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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.
Bu çalışma, hastanın kendi düzeltilmiş kök hücrelerini (otolog CD34+ hücreler) kullanan DREAM01 adlı bir gen terapisinin, orak hücre hastalığı (sickle cell disease) olan kişilerdeki etkililiğini ve güvenliliğini değerlendirmektedir. Çalışmaya, HbSS tipi ağır orak hücre hastalığı olan 12-35 yaş arası kişiler katılabilmektedir. Çalışma Faz 1/Faz 2 aşamasında yürütülmekte olup halen katılımcı almaktadır.
Yukarıdaki özet, resmî kaydın sade dile aktarılmış halidir. Orijinal İngilizce başlık referans için gösterilir.
Kriterler ClinicalTrials.gov kaydından orijinal İngilizce haliyle alınmıştır. Uygunluk kararını yalnızca deneyi yürüten ekip verebilir.
Inclusion Criteria: * Age 12 - 35 years * Acceptation of myelogram (bone marrow aspiration) * Diagnosis of HbSS by Hb electrophoresis and genetic analysis to analyse the alpha locus * Clinical history or ongoing evidence of severe sickle cell anemia with one OR more of the following clinical complications demonstrating disease severity: * At least 3 vaso-occlusive crises requiring hospitalization, under hydroxyurea or 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 year prior 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 without pulmonary hypertension confirmed by right heart catheterization (mPAP\>\<25mmHg) * Failed hydroxyurea (HU) therapy, OR Inadequate clinical response to HU, defined as any one of the following outcomes, while on HU for at least 3 months: 2 or more acute sickle pain crisis requiring hospitalization, requirement of transfusion to maintain 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 of double-barrier contraception for at least 12 months post-infusion (beyond 12 months at 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) or molecular abnormalities (detected by NGS) and retained dangerous by the Hemato-Oncology referent and validated during a specific multidisciplinary concerted meeting * Hematologic evaluation: Leukopenia (WBC \<3,000/µL) or neutropenia (ANC \<1,000/µL) or thrombocytopenia (platelet count \<100,000/µL) within 90 days prior to mobilization or harvest (not due to an erythrapheresis procedure or possible acute viral infection) * PT/INR or PTT \>1.5 times the upper limit of normal (ULN) or clinically significant bleeding 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/g dry weight) or liver cirrhosis suspicion on echography or elastometry or CT scan or MRI AND confirmed by histology * Measured GFR \<60ml/min/1.73 m² * Cardiac evaluation: LVEF \<40% by cardiac echocardiogram or by MUGA scan or clinically significant ECG abnormalities * Stroke with significant CNS sequelae i.e., Rankin \>2 * Specific sickle cell disease cerebral vasculopathy confirmed by MRA (magnetic resonance angiography) OR transcranial doppler ultrasound with or without Moya-moya WITH an indication of chronic transfusion program (target HbS\<30%) * Lung interstitial infiltrate AND Forced Vital Capacity less than 70% AND DLCO less than 60% at steady state * Confirmed pulmonary hypertension defined by a right heart catheterization (PAPm \>25 mmHg). Right heart catheterization is required if tricuspid regurgitation velocity \>2.8m/s on cardiac echocardiograph OR \>2.5m/s with an abnormal Brain Natriuretic Peptide dosage or an important decrease in transcutaneous Hb O2 saturation during the 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 active infection 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 of curatively 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 seriously impede 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 days of screening * Any condition, based on perspective of the medical monitor and treating investigator, which may lead to increased safety risk or inability to comply with the protocol