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. (DREPAMIR)

A Phase 1/2 Open Label Cohort Study Evaluating the Efficacy and Safety of Gene Therapy of the Sickle Cell Disease (SCD) by Transplantation of an Autologous CD34+ Enriched Cell Fraction That Contains Autologous CD34+ Cells Transduced ex Vivo by the Bifunctional βAS3m/miR7m Lentiviral Vector Expressing the Therapeutical Beta-globin βAS3m and a Micro-RNA (miRNA) Targeting Specifically the Endogenous βS-globin mRNA.

The purpose of this study is to evaluate the Safety and Efficacy of DREAM01, a gene therapy for Sickle Cell Disease (SCD). The therapy consists of transplanting autologous CD34+ cells transduced ex vivo with a bifunctional lentiviral vector expressing βAS3m-globin and an anti-βS miRNA. It aims to reduce or eliminate vaso-occlusive events and long-term organ damage in severe SCD patients lacking a Human Leukocyte Antigen (HLA) identical sibling donor.

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Genetic: DREAM01 drug product; Drug: anti-inflammatory therapy

Detailed Description

Sickle cell anaemia is a hereditary disease caused by a mutation in the gene for beta haemoglobin, essential for oxygen transport by red blood cells. This genetic mutation causes a deformation of the red blood cells, giving them a crescent shape (also known as a sickle) and leading to their massive destruction, resulting in anaemia. Other serious consequences are linked to this disease, such as recurrent painful obstructive crises, known as vaso-occlusive crises (VOC), as well as strokes, acute respiratory syndromes (ARS) and multi-organ damage. All these complications are linked to the obstruction of capillaries caused by deformed red blood cells.

Management of the disease consists of regular transfusions of healthy red blood cells and/or specific drug therapy such as hydroxyurea (HU). HU increases the production of foetal haemoglobin, which can prevent the deformation of red blood cells characteristic of sickle cell disease. By reducing the number of sickle-shaped red blood cells, hydroxyurea helps reduce the frequency of painful attacks and other complications associated with the disease. During these painful attacks, deformed red blood cells block small blood vessels, leading to intense pain and organ damage. These treatments help prevent the risks associated with the disease, but also entail transfusion-related risks (immunological response that may prevent the necessary transfusion).

The only curative treatment to date is a bone marrow transplant from a compatible sibling donor. Bone marrow contains stem cells capable of producing blood cells (red blood cells, white blood cells and platelets) throughout an individual's life. Unfortunately, this treatment is only available for 25% of patients, and is associated with significant immunological complications caused by the white blood cells present in the graft (graft-versus-host disease) or risk of rejection (if partially compatible donor). The aim of this study is to treat patients with severe sickle cell disease with a new experimental gene therapy treatment. This is a new therapeutic approach for patients without a compatible donor, and patients will be followed for 2 years.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Marina CAVAZZANA, MD, PhD; Phone Number: +33 01 44 49 50 68; Email: m.cavazzana@aphp.fr
• Study Contact Backup: Name: Nelly BRIAND, PhD; Phone Number: +33 01 44 38 18 62; Email: nelly.briand@aphp.fr

Study Locations

• France
  • Île-de-France Region
    • Paris, Île-de-France Region, France, 75015
      • Recruiting
      • Department of Biotherapy, Necker-Enfants Malades Hospital
      • Contact: Marina CAVAZZANA, MD, PhD; Phone Number: +33 01 44 49 50 68; Email: m.cavazzana@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: DREPAMIR drug product; DREAM01 is a genetically modified cell therapy product that consists of autologous CD34+ cells transduced ex vivo by the bifunctional βAS3m/mR7m lentiviral vector expressing the βAS3m-globin and a micro-RNA (miRNA) targeting specifically the endogenous sickle βS-globin gene. With or without prior administration of an anti-inflammatory therapy in case of severe inflammation detected at the inclusion phase

Genetic: DREAM01 drug product; Each patient will receive a single IV infusion of DREAM01, autologous CD34+ stem cells transduced with βAS3m/miR7m lentiviral vector; Drug: anti-inflammatory therapy; Patient will receive anti-inflammatory therapy if necessary

