Hemophilia is a bleeding disorder caused by a mutation in genes that provide instructions for blood clotting factors — the proteins that help in blood clotting. Mutations in the genes for clotting factors VIII, IX, and XI result in their deficiency, causing hemophilia A, hemophilia B, and hemophilia C, respectively.
Existing treatments such as Kovaltry and Kogenate by Bayer are recombinant (lab-made) factor VIII proteins identical to the ones produced by the body. They temporarily supplement the missing factor VIII and help in the normal clotting of blood. Other treatments included synthetically modified clotting factors with extended half-lives to prevent their quick degradation and thus extend their function in the body.
In addition to these existing treatments, several experimental treatments are being evaluated to identify a more long-term solution for patients with hemophilia.
Inserting functional copies of the genes for clotting factors into the cells of hemophilia patients is the goal of gene therapy. These treatments could help patients produce their own clotting proteins, allowing their blood to clot more effectively and eventually eliminating the need for repeated treatment infusions. SB-525, AMT-060, and AMT-061 are three gene therapy-based candidates being evaluated.
SB-525 is an investigational gene therapy being developed by Sangamo Therapeutics for hemophilia A. SB-525 provides a healthy copy of the gene for factor VIII to the body. A genetically modified virus incapable of causing an infection called an adeno-associated virus (AAV) is used as a vehicle to deliver SB-525 to liver cells where factor VIII protein is made.
Developed by UniQure, AMT-060 is a potential therapy for hemophilia B. Researchers are developing this therapy to deliver a functional copy of the gene encoding for clotting factor IX to the liver cells of hemophilia B patients. A modified AAV is also used to deliver the healthy gene copy to the target cells.
AMT-061 is another gene therapy candidate by UniQure for patients with hemophilia B. It is designed to provide patients with a high functioning variant of the gene encoding for factor IX called FIX-Padua. This gene carries a mutation that causes the factor IX protein it encodes to be eight times more active than the normal protein. AMT-061 is also an AAV-based gene therapy.
Extended half-life products
PEGylation is a technique in which a molecule called polyethylene glycol (PEG) is added to the clotting factors to prevent them from being degraded in the body, extending their half-life. The longer the engineered functional protein remains in the blood, the fewer treatment infusions the patient has to undergo. BAY 94-9027 by Bayer is a recombinant factor VIII combined with PEG for hemophilia A patients. Another PEGylated factor VIII candidate, N8-GP by Novo Nordisk, is also being evaluated.
Another technique to extend the half-life of clotting proteins is to create a recombinant clotting factor fused to another protein called Fc, which is a part of the antibodies found in the body. With Fc fusion, the body does not recognize the recombinant protein as foreign and does not break it down, prolonging its half-life. BIVV001, developed by Bioverativ (now a part of Sanofi Genzyme), is a factor VIII-Fc fusion product under investigation for the treatment for hemophilia A.
A genome editing tool called CRISPR/Cas9 can be used to identify and edit a region in the genome that is mutated. CRISPR stands for “clustered regularly interspaced short palindromic repeats.” Cas-9 is a CRISPR-associated protein 9. There are two main components to this system — an RNA guide and Cas9. The short stretch of RNA called the RNA guide binds to the target region in the genome to be edited and serves as a guide for the enzyme Cas9, which acts like molecular scissors to fix the mutation.
A CRISPR/Cas9-based approach to treat hemophilia is currently being developed at the Perelman School of Medicine at the University of Pennsylvania. Researchers have developed a gene therapy technique to deliver the CRISPR/Cas9 system to a mouse model of hemophilia B to correct the underlying genetic defect causing the disease.
In hemophilia patients, persistent bleeding in the joints leads to hemophilic arthropathy or permanent joint disease. TRM-201 (rofecoxib), being developed by Tremeau Pharmaceuticals, is an experimental non-steroidal anti-inflammatory drug designed to reduce joint inflammation and relieve pain.
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