Potential HIV gene therapy strategies

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Cord Blood ◽  
Gene Editing ◽  
Mortality Risks ◽  
Recent Advances ◽  
Whole Exome ◽  
Localization Signal ◽  
Cord Blood Cells ◽  
The Cost ◽  
Therapy Strategies

The CCR5 null genotype generation has been a main focus in the HIV gene therapy industry. The presence of the X4 tropic virus, mobilization of HSPCs, the quality of the cells for manipulation, and gene editing efficiency appear to be the main obstacles in translating this technique. Unintended off-target cleavage is a key problem in CRISPR/Cas9 editing. With the development of small molecule expansion methods for cord blood HSPC, it would be advantageous to modify CCR5 in cord blood cells and expand them for transplantation. The generation of engraftable HSPCS from iPSCs would be an ideal technique for HSCC gene therapy.The haplotype-characterized iPSC would be the donor for many patients, and it could be a commercially available product. The 32 C CR5 homozygous people had no elevated mortality risks according to whole-exome sequencing and whole-genome genotyping, according to CCR 5 positive people, and had no higher mortality risks compared to those who were HIV positive. Recent advances in gene editing, such as non-viral delivery of Cas9 ribonucleoproteins, incorporation of a 3X-nuclear localization signal into spCas9, and use of HiFi Cas9 with chemically modified sgRNAs, can be combined with recent advances in transplantation. Infusing modest doses of gene modified primitive HSPC fractions indicated by CD34 + CD90 + CD45RA-, which can engraft better, is another option for lowering the cost of gene therapy.

scholarly journals Gene therapy strategies for idiopathic pulmonary fibrosis: recent advances, current challenges, and future directions

2021 ◽  
Vol 20 ◽  
pp. 483-496
Author(s):  
Mitchel J.R. Ruigrok ◽  
Henderik W. Frijlink ◽  
Barbro N. Melgert ◽  
Peter Olinga ◽  
Wouter L.J. Hinrichs
Keyword(s):  
Gene Therapy ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Future Directions ◽  
Recent Advances ◽  
Therapy Strategies

scholarly journals A cell surface marker gene transferred with a retroviral vector into CD34+ cord blood cells is expressed by their T-cell progeny in the SCID- hu thymus

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 107-113 ◽  
Author(s):  
C Champseix ◽  
V Marechal ◽  
I Khazaal ◽  
O Schwartz ◽  
S Fournier ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cell ◽  
Cell Surface ◽  
Cord Blood ◽  
Blood Cells ◽  
Cell Lineage ◽  
Surface Marker ◽  
Cd34 Cells ◽  
A Cell ◽  
Cord Blood Cells

Gene transduction into immature hematopoietic cells collected at birth from the umbilical cord could be useful for the treatment of genetic or acquired disorders of the hematopoietic system diagnosed during pregnancy. The SCID-hu mouse is a convenient model to investigate T- cell lineage gene therapy, since it allows replication of human intrathymic T-cell development. CD34+ cells isolated from cord blood were cocultured with CRIP MFG-murine CD2 (mCD2) cells that produce recombinant retroviruses encoding the mCD2 antigen, a cell surface marker easily detectable by flow cytometry. After 3 and 4 days in coculture, a mean of 19% and 39% human hematopoietic cells, respectively, expressed the mCD2 antigen. CD34+ cells cocultured for 4 days were used to reconstitute human fetal thymus implanted in SCID mice. Five to 10 weeks later, the mCD2 antigen was detected on approximately 10% of human thymocytes repopulating the thymic grafts in four of nine SCID mouse chimeras. Vector genomes were detected in graft cell DNA by Southern blot. Analysis of vector integration indicated that positive cells were of polyclonal origin in three animals and predominantly monoclonal in the other one. Our data show that foreign genes can be transduced into CD34+ cord blood cells endowed with T-cell differentiation potential, and suggest strategies for T-cell lineage gene therapy in the neonate.

scholarly journals Successful gene therapy of Diamond-Blackfan anemia in a mouse model and human CD34+ cord blood hematopoietic stem cells using a clinically applicable lentiviral vector

Haematologica ◽  
2021 ◽  
Author(s):  
Yang Liu ◽  
Maria Dahl ◽  
Shubhranshu Debnath ◽  
Michael Rothe ◽  
Emma M. Smith ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Marrow ◽  
Mouse Model ◽  
Cord Blood ◽  
Lentiviral Vector ◽  
Bone Marrow Failure ◽  
Hematopoietic Stem ◽  
Diamond Blackfan Anemia ◽  
Clinical Gene Therapy ◽  
Cord Blood Cells

