The inventors here have identified small molecules that target palmitoyl-protein thioesterase 1 (PPT1), tripeptidyl peptidase 1 (TPP1), enzymes that are deficient and less active in Batten disease or Neuronal Ceroid Lipofuscinosis. The CLN1 and CLN2 genes regulate the production of these enzymes, respectively.
Batten Disease, or Neural Ceroid Lipofuscinosis (NCL), is a family of rare diseases caused by the autosomal recessive genetic mutations. Batten Disease is an inherited genetic disorder that affects the function of lysosomes and result in imbalance of the homeostasis of the cell and a consequential build-up of proteins and lipids. These diseases are currently incurable and healthcare providers focus on treating the symptoms of the disorder.
The CLN1 gene is responsible for the production of the enzyme palmitoyl-protein thioesterase 1 (PPT1) and deficiency of this enzyme leads to abnormal buildup of lipids and proteins. In CLN1 disease, symptoms can be seen before age 1 and progress rapidly. Developmental skills such as standing, walking, and talking are not achieved or are gradually lost. Children often develop seizures by age 2 and eventually become bind. By age 3, children often are completely dependent upon caregivers and may need a feeding tube. Most affected children die in early to mid-childhood.
For CLN2 disease, the tripeptidyl peptidase (TTP1) enzyme is insufficiently active. Developmental delay will usually begin around the age of 2 and children will develop seizures and begin to gradually lose their ability to walk and speak. Brief, involuntary jerks in muscles or muscle groups typically begin around age 4-5. By age 6, children often are completely dependent upon caregivers and may need a feeding tube. Most children with CLN2 disease will die between the ages of 6-12; however, symptoms can develop around this time in some children, and they will experience a slower disease progression, possibly living into their teenage years.
- Treatment of CLN1
- Treatment of CLN2
- Novel small molecule treatment approach
- Enzymatic activity is able to be rescued
- Increased potency
- Increased cell viability
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