Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

The effect of globopentaosylceramide on a depression model, mouse forced swimming.

We investigated the late effects of serotonergic drugs on mouse forced swimming and found that serotonin 1A antagonist NAN-190 hydrobromide (NAN-190) and serotonin 2 agonist R(-)-DO1 hydrochloride (DO1) increase the typical anti-depressive behavior climbing 6 hours after the intraperitoneal injection. With the use of ion exchanger, ultra filtration and chemical extraction methods, a substance having remarkable anti-depressive activity on mouse forced swimming was extracted from the serums of the mice treated with the drugs. The substance was strongly suggested to be a glycolipid having a specific sugar chain structure GalNAcalpha1-3GalNAc in its terminal. In fact, globopentaosylceramide, another glycolipid having the structure in the terminal also showed marked anti-depressive activity on mouse forced swimming, but globotetraosylceramide lacking the sugar chain structure did not. The GalNAcalpha1-3GalNAc-lipid reactivity in the serum and typical anti-depressive behavior climbing increased corresponding to the doses of NAN-190 and DO1. These findings clearly indicate that the terminal structure GalNAcalpha1-3GalNAc has the essential role in the anti-depressive activity of globopentaosylceramide, and that serotonin 1A antagonism and serotonin 2 agonism increase the production of an anti-depressive glycolipid having the terminal structure in mouse serum.

Inhibition of experimental ascending urinary tract infection by an epithelial cell-surface receptor analogue.

It has been shown that the establishment of urinary tract infection by Escherichia coli is dependent on attachment of the bacteria to epithelial cells. The attachment involves specific epithelial cell receptors, which have been characterized as glycolipids. Reversible binding to cell-surface mannosides may also be important. This suggests an approach to the treatment of infections--that of blocking bacterial attachment with cell membrane receptor analogues. Using E. coli mutants lacking one or other of the two binding specificities (glycolipid and mannose), we show here that glycolipid analogues can block in vitro adhesion and in vivo urinary tract infection.