SCIENCE & TECHNOLOGY
ATTACKING AMYLOIDS Efforts to DETER PROTEIN MISFOLDING yield promising drug candidates for degenerative diseases STU BORMAN, C&EN WASHINGTON
They identified a small molecule that with increasing age an unwelcome visibinds to transthyretin’s native state in tor often tags along: a greater tendency to hopes it might prevent the protein from “IT HAS BEEN a 20-year journey from badevelop degenerative diseases. A new drug aggregating. The researchers reported the sic research to an approvable drug,” Kelly discovery strategy—minimizing amyloid structure of the agent, now called tafamidsays. “FoldRx Pharmaceuticals performed deposition—is now being pursued to help is, in 2003. Transthyretin is stabilized by brilliantly in that they developed tafamidis fight these debilitating conditions. the binding of tafamidis to at least one of with a staff of 30 people and about $60 milIn degenerative diseases like Alzheimtwo largely unoccupied thyroxine-binding lion dollars”—a modest level of resources er’s, insoluble amyloid deposits for drug development, he notes. form from proteins gone awry Work by Kelly’s group and DOUBLE BIND Transthyretin tetramer is stabilized by in the brain or other organs. The FoldRx researchers “shows that tafamidis (stick representations), which can bind to both misbehaving proteins misfold a rational approach to therapies of the protein’s thyroxine-binding sites, as shown here. and aggregate to form fibrous against this class of disease is amyloid deposits. not just possible but has now Some drugs are available to been achieved in a specific and manage symptoms of amyloid important case,” says protein conditions, but they don’t alter folding and misfolding researchthe underlying process in these er Christopher M. Dobson of diseases: the accumulation the University of Cambridge, in of misfolded and aggregated England. proteins. Now, researchers are Dobson and coworkers developing a new generation of are also developing agents to agents, such as tafamidis and stabilize native states of probCPHPC, that might have a better lematic proteins. In 2003, they chance of completely preventing, found that newly discovered halting, or even reversing deantibodies from camels and generative diseases by attacking related humped animals could amyloid accumulation directly. stabilize the native structure of Protein misfolding specialist lysozyme. Misfolding and aggreJeffery W. Kelly of Scripps Regation of mutated lysozyme in search Institute places these new anti-amysites in a central region between the tehumans causes non-neuropathic systemic loid strategies into four categories: stabiliztramer’s four monomers, studies of the amyloidosis, another fatal amyloid dising the native state of an aggregation-prone agent’s mechanism have shown. ease. The researchers found that a highly protein so it doesn’t form amyloid, reducHuman clinical trials of tafamidis have stable and soluble single-chain antibody ing the concentration of amyloid-forming been carried out by FoldRx Pharmaceufragment raised against human lysozyme protein, inhibiting amyloid formation, and ticals, a firm in Cambridge, Mass., cobound the mutated enzyme and prevented removing toxic oligomers or amyloid fibrils founded by Kelly and Whitehead Institute it from aggregating. once they’ve formed. for Biomedical Research biology Dobson’s team is currently extending its Kelly’s group has demonstratprofessor Susan Lindquist. A studies by generating antibodies that bind OH ed that the first strategy arrests Phase II/III trial showed that α-synuclein, the protein responsible for O progression of amyloid disease tafamidis halts progression and the pathogenic amyloid-like deposits in pasymptoms in some patients (Acct. improves symptoms of familial tients with Parkinson’s disease. In related Chem. Res. 2005, 38, 911). They’ve amyloid polyneuropathy. It also work, Lindquist and coworkers recently focused on transthyretin, a tetra“appears to be safe and well tolidentified several small molecules that O N meric protein that can dissociate, erated,” according to the comprevent the accumulation of α-synuclein misfold, and aggregate, apparpany. The only treatment curdeposits in cells and protect against the ently causing three fatal degenrently available for this disease development of traits associated with Parerative diseases: senile systemic is liver transplantation. FoldRx kinson’s (Dis. Model. Mech., DOI: 10.1242/ Cl Cl amyloidosis, familial amyloid is also conducting a Phase II trial dmm.004267). cardiomyopathy, and familial of tafamidis in patients with faOther scientists are investigating the Tafamidis amyloid polyneuropathy. milial amyloid cardiomyopathy, stabilization of superoxide dismutase as a STEPHEN CONNELLY/SCRIPPS RESEARCH INSTITUTE
PEOPLE LIVE LONGER these days, and
for which heart transplantation is the lone therapy currently available. According to FoldRx President and Chief Executive Officer Richard Labaudinière, the firm anticipates filing marketing applications for tafamidis by later this year. The small molecule has orphan drug status in the U.S. and Europe and has been granted fast-track development status in the U.S.
