HIV-1-infection
Conditions
Brief summary
The investigators performed this study to evaluate the safety and feasibility of transplantation with CRISPR/Cas9 CCR5 gene modified CD34+ hematopoietic stem/progenitor cells for patients that develop AIDS and hematological malignances. Patients will be treated with antiviral therapy (ART) to achieve undetectable HIV-1 virus in peripheral blood before conditioning. CD34+ cells from donors will be infused into the patients after treatment with CRISPR/Cas9 to ablate CCR5 gene.
Detailed description
The primary objective of this study is to determine the safety of the infusion of CD34+ cells which are treated with CRISPR/Cas9 to disrupt the CCR5 gene. The secondary objective is to evaluate the resistance to HIV-1(R5) in infected patients after infusion of modified CD34+ cells with or without an antiretroviral therapy interruption (ATI). After the transplantation, the reconstitution time and frequency of multi-lineage hematopoietic cell will be analyzed against previously reported HSCT in HIV-1 patients. After the detection of high CD4+ T cells reconstitution (over 600 cells/μL) and CCR5 negative cells (over 1%) in peripheral blood, subjects will undergo an ATI. HIV-1 RNA level and CD4+ cell counts will be monitored biweekly for at least one month.
Interventions
GENETICCCR5 gene modification
CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 targeting CCR5 gene.
Sponsors
Peking University
Capital Medical University
Affiliated Hospital to Academy of Military Medical Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
CD34+ hematopoietic stem/progenitor cells from donor are treated with CRISPR/Cas9 before transplantation into the patient.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Age between 18 to 60, male of female; 2. Hematological neoplasms; 3. HIV-1 R5 tropic virus with no CXCR4-tropic or R5/X4 dual-tropic HIV; 4. On ART with undetectable HIV-1 level (\<40gc/ml, HIV-1 RNA); 5. Availability of a consenting HLA-matched donor; 6. No cardiomyopathy or congestive heart failure; 7. CD4+ T-cell counts ≥200 cells/µL and ≤750 cells/µL; 8. Absence of psychosocial conditions and be willing to comply with study-mandated evaluations for 2 years; 9. Life expectancy of at least 1 year.
Exclusion criteria
1. Acute or chronic hepatitis B or hepatitis C infection; 2. Any cancer or malignancy other than hematological neoplasms; 3. Subject with CMV retinitis or other active CMV infection related diseases; 4. Subject with organ dysfunction; 5. Non-pregnant and non-nursing; 6. Drug or alcohol abuse or dependence; 7. Currently enrolled in another clinical trial or underwent cell therapy; 8. Donor incapable for HSPC mobilization; 9. in the opinion of the site investigator, would interfere with adherence to study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Persistence of CCR5 gene disruption in engrafted cells | 12 months | Participants will be transplanted with CD34+ cells which are treated using the CRISPR/Cas9 system to disrupt CCR5 gene. The persistence of CCR5 gene disruption in engrafted cells will be evaluated by sequencing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CD34+ cell number | the first month | The CD34+ cell number pre-infusion |
Other
| Measure | Time frame | Description |
|---|---|---|
| Hematopoietic cell engraftment | Up to Year 3 | Measurement of multi-lineage hematopoietic cell engraftment time after transplantation to evaluate the hematological recovery |
| HIV-1 RNA level | Up to Year 3 | Level change of HIV-1 RNA in plasma after transplantation |
| CD4+ T cell number | Up to Year 3 | Level change of the CD4+ T cell number after transplantation |
| Gene disruption efficiency of bone marrow cells | Up to Month 12 | The percentage of disrupted CCR5 gene alleles in genome from bone marrow cells detected by sequencing. |
| HIV-1 RNA levels during ATI | Every two weeks, until the end of ATI or up to 3 months | HIV-1 RNA levels in plasma during ATI. |
| HIV-1 DNA level | Up to Month 12 | Changes of proviral DNA in PBMC pre- transplantation and 12 month post-transplantation |
| The ratio change of CD4/CD8 | Up to Year 3 | The ratio change of CD4/CD8 in peripheral blood after transplantation |
| CCR5 gene disruption efficiency of peripheral blood cells | Up to Month 12 | The percentage of disrupted CCR5 gene alleles in genome of peripheral blood cells by sequencing. |
Countries
China
Contacts
Primary ContactBin Zhang, MD, PhD
Backup ContactHu Chen, MD, PhD
Outcome results
None listed