Development of a protein palmitoylation assay to monitor treatment of CLN1 batten disease
Ended Project Grant Awarded Last action
- Award ID
- R41HD105560
- Recipient
-
Circumvent Pharmaceuticals Inc. UEI Y14DQ5VD56A7
- Awarding agency
-
National Institute of Child Health and Human Development
National Institutes of Health, Department of Health and Human Services
- Obligated
- $914,361
Award facts
- Assistance listing
- 93.865 Child Health and Human Development Extramural Research
- Completion date
- Originally
- Funding
-
- $609,574.00 Federal
- $304,787.00 Non-federal
- Place of performance
- Portland, OR 97239, USA
Award details come from USAspending.gov.
Description
- Abstract
- In the specific aims outlined by the following proposal for an NIH sbir phase 1 project, we will use a multi-faceted approach to identify key substrates for targeted assay development to monitor therapy in for CLN1 batten disease (CLN1). CLN1 is an ultra-rare neurodegenerative disease that affects children with autosomal recessive mutations in the gene for palmitoyl-protein thioesterase 1 (PPT1). PPT1 cleaves the thioesterase bond between a 16-carbon lipid chain, palmitate, and many proteins expressed in the brain. Circumvent pharmaceuticals is developing a small molecule thioesterase mimetic, CIRC825, for the treatment of CLN1 as there is currently no available therapeutic for CLN1 patients. We propose a multiplexed acyl-resin assisted capture (acyl-RAC) discovery assay coupled to an isobaric peptide-labeling strategy using tandem mass tags (TMT) to profile the neuronal and blood palmitoylomes of a CLN1-/- mouse model using LC-MS/MS. TMT assays will be followed up with targeted, parallel reaction monitoring (PRM) mass spectrometry to validate targets quantitatively. We will select proteins for their relative expression in brain and blood to enable pharmaceutically-relevant routine blood collection for standard of practice, clinical examination. We will adapt our assay to the assessment of CLN1 patient blood and cultured cells for PPT1 substrates by discovery acyl-RAC-PRM-MS to identify candidates for targeted assay development. Cultured cells will be treated with CIRC825 and assessed, compared to untreated controls, by targeted acyl-RAC-PRM-MS. To allow for further optimization and selection based on reproducibility, stability, and behavior in method development, we will identify 5-10 candidate palmitoylated protein substrates of PPT1 which are differentially expressed in patient-derived lcls or patient blood spot samples which are also match our findings in mouse brain and blood. Through a future NIH sbir phase II project, the optimal substrates will be used in the development of a commercial clinical assay which may be expanded to use in numerous diseases which display aberrant protein palmitoylation. Finally, we plan to perform proof-of-concept for our final assay during CLN1 phase i/II clinical trials before offering our assay for licensing.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $304,787 | $0 | |
| Original award | $304,787 | $304,787 |
Quick answers
Who received award R41HD105560?
R41HD105560 was awarded to Circumvent Pharmaceuticals Inc. by National Institute of Child Health and Human Development (National Institutes of Health) on September 15, 2021.
How much is award R41HD105560 worth?
$914,361 has been obligated on R41HD105560: $609,574 in federal funding and $304,787 in non-federal funding.
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