Efficacy Safety Study of Gene Therapy for Sickle Cell DiseaseSCD Using Autologous CD34+ Cells Transduced ex Vivo, Carrying a Corrected Globin Gene and a Silencing RNA.

Inclusion Criteria:

• Age 12 - 35 years

• Acceptation of myelogram (bone marrow aspiration)

• Diagnosis of HbSS by Hb electrophoresis and genetic analysis to analyse the alphalocus

• Clinical history or ongoing evidence of severe sickle cell anemia with one OR moreof the following clinical complications demonstrating disease severity:

• At least 3 vaso-occlusive crises requiring hospitalization, under hydroxyureaor transfusion, within 2 years prior to enrolment

• One severe acute chest syndrome (ACS) hospitalized in the intensive care unit

• At least 2 episodes of ACS, including one under HU.

• Acute priapism (at least 2 episodes >3h in the preceding year or in the yearprior to the start of a regular transfusion program), OR stuttering priapism ≥ 1 by week under sickle cell treatment (HU, transfusion or phlebotomy).

• Tricuspid regurgitation velocity >2.8m/s on cardiac echocardiograph withoutpulmonary hypertension confirmed by right heart catheterization (mPAP><25mmHg)

• Failed hydroxyurea (HU) therapy, OR Inadequate clinical response to HU, defined asany one of the following outcomes, while on HU for at least 3 months: 2 or moreacute sickle pain crisis requiring hospitalization, requirement of transfusion tomaintain Hb >6.0g/dL, an episode of ACS despite adequate supportive care measures

• Karnovsky/Lansky performance score ≥ 60%

• Sexually active patients must be willing to use an acceptable method ofdouble-barrier contraception for at least 12 months post-infusion (beyond 12 monthsat the discretion of the investigator)

• Procedure for obtaining consent (adults, dependent minors, to give their consent)

• Affiliation to social security

Exclusion Criteria:

• Existence of a matched sibling donor

• Based on myelogram, the presence of chromosomal (detected by karyotyping) ormolecular abnormalities (detected by NGS) and retained dangerous by theHemato-Oncology referent and validated during a specific multidisciplinary concertedmeeting

• Hematologic evaluation: Leukopenia (WBC <3,000/µL) or neutropenia (ANC <1,000/µL) orthrombocytopenia (platelet count <100,000/µL) within 90 days prior to mobilizationor harvest (not due to an erythrapheresis procedure or possible acute viralinfection)

• PT/INR or PTT >1.5 times the upper limit of normal (ULN) or clinically significantbleeding disorder

• Two alpha deletions (risk of alpha-thalassemia after gene therapy)

• Hypersensitivity to the active substances of the administered drugs (plerixafor,busulfan, anti-inflammatory therapy) or to any of their excipients

• Patients who have already been treated with gene therapy

Evaluations within 6 months prior to screening visit:

• ALT or AST >3 times ULN

• Severe liver iron overload evaluated by MRI (>15mg Fe/g dry weight or >270umol Fe/gdry weight) or liver cirrhosis suspicion on echography or elastometry or CT scan orMRI AND confirmed by histology

• Measured GFR <60ml/min/1.73 m²

• Cardiac evaluation: LVEF <40% by cardiac echocardiogram or by MUGA scan orclinically significant ECG abnormalities

• Stroke with significant CNS sequelae i.e., Rankin >2

• Specific sickle cell disease cerebral vasculopathy confirmed by MRA (magneticresonance angiography) OR transcranial doppler ultrasound with or without Moya-moyaWITH an indication of chronic transfusion program (target HbS<30%)

• Lung interstitial infiltrate AND Forced Vital Capacity less than 70% AND DLCO lessthan 60% at steady state

• Confirmed pulmonary hypertension defined by a right heart catheterization (PAPm >25mmHg). Right heart catheterization is required if tricuspid regurgitation velocity >2.8m/s on cardiac echocardiograph OR >2.5m/s with an abnormal Brain NatriureticPeptide dosage or an important decrease in transcutaneous Hb O2 saturation duringthe 6 minutes' walk test.

• Seropositivity for HIV (Human Immunodeficiency Virus), HCV (Hepatitis C Virus),HTLV-1 (Human T-Lymphotropic Virus), or active Hepatitis B Virus, or activeinfection by CMV or parvovirus B19, based on positive blood PCR.

• Pregnancy or breastfeeding in a postpartum female

• Any current cancer or prior history of a malignant disease, with the exception ofcuratively treated non-melanoma skin cancer

• Immediate family member with an established or suspected Familial Cancer Syndrome

• Diagnosis of significant psychiatric disorder of the subject that could seriouslyimpede the ability to participate in the study

• Patients who failed previous HSCT

• Any clinically significant active infection

• Participation in another clinical study with an investigational drug within 30 daysof screening

• Any condition, based on perspective of the medical monitor and treatinginvestigator, which may lead to increased safety risk or inability to comply withthe protocol