Amyloidosis Models and Clinical Trials

Beyond our basic science interest in amyloid light chain (AL) amyloidosis, the lab also emphasizes translational research components utilizing the collaborative and clinical infrastructure of Mayo Clinic. To this end, we have ongoing projects in several diverse areas that collectively will support future endeavors transforming our basic science understanding of AL amyloidosis proteins (or AL proteins), allowing us to develop better diagnosis and therapeutic strategies.

A team of Mayo researchers led by Diane F. Jelinek, Ph.D., published the establishment of two cell lines derived from an AL amyloidosis patient, the first successful AL amyloidosis cell line ever reported. Using a comprehensive genetic approach, the genetic relationship between the cell lines and the primary patient cells was established. This allowed us to identify genetic changes accompanying tumor progression, which may explain the natural history of this patient's disease. Importantly, we demonstrate that free lambda light chains secreted by both cell lines had an immunoglobulin fold (β-sheet barrel) and formed amyloid fibrils. These cell lines provide an invaluable tool to better understand AL amyloidosis from the combined perspectives of amyloidogenic protein structure and amyloid formation, genetics, and cell biology. Future studies will utilize this cell line to understand the role of the plasma cell biologyin the protein secretion and deposition rates.

To further our cellular studies and to examine the complex processes of AL amyloidosis, we established an AL amyloidosis zebrafish model system. The zebrafish (Danio rerio) is the premier nonmammalian vertebrate model organism. This small fish is being used by more than a thousand laboratories around the world because of its biological similarity to humans, its advanced molecular genetics, the elucidation of its genome sequence, and the ever-expanding and outstanding new biological tools now available to the zebrafish researcher.

The culmination of all of our research is ultimately to improve treatment options for AL amyloidosis patients through increased understanding of the disease process. To this end, we are also involved in clinical trials at Mayo Clinic. The clinical trial study with which we are currently involved addresses whether patients with AL amyloidosis receiving high-dose therapy in combination with stem cell transplant have superior response rates to those treated with more conventional chemotherapy. We are combining this with a study of the specific B-cell characteristics and immunoglobulin light chain misfolding kinetics to understand if there is a correlation in clinical outcomes between the B-cell biology and protein misfolding.