New treatments addressing the pathophysiology of hereditary angioedema

Hereditary angioedema is a serious medical condition caused by a deficiency of C1-inhibitor. The condition is the result of a defect in the gene controlling the synthesis of C1-inhibitor, which regulates the activity of a number of plasma cascade systems. Although the prevalence of hereditary angioedema is low – between 1:10,000 to 1:50,000 – the condition can result in considerable pain, debilitation, reduced quality of life, and even death in those afflicted. Hereditary angioedema presents clinically as cutaneous swelling of the extremities, face, genitals, and trunk, or painful swelling of the gastrointestinal mucosa. Angioedema of the upper airways is extremely serious and has resulted in death by asphyxiation

DNA/Amphiphilic Block Copolymer Nanospheres Promote Low-dose DNA Vaccination

Intramuscular (i.m.) DNA vaccination induces strong cellular immune responses in the mouse, but only at DNA doses that cannot be achieved in humans. Because antigen expression is weak after naked DNA injection, we screened five nonionic block copolymers of poly(ethyleneoxide)-poly(propyleneoxide) (PEO-PPO) for their ability to enhance DNA vaccination using a β-galactosidase (βGal) encoding plasmid, pCMV-βGal, as immunogen. At a high DNA dose, formulation with the tetrafunctional block copolymers 304 (molecular weight [MW] 1,650) and 704 (MW 5,500) and the triblock copolymer Lutrol (MW 8,600) increased βGal-specific interferon-γ enzyme-linked immunosorbent spot (ELISPOT) responses 2–2.5-fold. More importantly, 704 allowed significant reductions in the dose of antigen-encoding plasmid. A single injection of 2 µg pCMV-βGal with 704 gave humoral and ELISPOT responses equivalent to those obtained with 100 µg naked DNA and conferred protection in tumor vaccination models. However, 704 had no adjuvant properties for βGal protein, and immune responses were only elicited by low doses of pCMV-βGal formulated with 704 if noncoding carrier DNA was added to maintain total DNA dose at 20 µg. Overall, these results show that formulation with 704 and carrier DNA can reduce the dose of antigen-encoding plasmid by at least 50-fold