Masur Auditorium | NIH Clinical Center, Building 10

Plenary Session - Gains in Translation from Bench to Bedside

Disorders of lysosome-related organelles
William Gahl (NHGRI) and Juan Bonifacino (NICHD)

Investigations into the 8 known subtypes of Hermansky-Pudlak syndrome (HPS) represent the confluence of clinical medicine, molecular diagnostics, and cell biology. Clinically, HPS patients exhibit oculocutaneous albinism due to defects in melanosome trafficking or maturation. Patients also display a bleeding diathesis due to the absence of dense bodies in platelets. In addition, at least two of the 8 genetic subtypes are characterized by a fatal pulmonary fibrosis, and approximately 15% of all HPS patients suffer from granulomatous colitis. In part because of the existence of natural mouse models of HPS, the molecular basis for each known HPS subtype has been elucidated, making diagnosis, prognosis, and genotype/phenotype correlations possible. Nevertheless, the functions of 7 of the 8 products of the HPS-causing genes remain to be discovered. Only the gene mutated in HPS-2, i.e., AP3B1, codes for a protein of known function. The AP3B1 gene encodes the ≤3A subunit of Adaptor Protein complex-3, or AP-3. This complex effects the formation of lysosome-related organelles from membranes of the late endosome or Golgi complex; melanosomes and platelet dense bodies are among the lysosome-related organelles affected by AP3B1 mutations. The other 7 HPS genes code for proteins that combine in Biogenesis of Lysosome-related Organelles Complexes (HPS7 and HPS8 in BLOC1-1, HPS3, HPS5, and HPS6 in BLOC-2, and HPS1 and HPS4 in Bloc-3). BLOCs function in the formation and/or trafficking of intracellular organelles, but their exact roles remain to be elucidated. HPS patients and their cultured cells provide systems in which to investigate the normal biogenesis, maturation, and movement of intracellular vesicles and their roles in inflammation and fibrosis.

Development of the Taxol-coated Stent
Alan Heldman (JHMI) and Steven Sollott (NIA)      

Cardiovascular disease causes almost 40% of all deaths in the United States and is the single largest killer of American men and women.  Coronary artery atherosclerosis can be asymptomatic, or can cause chest pain, or heart attack.  Both coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are commonly used to improve blood flow to the heart muscle supplied by diseased coronary arteries.  Balloon dilation of coronary artery narrowings was generally effective, but outcomes were sometimes limited by renarrowing, or restenosis.  Decades of effort at preventing restenosis through angioplasty techniques or with pharmacotherapy were unsuccessful.  The mid 1990s saw the rapid adoption of coronary stents, tiny mesh-like scaffolding devices which were shown to reduce modestly the risk of restenosis.  These devices propped open the coronary narrowing and generally prevented its collapse, elastic recoil, or remodeling.  However, restenosis remained problematic in ~20-50% of coronary stent cases because of the artery's exuberant healing reaction; cellular growth of neointimal tissue inside the stent compromised the lumen available for blood flow, creating “in-stent restenosis.”

The search for an effective molecular approach to preventing restenosis drove vascular biology research.   Some efforts were targeted to specific cellular mechanisms considered unique to the pathology, to try to render effectiveness without significant toxicity. We reasoned that this strategy per se could actually be the cause of failure, because critical biological processes in cells often operate redundantly at multiple levels. Specifically inhibiting just one such pathway thus would be unable to prevent restenosis because other redundant pathways could be unaffected. Our innovation was to take the opposite strategy, utilizing the anti-cancer drug, paclitaxel, to inhibit microtubule function, a target critical for multiple, diverse cellular processes, and sufficient to stop cells which cause restenosis from growing, dividing, and migrating. By virtue of the ability to simultaneously block the redundant pathways needed to produce restenosis, another benefit of this approach was that much lower overall drug levels would be effective since a static effect on cells would be sufficient to prevent restenosis, unlike cancer treatment where the requirement is to kill abnormal cells. This would limit toxicity and help to ensure safety. We found that paclitaxel prevents restenosis in small- and large-animal models, leading to confirmation of safety and efficacy in multiple human clinical trials worldwide.

The technique of local arterial drug therapy with drug-eluting coronary stents has had explosive growth.   Paclitaxel is one of two drug stent coatings proven to prevent in-stent restenosis.  Stents coated with paclitaxel deliver it locally only to the site where needed, dramatically reducing the incidence of in-stent restenosis by 50-90% vs. bare-metal stents. Since 2003 when the paclitaxel drug-eluting stent was introduced for clinical use in Europe and 2004 in the U.S., 3 million have been implanted in patients worldwide.