Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side
Abstract
:1. Introduction
2. Product Development
2.1. Target Cells of Interest
2.2. Vector Design: Balancing Insertion Site and Therapeutic Expression
3. Proof-Of-Concept
3.1. Ex Vivo Manipulation: Transduction Efficiency
3.2. Call for Suitable Models to Test the Efficacy of Gene Therapy
3.2.1. Animal Models
3.2.2. In Vitro Models
3.3. Safety and Toxicology Assessment for Gene Therapy
4. Pharmaceutical and Clinical Development Phases: From Mouse to Human Treatment
4.1. Scaling Up: GMP Protocols and Manufacturing
4.1.1. GMP Compliant Virus Manufacturing
4.1.2. GMP Gene Therapy Product Manufacturing
4.2. Regulatory Hurdles
5. Conclusions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ADA | Adenosine Deaminase Deficiency |
ATMP | Advanced Therapy Medicinal Product |
BM | Bone Marrow |
CAR | Chimeric Antigen Receptor |
CAT | Committee for Advanced Therapies |
CCMO | Centrale Commissie Mensgebonden Onderzoek |
CGD | Chronic Granulomatous Disease |
CHMP | Committee for Human Medicinal Products |
CTA | Clinical Trial Application |
ddPCR | Digital Droplet PCR |
DL1 | Delta-Ligand 1 |
EC | European Commission |
EMA | European Medicines Agency |
EU | European Union |
FDA | U.S. Food and Drug Administration |
FTOC | Fetal Thymus Organ Culture |
GMO | Genetically Modified Organism |
GMP | Good Manufacturing Practice |
GvHD | Graft versus Host Disease |
HLA | Human Leukocyte Antigen |
HSC | Hematopoietic Stem Cell |
HSPC | Hematopoietic Stem Progenitor cell |
IB | Investigator Brochure |
IMPD | Investigational Medicinal Product Dossier |
iPSCS | Induced Pluripotent Stem Cell |
IVIM | In Vitro Immortalization Assay |
LAM-PCR | Linear Amplification Mediated PCR |
LSK | Lin−Sca+cKit+ cells |
LTR | Long Terminal Repeat |
LUMC | Leiden University Medical Center |
LV | Lentiviral vector |
MA | Marketing Authorization |
mPB | Mobilized Peripheral Blood |
NSG | NOD Scid Gamma |
nrLAM-PCR | Non-restrictive LAM-PCR |
PCR | Polymerase Chain Reaction |
PRIME | Priority Medicines |
RAG1/2 | Recombinase-Activating Gene 1/2 |
RV | Retroviral Vector |
SAGA | Surrogate Assay for Genotoxicity Assessment |
SCID | Severe Combined Immunodeficiency |
SIN | Self-Inactivating |
TE | Transduction enhancer |
USA | United States of America |
VCN | Vector Copy Number |
VHP | Voluntary Harmonized Procedure |
WAS | Wiskott–Aldrich Syndrome |
WPRE | Woodchuck hepatitis virus Post-transcriptional Regulatory Element |
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Disease | Gene | Vector | Clinical Study | Phase | Participants | Location | Study Type | Status | Outcome/References | |
---|---|---|---|---|---|---|---|---|---|---|
ADA-SCID | ADA | RV | NCT01279720 | Phase 1/2 | 8 | EU | interventional | completed | Positive benefit-risk profile [28,29,30,31,32,33,34,35,36] | |
NCT00018018 | Phase 1 | 8 | USA | interventional | completed | |||||
NCT00794508 | Phase 2 | 10 | USA | interventional | completed | |||||
NCT00599781 | Phase 1/2 | 8 | EU | interventional | completed | |||||
Strimvelis (RV) | NCT00598481 | Phase 2 | 18 | EU | interventional | completed | Immune reconstitution [33,37] | |||
NCT03232203 | 10 | EU | observational | recruiting | ||||||
NCT03478670 | 50 | EU | observational | enrolling | ||||||
SIN LV | NCT01852071 | Phase 1/2 | 20 | USA | interventional | completed | Immune reconstitution, well tolerated [36,38,39] | |||
NCT02999984 | Phase 1/2 | 10 | USA | interventional | completed | |||||
NCT01380990 | Phase 1/2 | 36 | EU | interventional | completed | |||||
