Thread by @isth

Exciting new treatments for #hemophilia A and B are in development, one of which is gene therapy.

How would you characterize your interest in hemophilia?

Let’s test your current knowledge of gene therapy for hemophilia (GTH). Of the available methods, which is closest to approval?

Hemophilia is caused by a mutational defect in the gene for a protein in the coagulation cascade: factor VIII (F8) for hemophilia A, or factor IX (F9) for hemophilia B.

GTH encompasses multiple efforts to correct the defect by:
1. Replacing the gene with one that produces a working version of the defective protein using viral or non-viral gene transfer or cell-based gene therapy, or
2. Editing the gene to repair the mutation.

While all 4 methods are being studied, the one closest to regulatory approval involves the transfer of a therapeutic transgene into a target cell using a viral vector, resulting in the synthesis of a working therapeutic protein.

Several viral vectors have been developed for gene transfer, including the adenovirus, adeno-associated virus (AAV), and the lentivirus. AAV is currently the vector of choice for late-stage HGT. pubmed.ncbi.nlm.nih.gov/32042148/

AAV is a non-pathogenic parvovirus with minimal immunogenicity and multiple serotypes based on capsid protein differences. Creating transgenes involves replacing Rep and Cap gene segments with therapeutic transgene, F8 or F9, and liver-specific promoter. pubmed.ncbi.nlm.nih.gov/30710128/

Use of a liver-specific promoter ensures that most of the expression of the therapeutic protein will occur in the liver, the main site for FVIII and FIX synthesis.

Once transgene-containing encapsulated AAV particles are created they are delivered to patients through IV infusion. Upon reaching the liver, particles enter liver cells, where episomal transgene is expressed and resulting therapeutic protein is secreted. pubmed.ncbi.nlm.nih.gov/35521727

The effectiveness of gene expression is measured in several ways, including changes in plasma levels of FVIII or FIX, changes in annualized bleed rate, and quantity of exogenous factor used to stop spontaneous and traumatic bleeds.

While AAV-transgene infusions have been safe and tolerable overall, some concerns encountered in clinical trials include infusion reactions, increased liver enzymes, rare thrombotic events, and the need for steroids to preserve efficacy.

GTH therapies currently being tested in Phase 3 clinical trials for patients with hemophilia A or B have shown promising results. pubmed.ncbi.nlm.nih.gov/35521727/

Let’s test your new knowledge of gene therapy for hemophilia (GTH). Of the available methods, which is closest to approval?

For more detailed descriptions of the fundamental principles of GTH; the status of clinical trials for hemophilia A and B; the inclusion and exclusion criteria for clinical trials; and key patient, caregiver, and clinician concerns regarding GTH, go to genetherapy.isth.org