Gene Transfer for Patients With Sickle Cell Disease


The purpose of this Phase 1/2 study is to determine the efficacy and safety of gamma-globin gene transfer in subjects with sickle cell disease.(Open label)

Full Title of Study: “Gene Transfer for Patients With Sickle Cell Disease Using a Gamma Globin Lentivirus Vector: An Open Label Phase I/II Pilot Study”

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2035

Detailed Description

This study will assess the safety and efficacy of gene transfer using a gamma-globin lentiviral vector. Gene transfer will occur ex-vivo into human bone marrow or mobilized peripheral blood CD34+ hematopoietic stem cells of subjects with sickle cell disease. Reduced intensity chemotherapy conditioning with single dose melphalan will be used to facilitate engraftment of ex-vivo transduced cells.


  • Genetic: Gene transfer
    • Autologous CD34+ hematopoietic stem cells transduced ex-vivo with a gamma-globin lentiviral vector Subjects with sickle cell anemia will undergo hematopoietic stem cell procurement by bone marrow harvest or apheresis after mobilization with plerixafor Reduced intensity chemotherapy conditioning with single dose melphalan will be used to facilitate engraftment of ex-vivo transduced cells.

Arms, Groups and Cohorts

  • Experimental: Gene transfer: ARU-1801 drug product
    • Autologous CD34+ hematopoietic stem cells transduced ex-vivo with a gamma-globin lentiviral vector

Clinical Trial Outcome Measures

Primary Measures

  • Evaluate Safety of Gene Transfer Therapy for Sickle Cell Disease
    • Time Frame: from study entry to 15 years post infusion of gene modified cells
    • Evaluate the safety of bone marrow collection, gene transfer and chemotherapy conditioning in subjects with sickle cell disease
  • Evaluate the Feasibility of Gene Transfer Therapy for Sickle Cell Disease
    • Time Frame: 1 year
    • Evaluate the feasibility of obtaining sufficient autologous gene modified CD34+ hematopoietic stem cells that can engraft the subject with sickle cell disease

Participating in This Clinical Trial

Inclusion Criteria for sickle cell disease

1. Patients 3-35 years old. The first six subjects, at minimum, will be 18-35 years of age accrual in this age range will continue until six subjects are evaluable and permission from the IRB and FDA to enroll pediatric patients has been given.

2. Confirmed diagnosis of sickle cell disease genotype Hb- S/beta-thalassemia or Hb-S/ beta + thalassemia disease or HbS/Hb-S, confirmed by beta-globin gene analysis and a hemoglobin separation method. Preference will be given to Hb S/ beta- thalassemia, followed by HbS/ beta + thalassemia, followed by HbS/Hb-S.

3. Severe sickle cell disease, defined as one or more of the following

1. Minimum of two episodes of clinically diagnosed acute chest syndrome requiring hospital admission, or one life threatening episode of acute chest syndrome requiring ICU admission for exchange transfusion and or intubation, or frequent acute chest syndrome episodes, which necessitate treatment with chronic transfusion therapy.

2. Frequent painful vaso-occlusive episodes which significantly interfere with normal life activities, defined as a history of 2 or more severe acute sickle pain events per year requiring additional treatment at a medical facility outside of home pain management over the preceding two year period prior to study enrollment, or which necessitate chronic transfusion therapy.

3. Patients on chronic transfusion therapy for severe disease symptoms other than those listed above, and which interfere with normal life activities.

4. Patients who have failed hydroxyurea therapy, were unable to tolerate hydroxyurea therapy, or, if 18 years of age or older, have actively made the choice to not take the recommended daily hydroxyurea advised for severe disease. Note: must be off hydroxyurea therapy for 3 months prior to stem cell collection. If refusing hydroxyurea, the patient must document that they have been educated about the benefits and continue to refuse the treatment. Patients who were placed on chronic transfusion therapy instead of hydroxyurea for severe disease are eligible. Patients who are unable to take hydroxyurea due to financial or safety monitoring constraints are eligible.

5. Adequate Functional Status and Organ Function as defined by

1. Lansky/Karnofsky performance score greater than or equal to 60.

2. Ability to undergo general or regional spinal or epidural anesthesia as per standard institutional practice.

3. Adequate renal function: defined as a cystatin C eGFR or creatinine clearance eGFR greater than 60ml/min/1.73 sq-m.

4. Adequate liver function as defined by a serum conjugated direct bilirubin les than 2.5x upper limit of normal ULN for age- AST and ALT less than 5XULN for age as per local laboratory.

