Gene Therapy for Thalassemia

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

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The patient has inherited ß-thalassemia major through the genes. These genes have mistakes in them, so the body cannot make normal red blood cells. Stem cells are made in the bone marrow. They are the earliest form of blood cells. This study is being done to see if the investigators can make the stem cells produce normal red blood cells and hemoglobin. The investigators do this by collecting the stem cells. The genes with mistakes are removed from the cells. These cells are then treated so they have the corrected gene for making normal hemoglobin. These treated cells are given back to the patient through an injection (shot) in the vein. This is also known as gene transfer. In order for the body to accept these cells, the patient will need to receive a low dose of a drug called busulfan. It is a drug that will prepare the body to receive the new stem cells. This study will let the investigators know: * If it is safe to give the patient the treated stem cells * If the treated stem cells will go into the bone marrow without causing side effects. Gene transfer has been used for the past five years. It has been successful in treating many blood disorders. At least 20 patients have received the type of treatment that the patient will get on this study. This treatment for B-thalassemia major was developed at Memorial Sloan Kettering (MSK). It was studied for a long time in the lab before being given to patients.

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 gene therapy using autologous CD34+ cells transduced with TNS9.3.55 safe for humans?

In clinical trials, this gene therapy was generally well-tolerated by patients with β-thalassemia, with no unexpected safety issues during treatment. However, there were moderate clonal expansions (growth of certain cell groups) near genes related to cancer, which suggests the need for careful monitoring. ^{1 2 3 4 5}

What makes the gene therapy treatment for thalassemia unique?

This gene therapy uses a patient's own stem cells that are modified to produce normal hemoglobin, potentially offering a long-term solution without the need for regular blood transfusions. It involves a specific vector to ensure stable and high expression of the beta-globin gene, which is crucial for correcting the anemia associated with thalassemia. ^{2 6 7 8 9}

What data supports the effectiveness of the treatment Autologous CD34+ cells transduced with TNS9.3.55 for thalassemia?

Research shows that gene therapy using modified stem cells can correct anemia in mice with thalassemia, leading to normal or improved blood conditions. This suggests that similar treatments could be effective in humans with thalassemia. ^{2 4 6 9 10}

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

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]

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]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of beta-thalassemia. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Strategy for a multicenter phase I clinical trial to evaluate globin gene transfer in beta-thalassemia. [2012]

3. England pubmed.ncbi.nlm.nih.gov

Both TALENs and CRISPR/Cas9 directly target the HBB IVS2-654 (C > T) mutation in β-thalassemia-derived iPSCs. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

In vivo hematopoietic stem cell gene therapy ameliorates murine thalassemia intermedia. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Establishment of human iPSC line from patient of Indian ethnicity carrying homozygous CD8/9 (+G) beta thalassemia mutation. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Safe mobilization of CD34+ cells in adults with β-thalassemia and validation of effective globin gene transfer for clinical investigation. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

One-Step Biallelic and Scarless Correction of a β-Thalassemia Mutation in Patient-Specific iPSCs without Drug Selection. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Stem cell engineering for the treatment of severe hemoglobinopathies. [2019]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Towards more successful gene therapy clinical trials for β-thalassemia. [2022]