bone Marrow Transplant
(EBMT)
European Medicines Agency
(EMA)
324, 347, 352, 386, 431, 433, 440
European Union, CDx regulation 410
clinical trials
IVDR
marketing authorization
Extracellularly expressed transgene
proteins 297–298
Ex vivo gene therapy
Ex vivo genome editing
Eye (ocular)
435
25, 36, 201, 261–263,
416–418
416–419
418–420
441
350–351
125–126
f
Fabrazyme 247
Fabrazyme Scoring System (FSS)
Fabry disease
Familial chylomicronemia syndrome
Familial hypercholesterolemia
FDA regulation of CDx
510(k) process
guidance documents
HDE process
IDE
marketing authorization 413–416
premarket approval 414–416
pre-submission feedback 416
Federal Drug Administration (FDA) 4,
First-in-human (FIH) dosing 102
510(k) process 413, 415–416
Fluorescence in situ hybridization
FluoroSpot 276
Food and Drug Administration
49, 248
(FCS) 36–37
409–410
413, 415–416
410, 436
414–415
410–412
6–8, 25
(FISH) 371
(FDA) 36, 64, 196, 248, 261, 278,
324, 347, 352, 385, 386, 389,
393–395, 431, 432, 440
247
50
454
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Index
Friedreich’s ataxia 47
FTD with GRN mutations
(FTD-GRN) 45
Functional protein activity, PD
biomarker measurement
248–249
g
Galafold 247
Gaucher disease 49, 248
Gene addition 18
Gene disruption,
nuclease-mediated 54–55
Gene editing 10, 14–15, 298–304
base and prime editing
cDNA replacement 15
CRISPR/Cas9, 16–17
gene therapy and 27–28
invivo 48, 51–54
magnetic nanoparticles 27
off-target 73–74
TALENs 15, 16
ZFNs 15, 16
Gene expression profiling
Gene expression ratio 259
General safety and performance
requirements (GSPR) 419–420
GeneRide technology 51, 53
Gene silencing 17–18
Gene therapy 432–433
biomarkers
FDA-approved 4, 6–8
gene editing and 27–28
history of 3–5
Gene therapy companion diagnostics
development 396
regulatory review and
434–438
(GTx CDx). See also Companion
diagnostics (CDx);
Regulation of CDx
approval of 406
17
277
treatment decisions 396
validation of
Gene therapy medicinal products
Genetic diseases
Genetic disorders
Genevestigator
Genome editing
clinical trials using
double-stranded break
efficiency
engineered nucleases 352–353
exvivo
homolog-directed repair 348, 349
insertions and deletions
amplicon sequencing
ddPCR
EMC assays
hybrid capture-based
IDAA
NGS
targeted approaches
TIDE and ICE
invivo 350–351
large genomic
AMP-seq 371, 374, 375
CAST-seq
comparison of molecular
LAM-HTGTS
technologies to measure 370, 375
UDiTaS
modalities 348–350
molecular outcomes of 348–349
non-homologous end joining 348,
off-target editing 349
off-target sites
395–396
(GTMP)
360, 366–367
sequencing 360–362
rearrangements 369–370
assays
349, 356
433
4
396
255
350–351
348–349
356
350–351
356
359–361
356, 358, 360, 365–366
356, 358,
356, 358, 360, 369
358, 359, 362–365
356, 358
368–369
372–375
374
371–372, 374, 375
372, 374, 375
Index 455
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biochemical methods 354
cellular methods 354, 355
evaluating 353–354
genome-wide 355–357
in silico methods 354
on-and off-target
assessment 352–353
regulatory guidance
translocations 348–349, 370
zinc finger nucleases 348, 351
Genome rearrangements 332
Genome wide off-target
activity 355–357
Genotoxic integration 334–335
Genotoxicity
AAV germline transmission risk 73
AAV vector-mediated insertional
mutagenesis risk
biomarkers for 72–74
off-target gene editing 73–74
Giant axonal neuropathy (GAN) 45
Gintuit 7
Giroctocogene fitelparvovec 103, 105
Global regulatory strategy
(GRS) 421–422
Glutamate dehydrogenase (GLDH)
Glybera 26, 36–38, 64, 325, 431
Glycogen storage disease
Glycosaminoglycans 244
GTx clinical trials, CTAs in 397–401
Guide RNAs (gRNAs) 16, 17
GUIDE-seq
356
352–353
72–73
76
50
h
Heart disease 47–48
Hematologic diseases 49–50
Hemgenix 7, 36, 64
Hemophilia 19, 220
hemophilia A 20–21, 49
hemophilia B 49, 273, 439
Heparan sulfate (HS) 244
Hepatitis B vaccine 4
Hepatitis B virus (HBV)
Hepatocellular carcinoma
(HCC)
72–73, 317, 319–323
Hepatotoxicity
HercepTest
High-quality control (HQC)
High-resolution mass spectrometry
Histology
Homologous recombination
Homology-directed repair (HDR)
Homology medicines
Humanitarian device exemption
Human transgene assessment
expressed therapeutics
intracellular proteins
non-secreted proteins
preclinical species
secreted proteins
Humoral immune response
gene editing systems
anti-Cas9 immunity
CRISPR/Cas9, 299–301
diversity of
transgene proteins 291
administration route 291–292
analytical methods 294–295
assay development 295–297
Bethesda assay 296
biodistribution
dose 293
electrochemiluminescence
ELISA 295, 296
expression level 293
extracellularly vs.