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ST EV E N J O H N SO N /SC R I P PS R ES E A RC H I N ST I T U T E
therapy for amyotrophic lateral sclerosis, a fatal neurodegenerative condition characterized by superoxide dismutase-based aggregates. A recent study demonstrated that small molecules can stabilize the native superoxide dismutase dimer, preventing it from dissociating and aggregating.
in the endoplasmic reticulum and to traffic to their proper location in cells. Small molecules called pharmacological chaperones can stabilize such variant proteins, allowing them to be transported to where they are needed. Amicus Therapeutics, in Cranbury, N.J., has conducted clinical trials on small-
AGGREGATION Dissociation of transthyretin tetramers produces natively
folded monomers that can reassociate, or partially denature and misfold. Misfolded monomers can assemble into amorphous aggregates and amyloid fibrils.
Protein stabilization using small molecules could also provide an effective therapy for lysosomal storage diseases such as Gaucher’s and Fabry’s and for cystic fibrosis. In these conditions, proteins are unable to fold
molecule pharmacological chaperones to treat Gaucher’s and Fabry’s diseases and related conditions. But protein stabilization isn’t the only game in town. The other three strategies
for fighting amyloid formation are also under investigation. A number of pharmaceutical and biotech companies are trying to treat Alzheimer’s disease by inhibiting secretase enzymes to decrease the production of amyloid-forming proteins. Secretase enzymes cleave amyloid precursor protein to form amyloid β peptide, which aggregates to form “plaques” in the brains of Alzheimer’s patients. Secretase inhibitors lower the production of amyloid β peptide, an effect researchers hope will slow the death of brain cells in Alzheimer’s patients. For example, a γ-secretase inhibitor called LY450139 is currently in Phase III clinical trials sponsored by Eli Lilly & Co. Inhibiting aggregation is also being explored as a strategy to deter amyloid formation. For instance, ProteoTech, in Kirkland, Wash., identified the small molecule Exebryl-1 in an antiaggregation screen and is developing it as a potential Alzheimer’s treatment. In vitro assays showed that Exebryl-1 prevents amyloid formation and helps dissolve existing fibrils. The agent im-
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SCIENCE & TECHNOLOGY
proved memory in animal trials and is currently in Phase I trials for humans. Exebryl-1’s ability to break up fibrils puts it partly in yet another antiaggregation category—last-resort agents that promote the clearance of toxic oligomers or fibrils once they’ve already formed. One pure-play approach in this area is a bis-d-proline-based small molecule called CPHPC. “CPHPC has the unique pharmacological property of totally depleting circulating serum amyloid P [SAP] component,” a universal constituent of all amyloid deposits, says Mark B. Pepys, director of the Centre for Amyloidosis & Acute Phase Proteins at University College London Medical School. CPHPC-based removal of SAP from the circulation “enables us to then administer anti-SAP antibodies, which target SAP remaining in amyloid deposits, leading to clearance of the deposits by macrophages. This takes place rapidly, safely, and completely. Such clearance of amyloid deposits from the major organs in systemic amyloidosis is unprecedented,” he says. Studies of CPHPC have so far been car-
ried out in mice in which human SAP has been introduced or expressed transgenically. GlaxoSmithKline has licensed the agent from Pepys’ company, a University College London spin-off called Pentraxin Therapeutics, and CPHPC in combination with anti-SAP antibodies will go into human clinical trials in 2012, Pepys says. MEANWHILE, findings disclosed last
month add a new level of complexity to scientists’ understanding of the way proteins aggregate and thus could influence future strategies for designing drugs for amyloid disease. A group led by Dobson and Mark E. Welland, head of Cambridge University’s Nanoscience Centre, reported finding an analytical solution to the complex equation that describes the kinetics of amyloid self-assembly (Science 2009, 326, 1533). Amyloid fibril formation is accompanied by occasional fragmentation of the growing chains. The study shows that the rate-limiting step in fibril growth is commonly fragmentation, not nucleation of polymerization by small oligomers, as has
been widely assumed. “This mechanism is crucial, not just in vitro,” Dobson says, noting that “analysis of data from transgenic mouse models shows that fragmentation of fibrils can be the critical feature that determines the onset of amyloid diseases.” The study has “real implications for strategic approaches to the design of therapeutics,” Dobson adds. “It makes it possible to assess with greater confidence the step in the aggregation process that is influenced by a potential inhibitor, and it gives deeper insight into how amyloid conditions develop.” Efforts to find new drugs to stop degeneration offer hope for the future. “The current breadth of a large number of discovery and clinical-stage programs suggests that we will soon see breakthrough results that will transform therapy for patients in desperate need,” says Mark A. Findeis, senior vice president of research at Satori Pharmaceuticals, in Cambridge, Mass., a neurodegenerative drug company. “The positive results at FoldRx are the beginning of this change.” ■
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