Cell-based Therapy Shows Promise in Mouse Model of Hemophilia A

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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

These are the findings of a study, “Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device,” recently published in the journal Molecular Therapy: Methods & Clinical Development.

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

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

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

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

Antonia Follenzi, MD, PhD, the study’s senior author and a professor at 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 for people suffering with severe hemophilia A.”

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

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

Modified cells are then transplanted back into the patient within Sernova’s experimental Cell Pouch, which is placed under the skin. This device merges with the patient’s tissue and forms highly vascularized chambers where the transplanted cells can grow and sustainably produce FVIII.

This way, the cell-based therapy is expected to provide continuous therapeutic FVIII levels to the patient’s bloodstream, thereby reducing or preventing bleeds and the need for preventive FVIII replacement therapies.

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

BOECs were collected from hemophilia A patients and modified to produce a working FVIII. 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, modified cells were shown to produce therapeutic FVIII levels for up to 13 weeks (a little over three months) and to significantly reduce bleeding relative to untreated mice.

After 4.5 months, FVIII activity “was almost absent, probably due to the death of BOECs,” the researchers wrote.

In the second case, the team found that transplanted cells within the Cell Pouch were still alive after four months and that these mice showed similar blood-clotting responses to healthy mice, “confirming that correction of the missing coagulation factor had been achieved,” the researchers wrote.

Further analyses 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 the feasibility of a method to correct [a patient’s own] cells based on a combined cell and gene therapy approach together with the use of a scaffold (i.e., Cell Pouch) able to guarantee long-term cell survival and, in case of need, a re-injection of new therapeutic cells,” the team wrote.

This is “the first demonstration showing the safety and feasibility of transplantation of lentiviral-corrected blood outgrowth endothelial cells (BOECs) within an implantable medical device using [good manufacturing practice]-like 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 to further characterize cells within the device in terms of cell markers, longevity, growth, and aging.

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

The Cell Pouch was previously shown to provide a biologically compatible environment for insulin-producing cells in people with type 1 diabetes participating in a Canadian first-in-human clinical trial.

According to Sernova, the diabetes-directed therapeutic approach is now being tested in type 1 diabetes patients in a U.S.-based Phase 1/2 trial (NCT03513939), and initial results have been positive.