User:Lrumph/Cerliponase alfa

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 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.

History

Structure of tripeptidyl peptidase 1 (TPP1) enzyme for which Cerliponase alfa is a replacement for.

TPP1 was identified as the enzyme deficient in CLN2 Batten disease in the 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. In 2012, BioMarin began the first clinical trial on affected patients using their recombinant DNA technology Brineura (Cerliponase alfa) which is synthesized using Chinese hamster ovarian (CHO) cell lines.

After the success of this clinical trial, the U.S. FDA approved the marketing of Brineura to patients with CLN2 disease. The approval only applied to patients 3 years or older as the FDA wants to have more data available on children under the age of three before approving it for younger patients. A current 10 year study is being performed to asses the long term affects of continued use of this drug. Brineura is currently developed by BioMarin Pharmaceutical and the drug application was granted both Orphan Drug status to provide incentives for rare disease research and the tenth Rare Pediatric Disease Priority Review Voucher. Brineura was also approved by European Medicines Agency on 30 May 2017. In the United Kingdom NICE evaluated Cerliponase alfa for the treatment of CLN2 and deemed it not cost-effective. BioMarin announced that the price per infusion is $27,000, coming to $702,000 per year for treatment, though using Medicaid could potentially lower the cost.

Structure and Biomolecular Mechanism

Mannose-6-phosphate molecules are added to oligosaccharides on Cerliponase alfa amino acid residues to target the enzyme to the lysosome by binding mannose-6-phosphate receptors.

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 5 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 proenzyme's M6P targeting sequences to their receptors. Once brought into the cell, the receptor-proenzyme complex vesicle is transported to the lysosome where the lower pH promotes both dissociation of the proenzyme from the receptor and activation of the proenzyme to its active catalytic form via cleavage of the proenzyme sequence.

Like natural TPP1, Cerliponase alfa functions as a serine protease, cleaving N-terminal tripeptides from a broad range of protein substrates. The enzyme uses a catalytic triad active site composed of the three amino acids, aspartic acid, glutamic acid, and serine. Serine functions as the amino acid that performs the nucleophilic attack during the ping pong catalytic activity of a serine protease. The products of this reaction are a tripeptide and the remaining length of the protein substrate with a new N-terminal end that can be cleaved again. In CLN2 disease, TPP1 is deficient or not made at all, meaning that proteins are unable to be degraded in the lysosome and accumulate, leading to damage in nerves. As a protein, Cerliponase alfa gets degraded by proteolysis. Therefore, Cerliponase alfa is administered repeatedly to maintain sufficient levels of the recombinant TPP1 enzyme in place of the deficient form to degrade proteins and prevent further build up. Cerliponase alfa is a treatment that can potentially slow disease progression but does not cure the disease itself.

Administration

Brinuera (Cerliponase alfa) is administered via intracerebroventricular infusion directly to the the cerebrospinal fluid using an implanted catheter. The catheter system used in the U.S. is a Codman Ventricular Catheter with a B Braun Perfusor Space Infusion Pump. The catheter must be surgically implanted by a trained professional. A dose of 300 mg is administered to patients every two weeks followed by an electrolyte infusion to wash residue drug out of the catheter tube. The dose is slowly dripped in so each infusion takes approximately 4.5 hours. Patients are regularly treated with corticosteroids or antihistamines prior to each infusion.