Gene Therapy for Hemophilia A

Overseen By Parameswaran Hari, MD

Age: 18+

Sex: Male

Trial Phase: Phase 1

Sponsor: Parameswaran Hari

Must be taking: Factor VIII mimetics

Disqualifiers: Thrombophilic disorders, Active malignancy, HIV, others

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

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy approach to treat severe hemophilia A, a condition where blood doesn’t clot properly due to low levels of Factor VIII. Researchers are testing a method that uses a modified virus to deliver a gene into a patient's stem cells, enabling them to produce and store Factor VIII in platelets. The study seeks adult males with severe hemophilia A who have experienced frequent bleeding episodes and may have or had inhibitors against Factor VIII. The trial aims to determine if this gene therapy can improve blood clotting over time. 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 protocol does not specify if you need to stop taking your current medications. However, if you are on factor VIII for immune tolerance induction, you must stop it 30 days before joining the study.

What prior data suggests that this gene therapy is safe for humans?

Research has shown that a new gene therapy for hemophilia A shows promise in early studies. This therapy involves taking a person's own stem cells, modifying them to produce a protein called Factor VIII, and then reintroducing them into the body. Factor VIII plays a crucial role in blood clotting.

Studies have found that this method can lead to stable levels of Factor VIII, which is a positive sign. So far, the treatment appears well-tolerated, with no major safety concerns reported in these early trials. Any mild side effects have been manageable and are typical for gene therapy treatments.

As this is a Phase 1 trial, the main focus is on safety. Researchers closely monitor the treatment to ensure its safety for participants. The use of similar methods in other conditions has demonstrated a good safety record, which is reassuring. However, since this remains an experimental treatment, all potential risks will be carefully studied. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for Hemophilia A, which typically involves regular infusions of clotting factor VIII, this gene therapy uses a lentiviral vector to deliver a modified gene directly into the patient's own stem cells. This approach allows the body to produce the factor VIII protein on its own, potentially reducing or eliminating the need for frequent infusions. Researchers are excited because this could lead to a more stable and long-term solution for managing the condition, offering increased independence and a better quality of life for patients.

What evidence suggests that this gene therapy might be an effective treatment for hemophilia A?

Research shows that a new gene therapy, administered to participants in this trial, might help treat severe hemophilia A. This therapy employs a special method to modify a patient's own stem cells, enabling them to produce Factor VIII, a crucial protein for blood clotting. Studies have found that this approach can lead to stable production of Factor VIII in patients, addressing the main cause of hemophilia A. Early results from both animal studies and initial human trials are promising, demonstrating consistent production of Factor VIII. Although this treatment remains experimental, it offers hope for those with severe hemophilia A. ^{1 2 4 6 7}

Who Is on the Research Team?

Mary Eapen, MD, MS

Principal Investigator

Froedtert Hosptial and Medical College of Wisconsin

Are You a Good Fit for This Trial?

Adult males over 18 with severe hemophilia A and a history of FVIII inhibitors. They must have had multiple bleeding episodes, adequate bone marrow reserve, renal and liver function, and be willing to document their condition for 15 years. Excluded are those recently in other trials or with certain medical conditions.

Inclusion Criteria

I may be taking medication to help with blood clotting before joining the study.

I am willing to keep a diary of my bleeding episodes and treatments.

My kidneys work well, with a creatinine clearance over 60 ml/min.

Exclusion Criteria

I do not have any active infections that would prevent me from receiving treatments that weaken my immune system.

My life expectancy is not majorly shortened by conditions other than hemophilia A.

I have an active cancer that is not a non-melanoma skin cancer or carcinoma in situ.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo reduced intensity conditioning prior to stem cell infusion

1-2 weeks

Gene Therapy Infusion

Single infusion of autologous CD34+PBSC transduced with a lentiviral vector

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after gene therapy infusion

3 months

Multiple visits (in-person)

Long-term Follow-up

Participants are monitored for long-term safety and effectiveness

Up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Auto CD34+PBSC, transduced with a lentiviral vector encoding the B domain deleted from of human coagulation factor VIII

Trial Overview This Phase I gene therapy trial is testing if genetically modified stem cells can produce platelets that create Factor VIII on their own in patients with severe hemophilia A. Patients' stem cells will be altered using a viral vector and then returned to them.

How Is the Trial Designed?

Group I: Autologous CD34+PBSC transduced with a lentiviral vector Experimental Treatment 1 Intervention

Patients will receive a patient specific (autologous) cytokine mobilized CD34+Peripheral Blood Stem Cells (PBSC) transduced ex vivo with a lentiviral vector containing cDNA encoding the human B-domain deleted FVIII protein.

Who Is Running the Clinical Trial?

Parameswaran Hari

Lead Sponsor

Trials

2

Recruited

40+

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

Published Research Related to This Trial

A new hybrid human/porcine coagulation factor VIII (fVIII) transgene, which is 89% identical to human fVIII, shows up to 100-fold greater expression than traditional human fVIII when delivered via lentiviral vectors to hematopoietic stem cells, indicating a promising approach for gene therapy in hemophilia A.

Transplanting these genetically modified stem cells into hemophilia A mice resulted in long-term therapeutic levels of fVIII expression, even with less than 5% of the blood cells being genetically modified, suggesting effective and sustained treatment potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Directed engineering of a high-expression chimeric transgene as a strategy for gene therapy of hemophilia A. Doering, CB., Denning, G., Dooriss, K., et al.[2022]

A new lentiviral vector system was successfully developed to express human coagulation factor VIII (FVIII) in CHO cells, achieving a high concentration of FVIII antigen (1724.9 mU/ml) and activity (10.58% FVIII:C) after 72 hours.

