Cerliponase alfa, marketed as Brineura, is an enzyme replacement treatment for Batten disease, a neurodegenerative lysosomal storage disease. Specifically, Cerliponase alfa is meant to slow loss of motor function in symptomatic children over three years old with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). The disease is also known as tripeptidyl peptidase-1 (TPP1) deficiency, a soluble lysosomal enzyme deficiency. Approved by the United States Food and Drug Administration (FDA) on 27 April 2017, this is the first treatment for a neuronal ceroid lipofuscinosis of its kind, acting to slow disease progression rather than palliatively treat symptoms by giving patients the TPP1 enzyme they are lacking.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. History
TPP1 was identified as the enzyme deficient in CLN2 Batten disease in 1997, via biochemical analysis that identified proteins missing a mannose-6-phosphate lysosomal targeting sequence. A gel electrophoresis was run for known brain proteins with lysosomal targeting sequences to see if a band was missing, indicating a deficiency in that protein. A band appeared to be missing at approximately 46 kDa, confirming its role in CLN2 disease, and almost the entire gene for this unknown protein was sequenced. The gene is located on chromosome 11. Today, it is known that varying mutation types occur in various locations of the gene including the proenzyme region, the mature enzyme region, or the signal sequence regions. After discovery, the recombinant form of TPP1, cerliponase alfa, was first produced in 2000, followed by testing in animal models until 2014.
Scores from the Motor domain of the scale range from 3 (grossly normal) to 0 (profoundly impaired).The U.S. Food and Drug Administration (FDA) requires the cerliponase alfa manufacturer to further evaluate the safety of cerliponase alfa in CLN2 patients below the age of two years, including device related adverse events and complications with routine use. In addition, a long-term safety study will assess cerliponase alfa treated CLN2 patients for a minimum of ten years.The application for cerliponase alfa was granted priority review designation, breakthrough therapy designation, orphan drug designation, and a rare pediatric disease priority review voucher. The FDA granted approval of Brineura to BioMarin Pharmaceutical Inc. Structure and biomolecular mechanism
Cerliponase alfa is an approximately 59 kDa molecule that codes for 544 amino acids in its proenzyme form while the activated mature enzyme only codes for 368 amino acids. Five amino acid residues have N-linked glycosylation sites. These five residues have additional mannose-6-phosphate (M6P) targeting sequences which function to target enzymes to the lysosome. When the cerliponase alfa proenzyme reaches target neurons during administration, it binds mannose-6-phosphate receptors on the cell surface to trigger vesicle formation around the receptor-proenzyme complex. The more neutral pH of the cytosol promotes binding of the proenzymes M6P targeting sequences to their receptors.