Gene Therapy for Thalassemia

Not currently recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: San Rocco Therapeutics

Must be taking: Busulfan

Must not be taking: Hydroxyurea, Erythropoietin

Disqualifiers: Active infections, Diabetes, Myelodysplasia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy for individuals with ß-thalassemia major, a condition where faulty genes prevent the body from making normal red blood cells. Researchers aim to correct this by fixing the genes in stem cells and returning these cells to the patient to produce healthy blood cells. The treatment uses autologous CD34+ cells transduced with TNS9.3.55, modifying the patient's own stem cells to correct the genetic defect. Participants must have ß-thalassemia major, require frequent blood transfusions, and lack a matching sibling donor. This study will determine if the therapy is safe and effective in reducing the need for transfusions. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking hydroxyurea (HU) or erythropoietin (EPO) at least three months before joining the study.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that gene therapy using the TNS9.3.55 lentiviral vector has been tested in patients with β-thalassemia, yielding promising results. In these studies, patients received stem cells treated with this vector and underwent long-term monitoring. Importantly, no unexpected safety issues emerged over several years.

The studies found that the treatment was generally well-tolerated, with most patients not experiencing severe or surprising side effects. Some patients experienced mild side effects, but these were manageable. Additionally, the process of preparing the body to receive these treated cells involves busulfan, a drug used safely in similar treatments.

Overall, the treatment has demonstrated a good safety profile in past patients, indicating it is relatively safe compared to other treatments. However, like any medical treatment, there can be risks, so discussing potential implications with a healthcare provider is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for thalassemia, which often include regular blood transfusions or bone marrow transplants, this gene therapy uses autologous CD34+ cells transduced with TNS9.3.55. This treatment is unique because it directly targets the genetic root of the disorder by using a lentiviral vector to introduce a functional version of the human ß-globin gene into the patient's own stem cells. Researchers are excited about this approach because it has the potential to offer a long-term solution by correcting the underlying genetic defect, reducing or even eliminating the need for ongoing transfusions. This innovative method could significantly enhance the quality of life for patients by providing a more sustainable and less invasive treatment option.

What evidence suggests that this gene therapy could be an effective treatment for thalassemia?

Research has shown that a type of gene therapy, which participants in this trial will receive, can help people with ß-thalassemia major, a serious blood disorder. This therapy modifies a patient's own cells to correct the faulty gene causing the problem. In one study, this treatment reduced or eliminated the need for blood transfusions in 22 patients. Another study found that 89% of patients who received a similar gene therapy no longer needed transfusions. By correcting the gene in stem cells, this therapy enables the body to produce normal red blood cells. These findings suggest a promising way to manage ß-thalassemia major. ^{1 2 6 7 8}

Who Is on the Research Team?

Farid Boulad, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Andromachi Scaradavou, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with ß-thalassemia major who are part of a hypertransfusion program and have no HLA-matched sibling donor. They should not have severe liver or heart issues, active infections like Hepatitis B/C or HIV, diabetes, uncontrolled seizures, or be pregnant/breastfeeding. Adequate organ function and off certain treatments for three months prior to the study are required.

Inclusion Criteria

Subjects with an evaluation of cardiac function indicating normal function on MUGA scan or other methodology

As the inclusion criteria are more specific than the Lucarelli/Pesaro thalassemia pre-transplant classification, the criteria stated above will be used in lieu of the Lucarelli/Pesaro classification

Subjects with asymptomatic pulmonary function based on Lung Diffusion Testing DLCO Test DLCO ≥ 50% of predicted (corrected for hemoglobin)

Exclusion Criteria

Definition of active Hepatitis C include: Positive HCV RNA Viral load by quantitative PCR testing Or if Negative HCV RNA viral load BUT on antiviral treatment Liver biopsy with pathologic evidence of Necrosis and inflammation around the portal areas - piecemeal necrosis or interface hepatitis or necrosis of hepatocytes and focal inflammation in the liver parenchyma, Inflammatory cells in the portal areas ('portal inflammation'), Fibrosis, with early stages being confined to the portal tracts, intermediate stages being expansion of the portal tracts and bridging between portal areas or to the central area, and late stages being frank cirrhosis characterized by architectural disruption of the liver with fibrosis and regeneration

I do not have active infections like Hepatitis B or C.

