The Amyloidosis Foundation is a non profit 501(c) (3) corporation and is an approved Charitable
Trust. In addition to our mission statement, the foundation is dedicated to all who have passed on
from amyloid, amyloid sufferers, their caregivers and family members; and also to the researchers
that are looking for the cure.
Ping Zhou, MD, PhD - Tufts Medical Center
"Off the shelf Lambda Light Chain Knockdown Therapy "
Despite the advances of stem-cell transplant and proteasome inhibitor therapy, systemic AL amyloidosis (AL) remains a lethal disease for patients who die of AL within 3 to 4 years of diagnosis, representing about half of newly diagnosed patients. We need to develop targeted therapies that directly and rapidly eliminate production of toxic amyloid-forming light chains in order to improve patient outcomes and survival. We will extend our work developing an off-the-shelf lambda light chain specific gene silencing agent that interferes directly, specifically and promptly with production of the protein that causes 80% of cases of AL - the lambda light chain protein. We have shown in plasma cells from patients with AL lambda type, that our agent markedly and rapidly reduces lambda light chain production. This grant will allow us to extend our pre-clinical study of this agent in an additional 20 patient specimens and in a mouse model.
Primary systemic AL (amyloid light chain) amyloidosis is caused by the light chain (LC) of an antibody that misfolds, aggregates and forms amyloid fibrils that deposit throughout the body. Targeting the plasma cells which produce antibodies with chemotherapy has been successful at stopping progression of disease but there still remains no approved therapy against the amyloid fibrils that remain in tissues. We have built upon studies with other amyloidogenic proteins to demonstrate that the tetracycline antibiotic doxycycline can disrupt light chain AL amyloidosis fibrils isolated from human tissue. We propose to treat transgenic mice with doxycycline to determine if doxycycline can break up the amyloid deposits and we will determine the time and dose needed. We will test if doxycycline treated fibrils are toxic to cardiac and renal cells. We believe that successful treatment of AL amyloidosis will be achieved using a combination of therapies targeting both the plasma cell and the fibrils themselves.