Claudio Soto at Serono Pharmaceutical Research Institute in Plan-les-Ouates, Switzerland, first summarized general issues of protein misfolding disorders. They include intracellular vs. extracellular inclusions, peptide-specific vs. generalized inclusions, the deposition of misfolded protein aggregates vs. misfolding of soluble (dysfunctional) protein, loss-of-function vs. gain-of-toxic-function, and the involvement of posttranslational modifications.
Soto talked about developing β-sheet breakers based on peptides that intercalate with the amyloid-seeding peptide sequence of aggregation-prone proteins spiked with conformation-breaking proline residue(s). In the case of Aβ, such an anti-aggregation peptide specifically prevents Aβ (but not prion or amylin) fibrillization in vitro as well as in AβPPld-transgenic mice. Administration of the β-sheet breaker ameliorated the astrogliosis and microglial activation, as well as the minor neurodegeneration normally observed in this mouse model. β-Sheet breakers led to improvement in water maze performance in a rat model of amyloidosis caused by Aβ injection, but there was only partial reduction of plaque burden. The groups’ current focus is on the development of Aβ-sheet breakers with improved pharmacokinetics. Soto said that the toxicology so far is encouraging and no immunological responses to β-sheet breaking peptides were seen. Compound optimization strategies include the development of small peptidomimetics and nonhydrolysable peptide derivatives. Peptidomimetic approaches are being pursued for various different indications but have not, to date, generated novel drugs, as technical challenges remain.
Leon Thal, also at University of California, San Diego, concluded the program by reviewing the clinical course of AD with a specific emphasis on the design of prospective clinical trials. He pointed out that the study end-points must be carefully selected and followed through. More importantly, patients must be recruited early in the disease, ideally right around the first manifestation of mild cognitive impairment, or even prior to symptoms. He also noted that although AD varies considerably from patient to patient, the progression of this disease is rather uniform and predictable, even in limited cohort sizes.
This was a great meeting that brought together interesting people who presented excellent science with great enthusiasm. Never has it been clearer that improved therapy is within reach for Alzheimer’s disease, and that improvements are underway for Parkinson’s, as well. The enchanting scenery of the locale served as an allegory for the hopeful vista we received toward the future.—Philipp Kahle, Ludwig Maximilians University of Munich, Germany, and Bart De Strooper, Flanders Interuniversity Institute for Biotechnology and KU Leuven, Belgium.