Summary The neuronal ceroid lipofuscinoses (NCLs) are a group of incurable neurodegenerative storage disorders primarily affecting the brain and the retina of children and young adults, leading to dementia, blindness, epilepsy, and early death, with a prevalence of approximately 1.5 to nine per million population (1.3 to 7 per 100,000 live births). The infantile onset form CLN1 disease is caused by mutations in the CLN1/PPT1 gene, which codes for the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) resulting in a reduction or absence of enzyme activity. CLN1 disease usually presents between 6 and 24 months of age and there are 2-3 children with this form identified each year and currently 24 known children with CLN1 in the US, 11 in Brazil and at least 10 in the UK (with likely many more undiagnosed). There are currently no treatments available other than palliative therapies and the disease is fatal. Human recombinant PPT1 (rhPPT1) expressed in CHO cells has been previously reported to modify disease phenotypes following a single intrathecal (IT) and intravenous (IV) administration in PPT1 deficient mice (Ppt1-/-). After successful completion of our Phase I SBIR in which we exceeded our milestones monthly intracerebroventricular (ICV) administration of rhPPT1 produced statistically significant treatment effects in Ppt1-/- mice, such as rescue of more than 60% PPT1 enzyme activity decreased secondary enzyme levels, decreased the loss of neurons in all regions of brain and spinal cord and improved gait and rotarod results. The CLN1 ERT data clearly pointed to ICV dosing as ideal for future studies, which is also a preferred route according to physicians. Our Phase II SBIR has enabled us to 1. Prepare our quality documents, 2 identify a CDMO (STC Biologics) who has manufactured our GLP quality protein for preIND toxicity studies in rat. 3. Submitted a preIND request to the FDA (with the assistance of RTI International,). We now propose in this project 1. production of GMP protein (with STC Biologics), 2. Continued development of quality procedures, 3. Prepare a clinical trial protocol (with assistance from CTI Clinical Trial Services, Inc.), 4 and submit an IND (with assistance from RTI). These collaborations will enable us to cost effectively and more rapidly translate this potential treatment to the clinic that can potentially save the lives of children living with this devastating disease. We have already obtained an Orphan Drug Designation and rare pediatric disease designation from the FDA for rhPPT1 as a biological product for a “rare pediatric disease” which offers several benefits in future upon FDA approval, including marketing exclusivity for 7 years and the potential to obtain a rare pediatric disease voucher and thus provide a return on investment (current value ~$100 M). We are engaged with CLN1 families and we are now well positioned to continue the development of this potential treatment for a devastating disease. This propos...