Approximately 400,000 Americans undergo regular dialysis treatment because of complete kidney failure, otherwise known as end-stage renal disease (ESRD). The number of patients afflicted with this condition increased six-fold between 1980 and 2009. In ESRD patients, serum concentrations of 2- microglobulin (2m) readily accumulate 10-50 times higher than normal levels, leading to the formation of 2m fibrils that deposit in the bone and joint space in a painful, debilitating condition termed dialysis-related amyloidosis (DRA). Current data indicates that depleting 2m from the circulation of ESRD patients reduces the severity of DRA symptoms. Furthermore, the amount of 2m removed is proportional to the extent of symptom improvement. This suggests that removal of 2m from circulation is an effective strategy for treating DRA, and that treatment efficacy would be maximized by removing as much 2m as possible. To this end, we will develop plasmapheresis columns that use small peptides to selectively deplete 2m from human plasma. In the apheresis product we envision, an automated and continuous in-line circuit will be used to remove an ESRD patients' blood, which will then be separated into cell and plasma fractions. The plasma fraction will flow through our 2m-depletion column, recombine with the patient's blood cells, and then be safely reintroduced into the body. Current apheresis columns for treating DRA (e.g. Lixelle; approved in Japan but not available in the U.S.) deplete 2m from blood. This device depletes only 75% of 2m from ESRD patients even when using the maximum, safely allowable column size (~350 mL). Moreover, the column is non-specific. Lixelle depletes other proteins such as cytokines, and also binds blood cells through non-specific interactions with the column substrate. This lack of specificity (coupled with the column's large volume) leads to significant adverse events such as hypotension and anemia that require many patients to halt treatment. To remedy specificity concerns, researchers have developed antibody-based columns that can deplete 2m from plasma, but these columns deplete even less 2m (~60-90% lower than Lixelle) due to the large mass of antibodies. We expect that depletion columns made with small peptides will be specific for 2m and bind up to 7-fold more 2m than all existing techniques. The specificity of peptide-mediated 2m depletion from perfused plasma will drastically reduce side effects, maximizing the benefits of this treatment for the largest number of patients. Moreover, mass-scale production of peptides will be significantly less expensive than antibodies, enhancing the commercialization potential of our device. In this Phase 1 application, we will use phage display biopanning to identify small (~2.5 kD) peptides that bind with high affinity and specificity to 2m. These peptides will be grafted onto agarose substrates and used to capture 2m from human plasma. Ultimately, this technology will improve the quality of life for ESRD patients on long-term dialysis.
Dialysis-related amyloidosis (DRA) is a painful, debilitating condition caused by excess 2- microglobulin concentrations. DRA affects a large portion of end-stage renal disease patients undergoing dialysis. Presently, no treatments for this condition are available in the United States. In Japan, sorbent columns that deplete the 2-microglobulin protein are available, but current technologies bind low quantities of the protein or are non-specific. In this application, we propose the development of peptide-based sorbent columns that bind large quantities of 2-microglobulin with high specificity.
