BUFFALO, N.Y. -- A tiny lipid particle developed by
pharmaceutical scientists at the University at Buffalo School of
Pharmacy and Pharmaceutical Sciences has the potential to improve
significantly the lives of hemophiliacs who have developed a
dangerous immune response to the frequent injections of factor
VIII, the clotting factor that keeps them alive.
These lipid spheres contain significantly less water than
conventional lipid particles, called liposomes, increasing their
stability and allowing them to circulate in the body longer. This
characteristic has potential advantages for other drug delivery
applications as well.
According to Sathyamangalam V. Balasubramanian, Ph.D., UB
assistant professor of pharmaceutical sciences, who is principal
investigator, the lipid spheres act as "stealth" particles,
sneaking past the body's immune system the factor VIII protein that
hemophiliacs cannot adequately produce on their own without
triggering a dangerous rejection.
Believed to be the only formulation in which lipid particles are
being used to tackle factor VIII immunogenicity, this lipid-protein
complex also would need to be administered less frequently, which
could lower the cost of treatment for hemophiliac patients.
A provisional patent has been filed on the methods for producing
these lipid-protein particles, which have been produced in the
nanometer (billionth of a meter) range.
The UB researchers have tested the particles in normal rats and
are beginning tests in a hemophiliac mouse model.
It is estimated that from 15-30 percent of all hemophiliacs
develop inhibitors, antibodies that cause the body to recognize and
destroy therapeutic factor VIII as a foreign substance. To overcome
inhibitor development, patients either must switch formulations or
undergo intensive therapy with factor VIII that can cost more
$500,000 per year.
"We believe that our stable formulation will lead to the
development of fewer inhibitors or none at all," said
Balasubramanian, also a research assistant professor of biophysical
sciences in the UB School of Medicine and Biomedical Sciences.
"The findings suggest that these factor VIII complexes not only
would help to reduce or possibly avoid inhibitor development in
patients who previously had not received treatment. They also may
allow for clotting activity to resume even in treated patients who
already have developed inhibitors," he said.
Balasubramanian took what he calls a "mechanistic" approach to
the problem, designing the new formulation based on detailed
bioinformatics and protein-folding studies that he conducted with
"With this novel formulation, we are hitting three birds with
one stone, overcoming three disadvantages of current formulations,"
he added. The disadvantages are:
* In vivo instability and rapid clearance, necessitating
frequent administration of the protein, which over time can trigger
an immune response
* Formation of aggregates, where two or three factor VIII
protein molecules clump together, rendering factor VIII protein
inactive and sometimes contributing to a more pronounced immune
* Exposure of a specific region on the protein -- the epitope
region -- that is responsible for causing inhibitors to
"From our structural studies of this extraordinarily large
protein, we were fortunate to find that the amino acid region that
triggers inhibitor development and aggregation also is the region
of the protein that binds to lipids," Balasubramanian explained.
"When the lipid binds to it, that epitope region is shielded from
recognition by the body, significantly decreasing immunogenicity,
and thwarting the formation of aggregates, allowing the protein to
And since the protein-lipid complex has the potential to
circulate in the blood for longer than does free factor VIII, the
drug can be administered less frequently, reducing the likelihood
of an immune response, and potentially lowering the cost of
This research was funded by the National Institutes of