Cell therapy shows promise in mouse model of hemophilia A

An experimental cell therapy using Sernova’s innovative medical device, Cell Pouch, safely and effectively increased levels of factor VIII (FVIII) – the missing clotting protein in hemophilia A – and reduced bleeding in a mouse model of the disease.

These are the conclusions of a study, “Effective and safe correction of hemophilia A by lentiviral vector-transduced CEBOs in an implantable device”, recently published in the journal Molecular therapy: methods and clinical development.

“This publication represents approximately four years of dedicated work by the HemAcure Consortium, from conceptualizing this new treatment approach to validating its potential as a safe, long-term treatment option for people with hemophilia A.” , Philip Toleikis, PhD, Sernova President and CEO, said in a press release.

The HemAcure project, supported by a grant of nearly 5.6 million euros (approximately $6.35 million) from a European Union research and innovation program called Horizon 2020, aimed to develop a cell therapy for hemophilia A which would ultimately improve the quality of life of patients.

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Its consortium was made up of three European academic institutions, the Canadian company Sernova and a quality management company.

“The Sernova Cell Pouch provides the environment required for transplanted cells to survive and function in the body, as evidenced by the production of FVIII to improve blood clotting, as reported by Dr. Follenzi and colleagues,” said added Toleikis.

Antonia Follenzi, MD, PhD, lead study author and professor at the Università del Piemonte Orientale in Italy, said that “if this therapy is successful in future clinical trials, it could become an important new therapeutic approach to improve the quality of life of people with severe hemophilia A.

Cell therapy involves first collecting a patient’s blood to isolate specific cells that line blood vessels, called blood outgrowth endothelial cells (BOEC). Endothelial cells are known to produce FVIII.

Then a harmless modified lentivirus is used to introduce a shorter but functional copy of F8 — the gene that provides the instructions to make FVIII and which is mutated in patients with hemophilia A — in the DNA of cells.

The modified cells are then transplanted back into the patient in Sernova’s experimental Cell Pouch, which is placed under the skin. This device fuses with the patient’s tissues and forms highly vascularized chambers where the transplanted cells can grow and sustainably produce FVIII.

In this way, cell therapy should deliver continued therapeutic levels of FVIII into the patient’s bloodstream, thereby reducing or preventing bleeding and the need for preventive FVIII replacement therapies.

In the present study, the therapeutic approach was tested in a mouse model of severe hemophilia A that was modified to prevent immune reactions against transplanted human cells.

CEBOs were collected from patients with hemophilia A and engineered to produce functional FVIII. The cells were then either attached to tiny carrier beads and transplanted into the animal’s abdominal cavity, or injected into a Cell Pouch device implanted under the skin.

In the first case, the modified cells were shown to produce therapeutic levels of FVIII for up to 13 weeks (just over three months) and significantly reduced bleeding compared to untreated mice.

After 4.5 months, FVIII activity “was nearly absent, likely due to CEBO death,” the researchers wrote.

In the second case, the team found that the cells transplanted into the cell pouch were still alive after four months and that these mice exhibited blood clotting responses similar to those of healthy mice, “confirming that the correction of the factor of missing coagulation had been obtained,” the researchers wrote.

Further analyzes on the modified cells showed no signs of chromosomal abnormalities or cancer-promoting genetic changes that can occur when the lentivirus and the relevant gene are introduced into a cell’s DNA.

“Our data attest to the feasibility of a method to correct [a patient’s own] cells based on a combined cell and gene therapy approach combined with the use of a scaffold (i.e., Cell Pouch) capable of ensuring long-term cell survival and, if needed, reinjection new therapeutic cells,” the team wrote.

This is “the first demonstration showing the safety and feasibility of lentivirus-corrected blood outgrowth endothelial cell (BOEC) transplantation into an implantable medical device using [good manufacturing practice]-similar procedures for the long-term treatment of hemophilia A,” Follenzi said.

Researchers now plan to analyze FVIII levels and activity in mice given the Cell Pouch-based approach and further characterize the cells within the device in terms of cellular markers, longevity, growth and of aging.

This type of cell therapy represents “a potential therapeutic option for people suffering from several rare diseases and we are proud that our technologies can contribute to the development and future delivery of functional cures for these diseases,” Toleikis said.

The Cell Pouch has already been shown to provide a biologically compatible environment for insulin-producing cells in people with type 1 diabetes participating in a first-in-man clinical trial in Canada.

According to Sernova, the diabetes-focused therapeutic approach is currently being tested in type 1 diabetic patients in a US-based Phase 1/2 trial (NCT03513939), and early results have been positive.

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