Researchers at the University of Gdansk in Poland have studied naturally occurring molecules that activate autophagy using patient-derived skin cells of all Sanfilippo subtypes and a mouse model of Sanfilippo syndrome type B.
Sanfilippo involves the build-up of the complex sugar heparan sulfate (HS), which impairs the function of cells throughout the body. Autophagy, part of the cell’s recycling process, is one function known to be affected in Sanfilippo. Several groups of Sanfilippo researchers are looking at how to best activate autophagy, hoping it will help clear HS and improve cell function.
In this study, the researchers wanted to find out if molecules known to activate autophagy show promise in removing HS in Sanfilippo. The molecules tested in the study were: resveratrol, genistein, trehalose, capsaicin, curcumin, and calcitriol.
Trehalose is a drug already being investigated for Sanfilippo, with drug company Seelos Therapeutics Inc. looking at it in their drug development pipeline. Genistein was previously the focus of a Phase III clinical trial for Sanfilippo that unfortunately showed no clinically-meaningful benefit in patients.
They first tested the six compounds in patient-derived skin cells of all Sanfilippo subtypes to confirm they were not toxic to the cells - while all of the molecules are naturally occurring, toxicity is still possible, especially at high doses. Only curcumin caused cell death at the highest concentrations tested.
Next, they tested the levels of HS in the cells at increasing concentrations of each molecule. All molecules were found to reduce HS levels in the cells of all Sanfilippo subtypes, and the most dramatic reductions were seen when using resveratrol, curcumin, and trehalose.
Based on the HS reductions and toxicity results, the researchers chose to look at resveratrol in more detail using a mouse model of Sanfilippo type B. Eight-week-old mice with and without Sanfilippo type B were administered resveratrol orally until they were 30 weeks old. At weeks 5, 10, 20, and 30, behavioural and urine HS tests were completed.
By weeks 20 and 30, HS urine levels were normalised in the Sanfilippo mice administered resveratrol while those not receiving the drug still showed significantly higher levels of HS in the urine.
Hyperactivity and anxiety were measured by investigating the movement of the mice and their behaviour in an open field. Untreated mice with Sanfilippo type B showed high levels of hyperactivity and anxiety, but when Sanfilippo type B mice were administered resveratrol, hyperactivity and anxiety were significantly reduced and did not differ from that seen in the mice without Sanfilippo.
Overall, the team’s results indicate that autophagy-activating molecules, like resveratrol, may show promise as drug candidates for patients with Sanfilippo. However, as the genistein clinical trial example shows, encouraging results in mice do not always predict a successful result in clinical trials in patients. This is particularly the case where very high concentrations of a potential drug are needed to achieve an effect. Mixed results of autophagy-inducing drugs have also been observed in clinical trials in adult neurodegenerative diseases such as Alzheimer’s disease. Carefully designed clinical trials will be needed to test whether resveratrol can have a beneficial effect in patients with Sanfilippo syndrome.
This study was made possible by grants from Fundacja Sanfilippo (Poland) and the National Science Center (Poland).
