Gene therapy using corrected β-globin and a silencing RNA in your own CD34+ stem cells for severe sickle cell disease

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.

This trial will try a one-time gene therapy using a patient’s own modified CD34+ stem cells to reduce painful vaso-occlusive crises and long-term organ damage in people aged 12–35 with severe sickle cell disease.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 15 (estimated)
• Ages: 12 Years to 35 Years
• Sex: All
• Sponsor: Assistance Publique - Hôpitaux de Paris (other)
• Locations: 1 site (Paris, Île-de-France Region)
• Trial ID: NCT07432867 on ClinicalTrials.gov

What this trial studies

This phase 1/2 interventional trial transduces autologous CD34+ hematopoietic stem cells ex vivo with a bifunctional lentiviral vector expressing βAS3m-globin and an anti-βS microRNA (DREAM01) and then returns the cells to the patient after conditioning. The primary focus is on safety and on whether the therapy reduces or eliminates vaso-occlusive events and prevents progressive organ damage. Eligible participants are 12–35 years old with HbSS and a history of severe disease who lack an HLA-identical sibling donor. Procedures include bone marrow aspiration, cell manufacturing at the treating center, conditioning, infusion of the gene-modified product, and extended clinical follow-up at the treating site in Paris.

Who should consider this trial

Good fit: Ideal candidates are patients aged 12–35 with HbSS and severe disease manifestations (recurrent vaso-occlusive crises, acute chest syndrome, priapism, or other complications) who lack an HLA-identical sibling donor and can undergo bone marrow aspiration and conditioning.

Not a fit: Patients with milder sickle cell disease, non-HbSS genotypes, active uncontrolled infections, or who are eligible for and prefer a matched-sibling bone marrow transplant may not benefit from this intervention.

Why it matters

Potential benefit: If successful, the therapy could markedly reduce painful crises and organ complications and offer a durable, potentially curative option without a matched sibling transplant.

How similar studies have performed: Other lentiviral gene therapy programs for sickle cell disease have shown promising reductions in crises and transfusion needs, but this specific bifunctional vector combining corrected globin and an anti-sickling microRNA represents a novel modification.

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

Where this trial is running

Paris, Île-de-France Region

• Department of Biotherapy, Necker-Enfants Malades Hospital — Paris, Île-de-France Region, France (RECRUITING)

Study contacts

• Study coordinator: Marina CAVAZZANA, MD, PhD

Conditions: Sickle Cell Disease, Gene therapy, Lentiviral vector, Vaso-occlusive events, CD34+ hematopoietic stem cells, Hematopoietic stem cells transplantation