immune status 293–294
74–76
387
(HR-MS)
246–248
52–54, 348, 349
414–415
(HDE)
assay 295–297
intracellularly 297–298
324
232–233
243
48, 51–52
48,
52
221
216–218
218–220
216
220
271–272
301–304
298–299
293
456
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Index
Humoral immune response
(continued)
immunoassay 295
response induction vs.
boosting 294
serotype
Huntington’s disease (HD) 45, 195
293
i
IF-stimulated genes (ISGs) 118
Imlygic 7
Immune-mediated toxicity
biomarker 74–78
Immune toxicity 441–442
Immunoassays
biomarker validation 249, 252–253
high sensitivity 249
LC-MS vs., 244–245
multiplexing 249
PD biomarker measurement 248–253
technologies and platforms 249–251
Immunocapture qPCR
(iqPCR) 187–189
Immunogenicity assessment
AAV gene therapies 77–78
adaptive immunity
AAV-mediated activation
118–119
of
animal models 122–123
animal selection 123
clinical mitigation strategy 127–129
innate immunity
AAV-mediated activation
of 117–119
animal models 122
interpretation of results 123
nonclinical 121
preexisting antibodies 123–124, 127
TAb assays 127
transgene protein 124–125
treatment-induced antibodies 124
Immunogenicity risk 119
administration route 125, 128
125–126
CNS
eye
125–126
126
liver
muscle
126
manufacturing-related
patient-related 120–121
process-related
product-and process-related
impurity
product-related 119–120
Immunohistochemistry (IHC) 204,
219, 223, 246, 265
Immunomodulation
Immunosuppression 292
Impurity analysis 332
Incubation temperature
Incurred sample reanalysis (ISR) 183
Indel detection by amplicon analysis
(IDAA)
Indel detection by NGS
background 362
bioanalytical characterization
364–369
sensitivity
Inference of CRISPR Edits
(ICE)
Inherited metabolic disorders 70
Innate immune response
AAV-mediated activation of 117–119
animal models for assessing 122
Insertions and deletions, genome editing
analysis 356
amplicon sequencing 359–361
ddPCR 356, 358, 360, 365–366
EMC assays 356, 358, 360, 366–367
hybrid capture-based
sequencing 360–362
IDAA 356, 358, 360, 369
NGS 358, 359, 362–365
targeted approaches 356, 358
TIDE and ICE 368–369
126–127
356, 358, 360, 369
362–364
368–369
120
120
128, 292
230
359
Index 457
https://t.me/medicina_free
In situ hybridization (ISH) 246, 265
discovery studies
hybridization and detection
probe preparation
signal quantification
205, 209
steps in
tissue section preparation 208
transgene expression
analysis
Institutional Review Board
(IRB)
Insulin, synthetic 3
Integration site (IS) analysis
See also rAAV integration
Intracellular cytokine staining
(ICS)
Intracellularly expressed transgene
proteins
Intracellular proteins 216–218
Intravenous (IV) 68
Inverted terminal repeats (ITRs) 63, 64
Investigational device exemption
(IDE)
Investigational new drug (IND)
application
Investigational use only (IUO)
device
In vitro diagnostic (IVD) 395
In vitro diagnostic regulation
(IVDR) 386, 416–419
In vivo gene editing 48, 51–54
In vivo genome editing
Isaralgagene civaparvovec 103, 105
ISO 13485, 388
204–205
209–210
208
210
204–205, 208–210
25–26, 389, 398
332–333.
276
297–298
389, 395, 396, 410–412
25
389, 390
350–351
j
Japan, CDx regulation 410, 421
k
Karyotyping 371
Keratan sulfate (KS) 244
Kymriah 7, 431
l
LAM-HTGTS 371–372, 374, 375
Large genomic rearrangements
AMP-seq
CAST-seq
comparison of molecular assays
LAM-HTGTS
technologies to measure
UDiTaS
Laviv
LC–MS methodology
Lebers congenital amaurosis (LCA)
LCA1, 41
LCA2, 38, 41
Leber hereditary optic neuropathy
Ligand binding assay (LBA)
Limb girdle muscular dystrophy 2E
Limb girdle muscular dystrophy 2I
Limit of detection (LOD)
Linear amplification-mediated
Lipids 242
Lipoprotein lipase deficiency
Liquid chromatography with tandem
immunoassays vs. 244–245
lack of analyte-free matrices 242
method development
method validation 245–246
small molecule biomarker
stability issues 241–242
surrogate matrix/analyte
371, 374, 375
372–375
371–372, 374, 375
372, 374, 375
7
222–223
(LHON)
222, 262
(LGMD2E) 51
(LGMD2I) 51
178, 280
(LAM)-PCR
(LPLD) 36
mass spectrometry
(LC-MS/MS) 241
quantitation 241
approach 242–244
41
326–327
369–370
374
370, 375
54
216,
148–149,
241–245
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