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure disorder with pure red blood cell aplasia associated with physical malformations and a predisposition to cancer. Twenty-five percent of patients with DBA have mutations in a gene encoding ribosomal protein S19 (RPS19). Our previous proof-of-concept studies demonstrated that DBA phenotype could be successfully treated using lentiviral vectors in Rps19-deficient DBA mice. In our present study, we developed a clinically applicable single gene self-inactivating lentiviral vector, containing the human RPS19 cDNA driven by the human elongation factor 1α short promoter, that can be used for clinical gene therapy development for RPS19-deficient DBA. We examined the efficacy and safety of the vector in a Rps19-deficient DBA mouse model and in human primary RPS19-deficient CD34+ cord blood cells. We observed that transduced Rps19-deficient bone marrow cells could reconstitute mice longterm and rescue the bone marrow failure and severe anemia observed in Rps19-deficient mice, with a low risk of mutagenesis and a highly polyclonal insertion site pattern. More importantly, the vector can also rescue impaired erythroid differentiation in human primary RPS19-deficient CD34+ cord blood hematopoietic stem cells. Collectively, our results demonstrate the efficacy and safety of using a clinically applicable lentiviral vector for the successful treatment of Rps19-deficient DBA in a mouse model and in human primary CD34+ cord blood cells. These findings show that this vector can be used to develop clinical gene therapy for RPS19-deficient DBA patients.

scholarly journals A cell surface marker gene transferred with a retroviral vector into CD34+ cord blood cells is expressed by their T-cell progeny in the SCID- hu thymus

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 107-113 ◽  
Author(s):  
C Champseix ◽  
V Marechal ◽  
I Khazaal ◽  
O Schwartz ◽  
S Fournier ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cell ◽  
Cell Surface ◽  
Cord Blood ◽  
Blood Cells ◽  
Cell Lineage ◽  
Surface Marker ◽  
Cd34 Cells ◽  
A Cell ◽  
Cord Blood Cells

Abstract Gene transduction into immature hematopoietic cells collected at birth from the umbilical cord could be useful for the treatment of genetic or acquired disorders of the hematopoietic system diagnosed during pregnancy. The SCID-hu mouse is a convenient model to investigate T- cell lineage gene therapy, since it allows replication of human intrathymic T-cell development. CD34+ cells isolated from cord blood were cocultured with CRIP MFG-murine CD2 (mCD2) cells that produce recombinant retroviruses encoding the mCD2 antigen, a cell surface marker easily detectable by flow cytometry. After 3 and 4 days in coculture, a mean of 19% and 39% human hematopoietic cells, respectively, expressed the mCD2 antigen. CD34+ cells cocultured for 4 days were used to reconstitute human fetal thymus implanted in SCID mice. Five to 10 weeks later, the mCD2 antigen was detected on approximately 10% of human thymocytes repopulating the thymic grafts in four of nine SCID mouse chimeras. Vector genomes were detected in graft cell DNA by Southern blot. Analysis of vector integration indicated that positive cells were of polyclonal origin in three animals and predominantly monoclonal in the other one. Our data show that foreign genes can be transduced into CD34+ cord blood cells endowed with T-cell differentiation potential, and suggest strategies for T-cell lineage gene therapy in the neonate.

scholarly journals Recent advances in cardiac gene therapy strategies targeting advanced heart failure

2017 ◽  
Vol 3 (4) ◽  
pp. 163-169 ◽  
Author(s):  
C. Chen ◽  
T. Seeger ◽  
V. Termglinchan ◽  
I. Karakikes
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Advanced Heart Failure ◽  
Recent Advances ◽  
Cardiac Gene ◽  
Therapy Strategies

scholarly journals New Gene Therapy Strategies for the Deletion of Exon 44 of Dystrophin Gene Based on Gene Editing by TALENs

2013 ◽  
Vol 03 (01) ◽  
pp. 1-6
Author(s):  
Ping Li ◽  
Yunzhi Pan ◽  
Alice S. S. Li ◽  
Aijuan Sun ◽  
Jia Zhang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Editing ◽  
Dystrophin Gene ◽  
New Gene ◽  
Therapy Strategies
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