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.

Official title

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.

Overview

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.

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.

Interventions

• 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

Primary outcome measures

• Neutrophil recovery [Time frame: within the 24 months following IV infusion of DREAM01]
• Platelet recovery [Time frame: within the 24 months following IV infusion of DREAM01]
• In vivo engraftment (neutrophils and platelets) [Time frame: every 3 months between 3 to 24 months following IV infusion of DREAM01]
• Adverse event [Time frame: within the 24 months following IV infusion of DREAM01]
• Transplant-related mortality (TRM) [Time frame: within 100 days following IV infusion of DREAM01]
• Transplant-related mortality (TRM) [Time frame: within the first year following IV infusion of DREAM01]
• All-cause mortality [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Efficacy of DREAM01 [Time frame: between 3 and 15 months following IV infusion of DREAM01]
• Efficacy of anti-inflammatory therapy [Time frame: within the 3 months following administration of anti-inflammatory therapy]

Secondary outcome measures (12)

• Annualized rate of VOE [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Transfusion requirement [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Change in number of units of RBCs transfused [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Percentage of HbAS3 [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Percentage of HbS [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Quantification of the transgene copy number (VCN) [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Rate of hemolysis [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Rate of anemia [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Changes in brain function [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Changes in brain function [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Changes in ocular function [Time frame: Up to the 24 months following IV infusion of DREAM01]
• Changes in ocular function [Time frame: Up to the 24 months following IV infusion of DREAM01]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

France · 1 center

• Department of Biotherapy, Necker-Enfants Malades Hospital — Paris

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 Monta PMID 35075288
• 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. PMID 37090420
• 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 linea PMID 40169559

Identifiers

NCT: NCT07432867 · APHP241664 · 2025-521257-17

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