NCT04140539 | Phase 2/3 | 3 | USA | interventional | recruiting | |||||
NCT03645460 | n.a. | 10 | China | interventional | recruiting | |||||
NCT04049084 | 70 | USA/EU | observational | enrolling | ||||||
Artemis-SCID | DCLRE1C | SIN LV | NCT03538899 | Phase 1/2 | 15 | USA | interventional | recruiting | Immune reconstitution [40] | |
Chronic granulomatous disease | Gp91 phox | RV | NCT00927134 | Phase 1/2 | 2 | EU | interventional | completed | Sustained engraftment, insertional mutagenesis, [41,42] | |
NCT00564759 | Phase 1/2 | 2 | EU | interventional | unknown | |||||
SIN | NCT01906541 | Phase 1/2 | 5 | EU | interventional | unknown | ||||
NCT00778882 | Phase 1/2 | 2 | Korea | interventional | active | |||||
SIN LV | NCT01855685 | Phase 1/2 | 3 | EU | interventional | active | [16] | |||
NCT02757911 | Phase 1/2 | 3 | EU | interventional | active | |||||
NCT02234934 | Phase 1/2 | 10 | USA | interventional | active | |||||
NCT03645486 | n.a. | 10 | China | Interventional | active | |||||
Leukocyte Adhesion Deficiency-I | CD18 | RV | NCT00023010 | Phase 1 | 2 | USA | observational | completed | ||
SIN LV | NCT03812263 | Phase 1/2 | 9 | USA | interventional | recruiting | ||||
NCT03825783 | Phase 1 | 2 | EU | interventional | recruiting | |||||
Wiskott–Aldrich Syndrome | WAS | SIN LV | NCT01347242 | Phase 1/2 | 6 | EU | interventional | completed | Successful engraftment, immune reconstitution, no adverse reactions [15,43,44] | |
NCT01347346 | Phase 1/2 | 5 | EU | interventional | completed | |||||
NCT02333760 | Phase 1/2 | 10 | EU | interventional | active | |||||
NCT03837483 | Phase 2 | 6 | EU | interventional | active | |||||
NCT01410825 | Phase 1/2 | 5 | USA | interventional | active | |||||
NCT01515462 | Phase 1/2 | 8 | EU | interventional | active | |||||
X linked-SCID | IL2RG | RV | NCT00028236 | Phase 1 | 3 | USA | interventional | completed | Sustained immune correction, risk acute leukemia [6,45,46,47,48] | |
SIN | NCT01175239 | n.a. | 1 | EU | interventional | unknown | ||||
NCT01410019 | Phase 1/2 | 5 | EU | interventional | unknown | |||||
SIN | NCT01129544 | Phase 1/2 | 8 | USA | interventional | active | ||||
SIN LV | NCT03315078 | Phase 1/2 | 13 | USA | interventional | recruiting | Multilineage engraftment, immune reconstitution [49] | |||
NCT03311503 | Phase 1/2 | 10 | USA | interventional | recruiting | |||||
NCT01512888 | Phase 1/2 | 28 | USA | interventional | recruiting | |||||
NCT01306019 | Phase 1/2 | 30 | USA | interventional | recruiting | |||||
NCT03601286 | Phase 1 | 5 | EU | interventional | recruiting | |||||
NCT04286815 | n.a. | 10 | China | interventional | recruiting | |||||
NCT03217617 | Phase 1/2 | 10 | China | interventional | recruiting |
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Garcia-Perez, L.; Ordas, A.; Canté-Barrett, K.; Meij, P.; Pike-Overzet, K.; Lankester, A.; Staal, F.J.T. Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side. Pharmaceutics 2020, 12, 549. https://doi.org/10.3390/pharmaceutics12060549
Garcia-Perez L, Ordas A, Canté-Barrett K, Meij P, Pike-Overzet K, Lankester A, Staal FJT. Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side. Pharmaceutics. 2020; 12(6):549. https://doi.org/10.3390/pharmaceutics12060549
Chicago/Turabian StyleGarcia-Perez, Laura, Anita Ordas, Kirsten Canté-Barrett, Pauline Meij, Karin Pike-Overzet, Arjan Lankester, and Frank J. T. Staal. 2020. "Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side" Pharmaceutics 12, no. 6: 549. https://doi.org/10.3390/pharmaceutics12060549