ETD

• autophagy
• CLN5
• drug screening
• in vitro studies
• lysosomal storage
• neuronal ceroid lipofuscinosis type 5
• neuronal-like disease models
• small molecules

CLN5 disease is a rare pediatric neurodegenerative disorder caused by mutations in the CLN5 gene. Its pathogenesis primarily involves defects in autophagy, lysosomal dysfunction, and impaired mitochondrial bioenergetics. Currently, no cure is available for patients with mutations in the CLN5 gene, and treatments remain largely palliative. However, several disease-modifying therapeutic strategies are under investigation, including gene therapy approaches and small molecules designed to modulate autophagy or reduce the accumulation of toxic substrates within lysosomes.
The research work described in this thesis investigates in vitro effects of three novel small molecules—namely, TG68, a β-thyromimetic prodrug; ES25, an HDAC6 inhibitor; and GF11, a potential autophagy enhancer—selected for their predicted pro-autophagic activity. Their efficacy in restoring autophagy and mitochondrial function was tested in cells with altered CLN5 gene dosage and compared to FDA-approved experimental compounds.
Some of the tested treatments demonstrated modulatory activity on key metabolic parameters, with varying degrees of effectiveness. Preliminary findings suggest a link between CLN5 deficiency, lipid metabolism, and cellular quality control systems. These results support further pharmacological investigations and reinforce autophagy modulation as a promising therapeutic strategy for CLN5 disease.