Trehalose, a natural non-reducing disaccharide and FDA-approved food additive, has attracted interest for its ability to stimulate autophagy and promote lysosomal clearance of cellular waste. Anecdotal reports from parents of children with neuronal ceroid lipofuscinoses (NCLs) suggest that daily oral trehalose may slow disease progression. A recent human trial confirmed the safety of oral trehalose in many forms of NCL, but the results were inconclusive, with caregiver-reported benefits not being supported by clinical findings. To further explore its therapeutic potential, we assessed intravenous trehalose in ovine CLN5 and CLN6 models.
Six nine-month-old sheep (n = 3 CLN5-/- and n = 3 CLN6-/-) received weekly intravenous trehalose infusions (0.5 g/kg; average 21 g/week) for three months. Treated animals were compared to age-matched historical and concurrent healthy control and untreated affected sheep. Clinical progression was monitored using established scoring systems, while disease-associated brain changes were assessed via CT imaging and post-mortem neuropathology.
Trehalose treatment had no significant therapeutic effect in CLN5⁻/⁻ sheep. However, treated CLN6⁻/⁻ sheep showed improved clinical scores and weight gain. CT imaging indicated a slower rate of intracranial volume loss compared to untreated controls. Post-mortem analyses of CLN6-/- treated brains revealed increased cortical thickness, reduced microglial activation in the primary visual and parieto-occipital cortices, and significantly lower lysosomal storage burden in the visual cortex (p = 0.0002). Astrocytosis remained unchanged.
Our findings suggest that trehalose offers no observable benefit in CLN5-/- sheep but may confer neuroprotective effects in CLN6-/- animals. While recent human studies remain inconclusive, our data support further investigation of trehalose as a potential adjunct therapy for CLN6 disease.
We acknowledge the Batten Disease Support & Research Association and Beyond Batten Disease Foundation for their generous donation of intravenous trehalose.