An analogous disease called familial amyloid cardiomyopathy (FAC) causes fibril formation in the heart, which leads to cardiac dysfunction. About one million African-Americans carry the gene that predisposes them to FAC. Another amyloid disease affecting the heart, Senile Systemic Amyloidosis (SSA), afflicts an estimated 10 to 15 percent of all Americans over the age of 80.
Some therapeutic approaches that have previously been tried involve administering drugs that inhibit the growth of fibrils from the misfolded state. However, this often proves ineffective because fibril formation is strongly favored once an initial, misfolded "seed" fibril forms.
Kelly's approach is to prevent amyloid formation by stabilizing the native state of proteins--keeping them folded in their proper form. Instead of preventing the misfolded protein subunits from conglomerating to form plaques, he is attempting to prevent them from becoming abnormal monomeric subunits in the first place--by stabilizing the tetrameric "native state" of the protein.
Stabilization through Binding
Last year, Kelly and his colleagues discovered that TTR tetramers composed of both disease-associated and suppressor subunits ameliorate disease by stabilizing the tetramer, thus preventing the disease-associated subunits from contributing to fibril formation. They found that even one such suppressor subunit incorporated into a tetramer otherwise composed of disease-associated subunits doubles its stabili
Contact: Jason Bardi
Scripps Research Institute