Scientists Receive Grant to Advance Nanotherapy for Lupus

Chris Cho | chris.cho@yale.edu May 1, 2010

Scientists Receive Grant to Advance Nanotherapy for Lupus

The Novel Research Award, presented by the Lupus Research Institute, grants $300,000 to scientists at the vanguard of lupus research. Tarek Fahmy, Associate Professor of Biomedical Engineering & Chemical Engineering, and Joseph Craft, Professor of Medicine (Rheumatology) and of Immunobiology and Section Chief of Rheumatology, both received this three-year grant to work towards developing a new therapy for lupus.

Lupus is a chronic autoimmune disease that affects approximately 6.5 million people around the world. Nor mally, when a foreign invader attacks the body, the immune system reacts by activating lymphocytes, which produce antibodies to the pathogen. With lupus, however, the immune system goes awry; the lymphocytes produce autoantibodies that target healthy tissue, damaging the skin, other organs, and joints.

Fortunately, recent medical research has provided critical insights into the molecular mechanism of lupus. As Craft explains, “We know which abnormally activated B and T lymphocytes are attacking self-tissue. If we could destroy those cells, we could help treat the disease.” However, effective methods for targeting the autoimmune cells are still under development.

Drugs such as anti-inflammatory medicines that attempt to alleviate the symptoms of lupus kill immune cells nonspecifically. As a result, medication can target healthy T-cells and severely compromise the immune system.

In order to improve therapeutic efficacy, Fahmy and Craft have come together to tackle the disease at a more localized, nanoscopic level: the plan is to engineer nanoparticles the size of viruses to deliver drugs specifically to lymphocytes, particularly T cells. As Fahmy explains, “You need to have something pretty small, something pretty fast, something that carries a lot of punch to it that moves just as stealthily as those renegade cells.”

Constructed from various polymeric materials, these biodegradable nanoparticles are tethered with protein ligands or receptors on the surface that address specific lymphocytes. Fahmy explains the fundamental biochemistry through an analogy: “Imagine a spaghetti strand – now imagine hundreds of them. Each one of those strands is a polymer chain. What we do is take the spaghetti strands, put them in water, dump the drug, drain the water, and compress everything into a tiny ball. You end up with this really compacted, intertwined polymeric capsule.”

Once this dry, compressed nanoparticle is introduced into the body, the polymeric chains begin to erode quickly, and the drugs inside are released at a gradual but exponential rate. Consequently, when the particle reaches its target, there is sustained release of the drug.

The drug of interest has been mycophenolic acid, an immunosuppressant currently used to treat lupus. The lab has used nanoparticles to deliver this drug to mice infected with the disease. Compared to the control that used free drug treatment, the experimental system yielded the same efficacy but with a 3000 fold lower dosage than that of the free drug. Also, the mice treated with the experimental system survived significantly longer than those treated with the control.

In the immune system, B cells, T cells, and antigen-presenting cells are in constant communication with each other. Because multiple cells are involved in immune responses, a future direction would be to target these three cell types as a potential combination therapy – a multi-faceted attack that may be able to reset the immune system. Furthermore, such treatment may potentially be translated to other autoimmune diseases. Craft notes, “One can envision that for any disease that is caused by too many abnormally activated T cells and B cells, the therapy would be effective.”