I do not have active infections like HTLV or HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive a low dose of busulfan to prepare the body for receiving new stem cells

1-2 weeks

Gene Transfer

Autologous CD34+ hematopoietic progenitor cells transduced with a lentiviral vector are infused into the patient

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment, including monitoring for insertional oncogenesis and engraftment levels

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Autologous CD34+ cells transduced with TNS9.3.55

Trial Overview The trial tests if stem cells with corrected genes can safely produce normal red blood cells in patients with ß-thalassemia major. Patients' own stem cells will be modified to correct the genetic defect and then re-injected after pre-treatment with low-dose busulfan to help their body accept the new cells.

How Is the Trial Designed?

Group I: Autologous CD34+ cells transduced with TNS9.3.55 Experimental Treatment 1 Intervention

An open label study using a non-myeloablative conditioning regimen of busulfan and 1 or several infusions of autologous hematopoietic stem cells transduced with a lentiviral vector encoding the human ß-globin gene.

Who Is Running the Clinical Trial?

San Rocco Therapeutics

Lead Sponsor

Trials

1

Recruited

10+

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

Gene therapy using lentiviral vectors has shown promise as a curative approach for β-thalassemia, with the first successful clinical trial conducted in France demonstrating significant disease improvement.

Advancements in vector design and methods for monitoring gene integration are paving the way for safer and more effective clinical trials in the future, addressing limitations of current treatments like blood transfusions and bone marrow transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards more successful gene therapy clinical trials for β-thalassemia. Drakopoulou, E., Papanikolaou, E., Georgomanoli, M., et al.[2022]

Using a combination of single-strand oligodeoxynucleotides and high-fidelity CRISPR/Cas9, researchers achieved a highly efficient and seamless correction of the β-thalassemia mutation in patient-specific induced pluripotent stem cells (iPSCs).

The corrected iPSCs showed minimal off-target effects and expressed normal β-globin transcripts when differentiated into hematopoietic progenitor cells, indicating a safe and effective approach for potential cell therapy in treating β-thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One-Step Biallelic and Scarless Correction of a β-Thalassemia Mutation in Patient-Specific iPSCs without Drug Selection. Liu, Y., Yang, Y., Kang, X., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01639690

Study Details | NCT01639690 | ß-Thalassemia Major with ... This study is being done to see if the investigators can make the stem cells produce normal red blood cells and hemoglobin.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9380046/

A phase 1 trial of lentiviral globin gene therapy with reduced ... We report 6–8 year follow-up of four adult patients with transfusion-dependent β-thalassemia who were infused with autologous CD34+ cells transduced with the ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1705342

Gene Therapy in Patients with Transfusion-Dependent β ... Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients ...

4. ajmc.com ajmc.com/view/gene-therapy-demonstrates-high-efficacy-in-severe--thalassemia

Gene Therapy Demonstrates High Efficacy in Severe β- ... Betibeglogene autotemcel gene therapy led to transfusion independence in 89% of patients with severe transfusion-dependent β-thalassemia. The ...

5. frontiersin.org frontiersin.org/journals/hematology/articles/10.3389/frhem.2024.1468952/full

Recent advancements in gene therapy for sickle cell ... Data from these clinical studies suggest that younger patients have better outcome from Lenti-globin gene therapy and a minimum transduction threshold of CD34+ ...

6. ashpublications.org ashpublications.org/blood/article/123/10/1483/32381/Safe-mobilization-of-CD34-cells-in-adults-with

Safe mobilization of CD34 + cells in adults with β-thalassemia ... We conducted a pilot trial to investigate the safety and effectiveness of mobilizing CD34 + hematopoietic progenitor cells (HPCs) in adults with β-thalassemia ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4994056/

Cell and Gene Therapy for the Beta-Thalassemias Interestingly, the CD34+ cells mobilized in this way, which were also transduced with the TNS9.3.55 vector, appeared less effectively transduced than CD34+ ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S1525001624001461

Autologous gene therapy for hemoglobinopathies ... cells transduced with the TNS9.3.55 lentiviral globin vector (Table 1). The patients, who were followed for 6–8 years and had no unexpected ...