A Phase 1/2 Open Label Cohort Comparative Study Evaluating the Efficacy and the safety of Gene Therapy of the Sickle Cell Disease 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 βAS3m and a micro-RNA (miRNA) targeting specifically the endogenous βS-globin mRNA in Patients with Sickle Cell Disease (SCD)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

25 Feb 2026 → ongoing

Decision date (initial)

2026-01-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Assistance Publique – Hôpitaux de Paris (AP-HP) · Association Française contre les Myopathies (AFM) · Institut Imagine

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To assess whether genetically modified stem cell transplants by a lentiviral vector expressing the corrected hemoglobin beta gene and a microRNA that specifically targets the defective haemoglobin (DREAM01) are safe and effective in patient for sickle cell disease, with or without prior administration of an anti-inflammatory therapy (Imatinib) in case of severe inflammation detected at the inclusion phase. This genetic modification aims to restore normal red blood cell production.

Secondary objectives 3

1. To assess the long-term efficacy of treatment with the drug product, DREAM01
2. To compare efficacy of gene therapy with βAS3m/miR7m lentiviral vector vs Standard Of Care (SOC)
3. To compare efficacy of gene therapy with βAS3m/miR7m lentiviral vector vs Haplo-identical bone marrow transplantation

Conditions and MedDRA coding

SCD severe patients

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Age 5 – 35 years
2. Acceptation of myelogram (bone marrow aspiration)
3. Diagnosis of HbSS by Hb electrophoresis and genetic analysis to analyse the alpha locus
4. Antécédents cliniques ou signes actuels de drépanocytose sévère avec au moins une des complications cliniques suivantes démontrant la sévérité de la maladie : o Au moins 3 crises vaso-occlusives nécessitant une hospitalisation, sous hydroxyurée ou transfusion, dans les 2 années précédant l’inclusion o Un syndrome thoracique aigu (STA) grave nécessitant une hospitalisation en unité de soins intensifs o Au moins 2 épisodes de STA, dont un survenu sous hydroxyurée o Priapisme aigu (au moins 2 épisodes de plus de 3 heures dans l’année précédente ou dans l’année précédant le début d’un programme transfusionnel régulier), OU priapisme récidivant (≥ 1 fois par semaine) sous traitement de la drépanocytose (hydroxyurée, transfusion ou phlébotomie) o Vitesse de régurgitation tricuspide >2,8 m/s à l’échocardiographie sans hypertension pulmonaire confirmée par cathétérisme cardiaque droit (PAP moyenne >< 25 mmHg)
5. Hydroxyurea (HU) treatment failure OR inadequate clinical response to HU.
6. Karnovsky/Lansky performance score ≥ 60%
7. 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)
8. Procedure for obtaining consent (adults, dependent minors, to give their consent)
9. Affiliation to social security
10. Effective method of contraception : Heterosexual female participants of childbearing potential who have, or may have, male sexual partners during the course of the study should be using an insertable (implant or IUD), injectable, transdermal or combination oral contraceptive approved by the TGA combined with a barrier contraceptive. Abstinent female participants must agree to start a double method if they start a sexual relationship with a male. Female participants must not be planning in vitro fertilisation within the required contraception period. Women of non-childbearing potential who will not require contraception during the trial are defined as: surgically sterile (tubal ligation is not considered surgically sterile), post-menopausal (spontaneous amenorrhoea for ≥12 months, or spontaneous amenorrhoea for 6-12 months and follicle-stimulating hormone (FSH) ≥40 IU/mL; either should be together with the absence of oral contraceptive use for >12months). Male participants who have, or may have female sexual partners must agree to use a double method of contraception including condom plus diaphragm, or condom plus stable insertable (implant or IUD), injectable, transdermal or combination oral contraceptive by the female partner, from the time of informed consent. Abstinent male participants must agree to start a double method if they begin a sexual relationship with a female. Male participants with female partners that are surgically sterile or post-menopausal, or male participants who have undergone sterilisation and have had testing to confirm the success of the sterilisation, may also be included and will not be required to use above described methods of contraception. In addition, all male participants must agree to not donate sperm.

Exclusion criteria 24

1. Existence of a matched sibling donor
2. Stroke with significant CNS sequelae i.e., Rankin >2
3. 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%)
4. Lung interstitial infiltrate AND Forced Vital Capacity less than 70% AND DLCO less than 60% at steady state
5. 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.
6. 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.
7. Pregnancy or breastfeeding in a postpartum female
8. Any current cancer or prior history of a malignant disease, with the exception of curatively treated non-melanoma skin cancer
9. Immediate family member with an established or suspected Familial Cancer Syndrome
10. Diagnosis of significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study
11. Patients who failed previous HSCT
12. 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
13. Any clinically significant active infection
14. Participation in another clinical study with an investigational drug within 30 days of screening
15. 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
16. Hematologic evaluation: Leukopenia (WBC <3,000µL) or neutropenia (ANC <1,000µL) or thrombocytopenia (platelet count <100,000µL) within 90 days prior to mobilization or harvest (not due to an erytrapheresis procedure or possible acute viral infection)
17. PT/INR or PTT >1.5 times the upper limit of normal (ULN) or clinically significant bleeding disorder
18. Two alpha deletions (risk of alpha-thalassemia after gene therapy)
19. ALT or AST >3 times ULN
20. 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
21. Measured GFR <60ml/min/1.73 m²
22. Cardiac evaluation: LVEF <40% by cardiac echocardiogram or by MUGA scan or clinically significant ECG abnormalities
23. Hypersensitivity to the active substances of the administered drugs or to any of their excipients
24. Patients who have already been treated with gene therapy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy and safety after intravenous infusion of DREAM01 gene therapy with or without prior administration of Imatinib treatment.

Secondary endpoints 10

1. 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. The evaluation starts 60 days after the last RBC transfusion for post-transplant support or SCD disease management
2. Transfusion requirement and change in number of units of RBCs transfused for SCD-related indications over time
3. Percentage of HbAS3 and HbS over time
4. Vector copy number over time
5. Biologic parameters that reflect hemolysis and anemia over time (Total hemoglobin, Reticulocytes, lactate dehydrogenase LDH, circulating erythroblasts, haptoglobin, free plasmatic heme, no conjugated bilirubin, erythropoietin EPO)
6. Biologic, functional and radiologic parameters reflecting organ function that may be affected by the disease or conditioning (evaluation of cerebral, ophthalmic, cardiac, renal, liver, pulmonary, bone, muscular)
7. Evaluation of iron overload (ferritin, liver and cardiac MRI) and specific treatment (chelator, phlebotomy)
8. Fertility evaluation: to be adapted according to sex: spermogram, hormone assays (estradiol, LH, FSH, testosterone, etc.), AMH, pelvic ultrasound for follicular count
9. Physical ability and capacity (6-minute walk-test, vertical jump test, physical ability questionnaire, cardiopulmonary exercise test)
10. Quality of life Evaluation: SF-36 (Short Form-36 Health Survey), FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue Scale), PROMIS (Patient-Reported Outcomes Measurement Information System) or PedsQL (Pediatric Quality of Life Inventory) Generic Core Scales

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Marina CAVAZZANA, MD, PhD

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Marina CAVAZZANA, MD, PhD

Locations

1 EU/EEA country · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

4 submissions — initial application plus substantial / non-substantial modifications