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neutrophil recovery	Neutrophil recovery defined as the first of three consecutive days with an ANC of > 500/µL	within the 24 months following IV infusion of DREAM01
Platelet recovery	Platelet recovery defined as the first of three consecutive days with a platelet count of > 20.000/µL sustained without platelet transfusion for at least seven days	within the 24 months following IV infusion of DREAM01
In vivo engraftment (neutrophils and platelets)	hematopoietic reconstitution after IV infusion of the drug product	every 3 months between 3 to 24 months following IV infusion of DREAM01
Adverse event	Adverse event will be measured using CTCAE	within the 24 months following IV infusion of DREAM01
Transplant-related mortality (TRM)	Transplant-related mortality	within 100 days following IV infusion of DREAM01
Transplant-related mortality (TRM)	Transplant-related mortality	within the first year following IV infusion of DREAM01
All-cause mortality	Mortality	Up to the 24 months following IV infusion of DREAM01
Efficacy of DREAM01	absence of vaso-occlusive events (VOE) in patients who have discontinued the transfusion program or/and hydroxyurea	between 3 and 15 months following IV infusion of DREAM01
Efficacy of anti-inflammatory therapy	Decrease of HSPCs inflammation assessed through a reduction of the score and/or the number of inflammatory pathways (among the 6 pathways established) by transcriptomic analysis on HSPCs between inclusion and after 3 months of anti-inflammatory therapy treatment before infusion	within the 3 months following administration of anti-inflammatory therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized rate of VOE	Proportion of subjects with reduction in annualized rate of VOE at the time of analysis from baseline by at least 90% up to 24 months after DREAM01 infusion	Up to the 24 months following IV infusion of DREAM01
Transfusion requirement	Number of transfusion requirement	Up to the 24 months following IV infusion of DREAM01
Change in number of units of RBCs transfused	change in number of units of RBCs transfused for SCD-related indications over time	Up to the 24 months following IV infusion of DREAM01
Percentage of HbAS3	Measure of HbAS3	Up to the 24 months following IV infusion of DREAM01
Percentage of HbS	Measure of Measure of HbS	Up to the 24 months following IV infusion of DREAM01
Quantification of the transgene copy number (VCN)	Quantification of the transgene copy number (VCN) on drug substance at time of cryopreservation, on PBMC, sorted T-CD3+ and sorted NK cells	Up to the 24 months following IV infusion of DREAM01
Rate of hemolysis	Biological parameters that reflect hemolysis : Total hemoglobin, Reticulocytes, lactate dehydrogenase LDH, circulating erythroblasts, haptoglobin, free plasmatic heme, no conjugated bilirubin, erythropoietin EPO	Up to the 24 months following IV infusion of DREAM01
Rate of anemia	Biological parameters that reflect anemia : Total hemoglobin, Reticulocytes, lactate dehydrogenase LDH, circulating erythroblasts, haptoglobin, free plasmatic heme, no conjugated bilirubin, erythropoietin EPO	Up to the 24 months following IV infusion of DREAM01
Changes in brain function	Occurrence of ischemic lesions, vascular stenosis, aneurysm assessed using cervical doppler ultrasound and cerebral MRI	Up to the 24 months following IV infusion of DREAM01
Changes in brain function	Occurrence of pathological flow acceleration or vascular stenosis using carotid and transcranial Doppler ultrasound	Up to the 24 months following IV infusion of DREAM01
Changes in ocular function	Assessed Using Fundus examination	Up to the 24 months following IV infusion of DREAM01
Changes in ocular function	Assessed Using angiography	Up to the 24 months following IV infusion of DREAM01
Changes in cardiac function	evaluated through electrocardiographic (ECG) assessment	Up to the 24 months following IV infusion of DREAM01
Changes in the occurrence of left ventricular ejection fraction [LVEF] right and left atrial	Occurrence of left ventricular ejection fraction [LVEF], right and left atrial, left assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography	Up to the 24 months following IV infusion of DREAM01
Changes in left ventricular size	Changes in left ventricular size assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography	Up to the 24 months following IV infusion of DREAM01
Changes in left ventricular wall thickness	Changes in the left ventricular wall thickness assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography	Up to the 24 months following IV infusion of DREAM01
Changes in systolic pulmonary artery pressure [sPAP]	Changes in systolic pulmonary artery pressure [sPAP], assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography	Up to the 24 months following IV infusion of DREAM01
