Beta-2 Microglobulin Depletion Columns for Amyloidosis Prevention and Treatment

DESCRIPTION provided by applicant Approximately 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 and In ESRD patients serum concentrations of microglobulin m readily accumulate times higher than normal levels leading to the formation of m fibrils that deposit in the bone and joint space in a painful debilitating condition termed dialysis related amyloidosis DRA Current data indicates that depleting m from the circulation of ESRD patients reduces the severity of DRA symptoms Furthermore the amount of m removed is proportional to the extent of symptom improvement This suggests that removal of m from circulation is an effective strategy for treating DRA and that treatment efficacy would be maximized by removing as much m as possible To this end we will develop plasmapheresis columns that use small peptides to selectively deplete m from human plasma In the apheresis product we envision an automated and continuous in line circuit will be used to remove an ESRD patientsandapos blood which will then be separated into cell and plasma fractions The plasma fraction will flow through our m depletion column recombine with the patientandapos 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 m from blood This device depletes only of m from ESRD patients even when using the maximum safely allowable column size 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 columnandapos 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 m from plasma but these columns deplete even less m lower than Lixelle due to the large mass of antibodies We expect that depletion columns made with small peptides will be specific for m and bind up to fold more m than all existing techniques The specificity of peptide mediated m 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 application we will use phage display biopanning to identify small kD peptides that bind with high affinity and specificity to m These peptides will be grafted onto agarose substrates and used to capture m from human plasma Ultimately this technology will improve the quality of life for ESRD patients on long term dialysis PUBLIC HEALTH RELEVANCE Dialysis related amyloidosis DRA is a painful debilitating condition caused by excess 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 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 microglobulin with high specificity