An Efficacy and Safety Study of shRNA-modified CD34+ Cells in HIV-infected Patients.

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy and safety of autologous CD34+ cells that stably express multiplexed shRNA to treat HIV infection.

Detailed Description
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CD34+ cells will be isolated from mobilized PBMC of HIV patients. The cells will be lentivirally transduced with multiplexed shRNAs in the same vector that target CCR5 and HIV genome. Such modified cells will be infused back to the patients who have received bulsufan preconditioning before infusion. The patients will then be evaluated for efficacy and safety.

Official Title
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A Pilot Study to Evaluate Efficacy and Safety of Multiplexed shRNA-modified CD34+ Cells in HIV-infected Patients.

Conditions
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HIV Infections, AIDS

Intervention / Treatment
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* Biological: shRNA-modified CD34+ cells
* Drug: Low dose busulfan preconditioning
* Drug: Busulfan preconditioning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) from 18 - 25; body weight ≥50kg. Diagnosis of HIV infections/AIDS based on Diagnostic Criteria for HIV/AIDS WS 293-2008. No antiretroviral therapy (ART) in the past 6 weeks and refuse to receive ART. CD4 T cell count ≥350/μl. No plan for pregnancy in the near future and agree to practice non-drug based contraception. Voluntary to participate in the study, comply with the study design to complete all monitory measurements, and agree to sign the study agreement. Exclusion Criteria: Existence of infections/opportunistic tumors. Mutations in the shRNA target sequences. White blood cell count <3x10^9/L, neutrophil count <1.5x10^9/L, hemoglobin <110g/L, platelet count <100x10^9/L. Liver diseases (HBV, chronic HCV infection, congenital liver metabolic disease), abnormal liver functions (test value 2x above normal). Kidney deficiency (Creatinine level above the upper limit of normal levels). Severe chronic disease, metabolic disease (e.g., diabetes), neurological and psychiatric diseases. History of pancreatitis. Women in pregnancy, lactating or at reproductive age who do not practice contraception. Allergy to agents or drugs used in the study. Verified or suspected abuse of alcohol and drugs. Participated in other clinical trials within 3 months. Based on investigator's assessment, those who are unfit for the study (e.g., general weakness, poor compliance with study design). Personal or family history of tumors.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Infusion of autologous CD34+ cells transduced with shRNAs targeting CCR5 and HIV genome
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: No busulfan preconditioning<br>shRNA-modified CD34+ cells without busulfan preconditioning. | Biological: shRNA-modified CD34+ cells<br>* Infusion of CD34+ cells transduced with shRNAs.<br>|
| Experimental: Low dose busulfan preconditioning<br>shRNA-modified CD34+ cells, with a single dose of 1 mg/kg busulfan administered every 6 hours for 4 times as preconditioning for transplantation. | Biological: shRNA-modified CD34+ cells<br>* Infusion of CD34+ cells transduced with shRNAs.<br>Drug: Low dose busulfan preconditioning<br>* A single dose of 1 mg/kg busulfan administered every 6 hours for 4 times as preconditioning for transplantation.<br>* Other names: Busulfex;|
| Experimental: High dose busulfan preconditioning<br>shRNA-modified CD34+ cells, with a single dose of 1 mg/kg busulfan administered every 6 hours for 8 times as preconditioning for transplantation. | Biological: shRNA-modified CD34+ cells<br>* Infusion of CD34+ cells transduced with shRNAs.<br>Drug: Busulfan preconditioning<br>* A single dose of 1 mg/kg busulfan administered every 6 hours for 8 times as preconditioning for transplantation.<br>* Other names: Busulfex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse side effects | Patients will be monitored for any signs of adverse effects. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of treatment | Evaluate the efficacy of modified autologous CD34+ cells by monitoring CD4 counts and HIV-1 RNA level. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, AIDS, Lentivirus, shRNA, Multiplex, Gene therapy