Changes in tricuspid regurgitation velocity [TRV]	Changes in tricuspid regurgitation velocity [TRV] assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography	Up to the 24 months following IV infusion of DREAM01
Changes in E/A ratio	Changes in of E/A ratio assessed using cardiac ultrasound, cardiac MRI (including myocardial imaging), Doppler echocardiography and transthoracic echocardiography	Up to the 24 months following IV infusion of DREAM01
Change in serum electrolyte panel		Up to the 24 months following IV infusion of DREAM01
Change in serum creatinine		Up to the 24 months following IV infusion of DREAM01
Change in estimated glomerular filtration rate (eGFR)	Renal function assessed through estimated glomerular filtration rate (eGFR) calculated using CKD-EPI equation	Up to the 24 months following IV infusion of DREAM01
Change in urinary microalbumin		Up to the 24 months following IV infusion of DREAM01
Change in protein excretion		Up to the 24 months following IV infusion of DREAM01
Change in urinary creatinine		Up to the 24 months following IV infusion of DREAM01
Changes in creatinine clearence		Up to the 24 months following IV infusion of DREAM01
Change in liver enzyme AST		Up to the 24 months following IV infusion of DREAM01
Change in liver enzyme ALT		Up to the 24 months following IV infusion of DREAM01
Change in liver enzyme GGT		Up to the 24 months following IV infusion of DREAM01
Changes in in liver enzyme ALP		Up to the 24 months following IV infusion of DREAM01
Change in total bilirubin		Up to the 24 months following IV infusion of DREAM01
Change in unconjugated (free) bilirubin		Up to the 24 months following IV infusion of DREAM01
Changes in hepatic function	Description of hepatic morphology assessed through abdominal ultrasound	Up to the 24 months following IV infusion of DREAM01
Change in diffusing capacity for carbon monoxide (DLCO)		Up to the 24 months following IV infusion of DREAM01
Change in vital capacity (VC)		Up to the 24 months following IV infusion of DREAM01
Change in residual volume (RV)		Up to the 24 months following IV infusion of DREAM01
Change in FEV1/FVC ratio (Tiffeneau index)		Up to the 24 months following IV infusion of DREAM01
Changes in bone metabolism	Assessed through Osteodensitometry, osteoarticular MRI	Up to the 24 months following IV infusion of DREAM01
Changes in muscular function	Assessed through physical capacity testing	Up to the 24 months following IV infusion of DREAM01
Occurrence of iron overload	Efficacy	Up to the 24 months following IV infusion of DREAM01
Fertility evaluation	Safety	Up to the 24 months following IV infusion of DREAM01
Walk ability	6-minute walk-test	Up to the 24 months following IV infusion of DREAM01
Jump	Vertical jump test : The jump height will be recorded using video analysis software. The average height of the 3 jumps will be calculated	Up to the 24 months following IV infusion of DREAM01
Cardiopulmonary capacity	Cardiopulmonary exercise test, using the Cardio Pulmonary Exercise Test	Up to the 24 months following IV infusion of DREAM01
Physical ability	Physical ability questionnaire, using the Global physical activity questionnaire (GPAQ) (16 items) developed by WHO	Up to the 24 months following IV infusion of DREAM01
Quality of life Evaluation : patient health	Medical Outcomes Study Short Form 36 SF-36 .The Short Form (36) Health Survey is a 36-item, patient-reported survey of patient health	Up to the 24 months following IV infusion of DREAM01
Quality of life Evaluation : fatigue	FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue Scale) FACIT-Fatigue is a 13-item self-report scale that assesses fatigue and its effect on daily activities and function.	Up to the 24 months following IV infusion of DREAM01
Quality of life Evaluation : physical, mental, and social health	PROMIS (Patient-Reported Outcomes Measurement Information System) PROMIS® (Patient-Reported Outcomes Measurement Information System) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children.	Up to the 24 months following IV infusion of DREAM01
Health-realted Quality of life Evaluation	Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales PedsQL is a modular system that assesses health-related quality of life in healthy and ill children and adolescents. It combines generic core scales and disease-specific modules into one measurement system.	Up to the 24 months following IV infusion of DREAM01
Changes in brain function	Description of neuropsychological status using functional performance testing	Up to the 24 months following IV infusion of DREAM01
Change in hepatic function	Occurrence of fibrosis and cirrhosis assessed through Liver elastography	Up to the 24 months following IV infusion of DREAM01
Change in hepatic function	Occurence of intrahepatic iron deposition assessed through liver MRI	Up to the 24 months following IV infusion of DREAM01

