Multiple sulfatase deficiency (MSD) is a severe autosomal recessive disease characterized by
the reduced activity of all sulfatases enzyme. The activity of sulfatases depends on a posttranslational
modification catalyzed by formylglycine-generating enzyme (FGE) encoded by
the sulfatase modifying factor 1 gene (Sumf1) that is mutated in MSD. There are no available
disease-specific therapies for MSD.
In this proposal we plan to test a novel therapeutic strategy for MSD using a pharmacological
approach. In particular, autophagy will be modulated in vivo using the TAT-Beclin1 peptide, a
recently developed selective and potent inducer of autophagy lacking evident signs of toxicity
(Shoji-Kawata et al., 2013). A group at TIGEM has tested this peptide in mice and found that it
was able to induce autophagy in different tissues including bone and cartilage (Cinque et al.,
2015). We plan to use the newly developed hypomorphic MSD mouse model (Nicola Brunetti
personal communication). The mice will receive different doses of the peptide at different
ages, we will then analyse autophagy induction and clearance of storage material. We are
currently performing dosing studies in wild-type animals and will use this data to determine
best dose in this experimental set-up. We plan to use different time points for treatment on
the base of phenotype progression of this new mouse model: early, starting before the onset
of the phenotype and late, once the phenotype begins to manifest. Each cohort of 10 MSD
mice will be daily intraperitoneal (IP) injected with TAT-scrambled (control peptide) or TAT–
beclin 1 at the different concentrations (2-15 mg/kg) for 3 months, according to the protocol
developed at the institute in the laboratory of Settembre (Cinque et al., 2015). Mice will be
sacrificed at different time points post injection and endpoints analysed, determined on the
basis of results obtained in the novel hypomorphic mouse model.
