Rheumatoid arthritis (RA) occurs in 2,100,000 people in the United States, and is associated with progressive joint destruction, functional disability and decreased life expectancy. Joint destruction does not occur without synovial inflammation. The treatment of RA is directed to suppressing inflammation, with the aim of establishing a state of remission. There is now evidence that active subclinical synovitis and progressive joint destruction occurs in patients despite ongoing drug therapy and apparent clinical remission by clinical criteria. These data suggest that well over 1,500,000 patients in United States are at risk for continued joint destruction. Even with the most effective disease-modifying antirheumatic drugs (DMARDs) currently available, the majority of patients fail to achieve remission. Thus, even if subclinical synovitis could be routinely detected, completely eradicating joint inflammation in most patients is likely to be untenable using the currently available armamentarium of DMARDs. A major paradigm shift in diagnostic and therapeutic approach is therefore required. Methotrexate (MTX) is the drug of first choice in treating RA, however, it fails to achieve clinical remission in about 80% of patients mainly because of (i) dose-limiting toxicities due to its narrow therapeutic index, and (ii) incomplete and highly variable cellular uptake. To increase the rate of eradicating clinical and subclinical joint inflammation in patients, we aim to pursue a strategy that will improve on the existing goldstandard DMARD. With 3,969,000 prescriptions for MTX in the United States in 2006, the potential impact of a new antifolate DMARD standard would be expected to be major, potentially affecting hundreds of thousands of patients with RA. We propose to develop and test a series of novel theranostic 99mTc-DTB- Antifol-Pteroyls (RadioDAPs) that we hypothesize will allow the highly targeted and concentrated delivery of antifolate (e.g. aminopterin, AMT) and 99mTc radionuclide to sites of subclinical synovitis for treatment and diagnosis by SPECT imaging. Our long-term hypotheses are that a theranositic RadioDAP (i) will significantly increase the rate of remission in RA through highly targeted and intense delivery of antifolate to sites of overt and subclinical synovial inflammation, and (ii) will detect subclinical synovitis earlier and with greater specificity, with the further ability to monitor for response to therapy over time, and relate this response in an individual patient to delivery of the agent. The two-year experimental plan in this SBIR Grant proposal aims to jumpstart the development of RadioDAPs by laying the initial groundwork for their chemical assembly and cellular uptake using in vitro models of folate transport.
Narrative Rheumatoid arthritis (RA) occurs in 2,100,000 people in the United States, and is associated with progressive joint destruction, functional disability and decreased life expectancy. The proposed RadioDAP technology will be used to simultaneously improve RA therapy and diagnosis.