The system demonstrated good biosafety, as no viral particles or gag gene were detected in the supernatant, indicating it does not produce offspring viruses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Establishment of a high efficient human coagulation factor VIII eukaryotic expression system using lentiviral vector]. Song, XG., Cao, J., Zeng, LY., et al.[2013]

The recombinant lentiviral vector pXZ208-BDDhFVIII was successfully created and showed effective integration into human liver (HLF), Chang-Liver, and mesenchymal stem cells (MSC), with infection rates of 74.52%, 27.24%, and 42.34%, respectively.

The expression of human coagulation factor VIII (FVIII) was confirmed, with HLF cells producing the highest activity at 54.1%, indicating the potential of this vector for gene therapy in hemophilia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Establishment of a high expressing system of human coagulant factor VIII in vitro]. Cheng, H., Xu, KL., Sun, HY., et al.[2009]

A lentiviral vector carrying the human coagulant factor VIII (FVIII) gene was successfully constructed and used to transfect 293T cells, achieving a transfection rate of 59.57%.

The transfected cells expressed FVIII with increasing activity levels of 12%, 43%, and 87% at 24, 48, and 72 hours post-infection, indicating the potential for this method in gene therapy for hemophilia A.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Expression of B domain-deleted human coagulant factor VIII gene in 293T cells mediated by lentiviral vector in vitro]. Cheng, H., Xu, KL., Sun, HY., et al.[2016]

The study demonstrated that canine bone marrow stromal cells (BMSCs) can effectively express and secrete human factor VIII (hFVIII) for potential gene therapy in hemophilia A, achieving secretion levels as high as 1000-4000 mU/10(6) cells/24 hr when using retroviral vectors.

The research highlighted that the B domain-deleted hFVIII with the proteolytic site retained over 93% of normal biological activity, making it a more suitable candidate for therapeutic applications compared to the unprocessed form, which had less than 55% activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone marrow stromal cell-mediated gene therapy for hemophilia A: in vitro expression of human factor VIII with high biological activity requires the inclusion of the proteolytic site at amino acid 1648. Chiang, GG., Rubin, HL., Cherington, V., et al.[2012]

The investigational product CD68-ET3-LV CD34+ shows promising safety and efficacy in treating hemophilia A, as demonstrated by sustained production of coagulation factor VIII in murine models without toxicity.

The genetically modified autologous hematopoietic stem and progenitor cells (HSPCs) effectively produced factor VIII, supporting the potential of this gene therapy approach for patients with hemophilia A.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Development of a Hematopoietic Stem and Progenitor Cell Bioengineered Factor VIII Lentiviral Vector Gene Therapy for Hemophilia A. Doering, CB., Denning, G., Shields, JE., et al.[2019]

Lentiviral vectors (LV) can effectively integrate therapeutic genes into host genomes, showing promise for treating hereditary diseases like hemophilia A, as demonstrated by high levels of factor VIII (FVIII) expression in various cell types.

In a study involving C57BL/6 FVIII knockout mice, while the LV successfully produced FVIII, the therapeutic levels were low due to the development of neutralizing antibodies against FVIII, highlighting the need to address immune responses for effective gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficient production of human FVIII in hemophilic mice using lentiviral vectors. Kootstra, NA., Matsumura, R., Verma, IM.[2022]

Shorter expression cassettes for factor VIII (FVIII), particularly those with a partial B domain deletion (N6), can significantly enhance FVIII secretion, achieving up to a 44-fold increase in expression compared to traditional constructs.

In hemophilic mice, gene therapy using these optimized FVIII constructs led to sustained expression of FVIII activity for over 250 days, indicating a promising approach for effective long-term treatment of hemophilia A.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Codon optimization of human factor VIII cDNAs leads to high-level expression. Ward, NJ., Buckley, SM., Waddington, SN., et al.[2022]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2410597

Lentiviral Gene Therapy with CD34+ Hematopoietic Cells ... Gene therapy for hemophilia A with the use of lentiviral vector–transduced autologous HSCs resulted in stable factor VIII expression.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03818763

NCT03818763 | Gene Therapy Trial for Platelet Derived ... This is a Phase I study. This research study is being conducted to find new ways to treat severe hemophilia A. This study is a gene therapy study.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39655790/

Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for ... Gene therapy for hemophilia A with the use of lentiviral vector-transduced autologous HSCs resulted in stable factor VIII expression.

4. researchgate.net researchgate.net/publication/386579704_Lentiviral_Gene_Therapy_with_CD34_Hematopoietic_Cells_for_Hemophilia_A/fulltext/67d0986fcc055043ce709846/Lentiviral-Gene-Therapy-with-CD34-Hematopoietic-Cells-for-Hemophilia-A.pdf?origin=scientificContributions

Lentiviral Gene Therapy for Hemophilia A Using CD34+ ... We have shown it is possible to achieve FVIII expression in hemophilia A mice using mouse hematopoietic stem cells (HSC) and in immunodeficient ...

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/ajh.27602

2025 Clinical Trials Update on Hemophilia, VWD, and ... Auto CD34+ PBSC transduced with lentiviral vector Pleightlet (MUT6) encoding BDD-FVIII, Phase 1, NCT03818763, Hemophilia A With Inhibitors, Male ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8649223/

Transduction of modified factor VIII gene improves lentiviral ... We synthesized a shortened F8 gene (F8-BDD) and cloned it into a lentiviral vector (LV). The F8-BDD produced mainly short cleaved inactive products in LV- ...

7. centerwatch.com centerwatch.com/clinical-trials/listings/NCT03818763/gene-therapy-trial-for-platelet-derived-factor-viii-production-in-hemophilia-a

Gene Therapy Trial for Platelet Derived Factor VIII ... Hemophilia. Treatment. Auto CD34+PBSC, transduced with a lentiviral vector encoding the B domain deleted from of human coagulation factor VIII ...