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin; Association Française contre les Myopathies (AFM), Paris; Imagine Institute
• Investigators: Study Director: Elisa MAGRIN, PhD, Department of Biotherapy, Necker-Enfants Malades Hospital

Publications and helpful links

General Publications

• Magrin E, Semeraro M, Hebert N, Joseph L, Magnani A, Chalumeau A, Gabrion A, Roudaut C, Marouene J, Lefrere F, Diana JS, Denis A, Neven B, Funck-Brentano I, Negre O, Renolleau S, Brousse V, Kiger L, Touzot F, Poirot C, Bourget P, El Nemer W, Blanche S, Treluyer JM, Asmal M, Walls C, Beuzard Y, Schmidt M, Hacein-Bey-Abina S, Asnafi V, Guichard I, Poiree M, Monpoux F, Touraine P, Brouzes C, de Montalembert M, Payen E, Six E, Ribeil JA, Miccio A, Bartolucci P, Leboulch P, Cavazzana M. Long-term outcomes of lentiviral gene therapy for the beta-hemoglobinopathies: the HGB-205 trial. Nat Med. 2022 Jan;28(1):81-88. doi: 10.1038/s41591-021-01650-w. Epub 2022 Jan 24.
• Brusson M, Chalumeau A, Martinucci P, Romano O, Felix T, Poletti V, Scaramuzza S, Ramadier S, Masson C, Ferrari G, Mavilio F, Cavazzana M, Amendola M, Miccio A. Novel lentiviral vectors for gene therapy of sickle cell disease combining gene addition and gene silencing strategies. Mol Ther Nucleic Acids. 2023 Mar 22;32:229-246. doi: 10.1016/j.omtn.2023.03.012. eCollection 2023 Jun 13.
• Sobrino S, Joseph L, Magrin E, Chalumeau A, Hebert N, Corsia A, Denis A, Roudaut C, Aussel C, Leblanc O, Brusson M, Felix T, Diana JS, Petrichenko A, El Etri J, Godard A, Tibi E, Manceau S, Treluyer JM, Mavilio F, Bushman FD, Marcais A, Castelle M, Neven B, Hermine O, Renolleau S, Magnani A, Asnafi V, El Nemer W, Bartolucci P, Six E, Semeraro M, Miccio A, Cavazzana M. Severe inflammation and lineage skewing are associated with poor engraftment of engineered hematopoietic stem cells in patients with sickle cell disease. Nat Commun. 2025 Apr 1;16(1):3137. doi: 10.1038/s41467-025-58321-4.

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2026
• Primary Completion (Estimated): February 1, 2032
• Study Completion (Estimated): February 1, 2033

Study Registration Dates

• First Submitted: January 2, 2026
• First Submitted That Met QC Criteria: February 24, 2026
• First Posted (Actual): February 25, 2026

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: March 2, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Sickle Cell Disease; Gene therapy; Lentiviral vector; Hematopoietic stem cells transplantation; Vaso-occlusive events; CD34+ hematopoietic stem cells
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; Vaso-Occlusive Crises
• Other Study ID Numbers: APHP241664; 2025-521257-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No