Cerliponase alfa for TPP1 c.622C>T (p.Arg208Ter) in CLN2 disease
CONCLUSION
For TPP1 c.622C>T (p.Arg208Ter), cerliponase alfa is a rational therapeutic option because the variant creates a loss-of-function stop codon and the approved treatment bypasses allele-specific repair by replacing TPP1 enzyme directly within the CNS. That makes this a strong disease-level fit for enzyme replacement, even though the drug does not correct the underlying DNA lesion.
EVIDENCE
ClinVar classifies c.622C>T (p.Arg208Ter) as pathogenic for CLN2/TPP1 deficiency. The current FDA label for Brineura, updated through 2026-04-03 in openFDA, indicates cerliponase alfa to slow the loss of ambulation in pediatric patients with CLN2 disease, also known as TPP1 deficiency. Clinical pharmacokinetic and pharmacodynamic data published in 2021 support intracerebroventricular enzyme replacement as a viable delivery route, and the first French cohort reported that cerliponase alfa changed the natural history of children with CLN2 compared with expected progression.
I would keep this in the other bucket rather than forcing it into gene therapy. For a nonsense TPP1 allele like p.Arg208Ter, enzyme replacement is clinically real and immediately actionable, whereas CNS gene therapy for CLN2 is still a development-stage discussion. The main tradeoff is durability and treatment burden, not biological plausibility.
LIMITATIONS
This is not curative therapy. Brineura requires chronic intracerebroventricular infusions and device management, and it primarily addresses CNS enzyme deficiency rather than restoring endogenous TPP1 production everywhere it is needed. The evidence is disease-level rather than specific to p.Arg208Ter, and treatment burden, infusion reactions, seizures, shunt complications, and incomplete control of extra-CNS manifestations remain important constraints.