Figure 3. Short-term treatment with AF38469 improves histopathological and behavioral outcomes in Cln2^R207X mice.

(A) Homozygous Cln2^R207X and littermatewild type mice received continuous treatment with AF38469 or vehicle via drinking water starting at wean until 11 weeks of age. (B) Treatment with AF38469 (0.03 μg/ml) significantly increased PPT1 enzyme activity levels in Cln2^R207X treated mice. (C) Treatment with AF38469 had no impact on TPP1 enzyme activity levels Cln2^R207X treated mice. (D, E) AF38469 treatment (0.3 μg/ml) in Cln2^R207X mice significantly prevented SubC accumulation and had no impact on microglial reactivity (CD68⁺) or astroglial activation (GFAP⁺) in the S1BF of the somatosensory cortex and CA3 of the hippocampus. (F) Treated Cln2^R207X mice (0.3 μg/ml) saw significant prevention of accumulation of mitochondrial ATP synthase subunit C (SubC⁺) and reduction of microgliosis (CD68⁺) in the VPM/VPL of the thalamus with no impact on astrocytosis (GFAP⁺). (G) Treatment with AF38469 had no impact on CLN2 Batten disease pathology in the dentate gyrus and hilus regions of the hippocampus. (H-K) Tremor index scores were reduced and restored to wild type levels in AF38469 treated Cln2^R207X mice when compared to vehicle treated mice. Mean ± S.E.M. (B-G) Nested one-way ANOVA with a Šidák post-hoc test (H-K) One-way ANOVA with a Šidák post-hoc test *^/#p<0.05, **^/##p<0.01, ***^/###p<0.001, ****^/####p<0.0001. Hashsigns indicate comparison to WT, asterisks indicate comparison to mutant vehicle. Scale bar, 100 μm. n = 6-8 animals/treatment.