In a press release from early January 2021, genetic medicines company Generation Bio Co. (“Generation Bio”) announced data from a variety of studies. In one, the company shared that it used its novel cell-targeted lipid nanoparticle (ctLNP) technology to deliver closed-ended DNA (ceDNA) to mice models of hemophilia A. Through this, Generation Bio achieved not only dose tolerability, but desired factor VIII expression levels. In other ceDNA-related studies, researchers were able to use ceDNA and ctLNP to deliver doses to both men and non-human primates. Additionally, it shows the translation of novel, liver-directed ctLNPs.

ceDNA and ctLNP

After using ceDNA and ctLNP, Generation Bio did see some achievements in their non-viral gene therapy program. Some of these milestones include:

• One dose of intravenously-administered ceDNA was expressed for months in the livers of mice with hemophilia A.
• ceDNA-ctLNP was relatively well-tolerated in doses of 0.5mg/kg, 1.0mg/kg, and 2.0mg/kg.
• Following one 2.0mg/kg dose of ceDNA, mice with hemophilia A saw a 23% increase in factor VIII expression within 10 days. The increase was 16% for those taking a 1.0mg/kg dose, and 9% for those taking a 0.5mg/kg dose.
• Because ceDNA-ctLNP does not create antibodies, as some other gene therapies do, ceDNA can be re-dosed. For example, after re-dosing mice after 5 weeks, researchers saw an increase in factor IX protein.
• Researchers were able to track translation of expression between mice and non-human primates through weight-adjusted doses of ceDNA-ctLNP. In one study, researchers saw an increase of ~1% in both non-human primates and mice within 5 and 7 days, respectively. In a secondary study, researchers saw a ~3% increase in mice at day 5, which translated pretty similarly in non-human primates.
• ceDNA and ctLNP were relatively safe and well-tolerated. No adverse reactions occurred. Both the liver and spleen were protected from damage.

Hemophilia A

Also known as factor VIII deficiency or classic hemophilia, hemophilia A is an inherited bleeding disorder. Patients with hemophilia A lack enough factor VIII, a type of clotting protein. Thus, the blood fails to clot properly, causing excessive bleeding. Men are more likely to develop this disease than women. Symptoms include:

• Frequent and easy bruising and bleeding
• Digestive and urinary tract bleeding, causing bloody stool or urine
• Excessive nose bleeds
• Bleeding after cuts, trauma, dental work, or surgery
• Joint pain and swelling
• Excessive menstruation or bleeding after childbirth (for females)
• Irritability

Learn more about hemophilia A here.