5. Adequate cardiac function, defined as left ventricular ejection fraction greater than 40 percent .

6. Female patients of childbearing potential defined as having achieved menarche must have a negative pregnancy test and not be lactating. All participants of reproductive potential must agree to a contraceptive method for a period of no less than one year post gene transfer. Women must agree not to breast feed for a period of one year post gene transfer as stipulated in the informed consent document.

Exclusion Criteria for sickle cell disease

1. Patients with an active malignant disease.

2. Sero-positivity for HIV.

3. On an investigational agent in the last 30 days.

4. Abnormal pulmonary function tests PFT. Most adults with sickle cell disease will have compromised PFTs. Therefore; we will accept patients who have mild or moderate obstruction or restriction or diffusion defects. However, patients with severe obstruction, restriction or diffusion defects will be excluded.

Moderate obstruction is defined as per ATS criteria as a FEV1 down to 60 percent of predicted, associated with a FEV1/FVC ratio below the 95 percent confidence intervals. Moderate restriction is defined as a TLC down to 60 percent of predicted. Moderate diffusion defect is defined as a DLCO corrected for hemoglobin down to 40 percent of predicted.

Patients will be ineligible for this study if their lung function falls below any of the 3 exclusion criteria- a- FEV1 less than 60percent predicted with a FEV1/FVC ratio less than 95 percent CI- b- TLC less than 60 percent of predicted; and c- DLCO corrected for hemoglobin less than 40 percent.

5. Patients with evidence of uncontrolled bacterial, viral, or fungal infections currently taking medication and progression of clinical symptoms within one month prior to starting the conditioning regimen. Patients with fever should await resolution of symptoms before starting the conditioning regimen.

6. Patients who are on chronic transfusions for clinical stroke with MRA cerebral vasculopathy will be excluded since patients in the SWITCH study who were randomized to the hydroxyurea arm had recurrent stroke, while none in the chronic transfusion arm. Moreover, weaning transfusions is necessary, so that a selective pressure on gene-modified red blood cells is evident, and this will place subjects with stroke risk at risk for a recurrent stroke. Patients with high TCD do equally well on chronic transfusions or hydroxyurea, as per a subsequent TWITCH study, where patients with elevated TCD were randomized to hydroxyurea or chronic transfusions to prevent stroke. The TWITCH study was closed early because it showed that hydroxyurea was not inferior to chronic transfusions86. Hence patients with elevated TCD on chronic transfusions would be eligible, and chronic transfusions would be gradually weaned as per Section 8.2 in the protocol, if there is evidence of gene transfer at 6 months.

7. Patients with alpha thalassemia two or more gene deletions or any alpha-globin structural variants sickle cell disease will be excluded. Rationale for alpha-thalassemia exclusion is to not create a state similar to alpha-thalassemia HbH disease by increasing the cellular production of beta-like globins exogenously delivered gamma-globin plus endogenously produced sickle beta-globin.

8. Liver biopsy is necessary if the patient has received chronic transfusions greater than 200mL/kg body weight and has evidence of iron overload a serum ferritin level of greater than1000 ng/ml and an MRI T2 or Ferriscan estimated liver iron greater than 15mg/g dry weight and evidence of liver fibrosis by non-invasive liver imaging. Liver biopsy showing cirrhosis, bridging hepatic fibrosis, or active hepatitis are excluded from enrollment.

9. Adults with matched sibling donors will not be eligible unless they were fully informed about the benefits and risks of HCT and have declined this option, or HCT is not an available treatment option due to financial constraints. Documentation of the informed consent process with an impartial witness is necessary for patients who have declined this option to be eligible. Children with matched sibling donors will be ineligible.

Unrelated donor HCT are not performed as the standard of care for sickle cell disease. This modality is only available to patients in the context of a phase I/II pilot study, to children. Therefore, adults and children who do not have matched sibling donors will be eligible for gene therapy and no NMDP search for unrelated donors will be performed.

10. Patients with medical history of pulmonary hypertension, PHT proved by cardiac catheterization. If patients have TR jet velocity greater than 3m/s by transthoracic echocardiography and/or clinical signs and symptoms of PHT, they will need to have cardiac catheterization to exclude PHT mean pulmonary artery pressures greater than 25mmHg to be eligible. If they have cardiac cath-proven PHT, they will be excluded from the study.

11. Any condition or chronic physical or mental illness, which in the opinion of the investigator makes participation ill advised.

Gender Eligibility: All

Minimum Age: 3 Years

Maximum Age: 35 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Aruvant Sciences GmbH
  • Collaborator
    • Doris Duke Charitable Foundation
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Michael S Grimley, MD, Principal Investigator, Children’s Hospital Medical Center, Cincinnati
  • Overall Contact(s)
    • Courtney Little, 513-354-3864,

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