Broad variations in TPP1 activity in children' cerebral CSF infused with Cerliponase alfa

VENIER ANA CLARA; GUELBERT NORBERTO; BECERRA ADRIANA; MUÑOZ ADRIAN; LEYES CLAUDIA; CISMONDI INES ADRIANA; NOHER INES; PESAOLA FAVIO

Congreso; NCL 2018 London; 2018

Background: Since 2017 in Córdoba (Argentina) Cerliponase alfa is infused as an enzyme replacement therapy for CLN2 disease. It is administered (ideally every 15 days) as an intrathecal infusion into the ventricular cerebrospinal fluid (CSF). The hallmark of CLN2 disease is Tripeptidyl Peptidase 1 (TPP1) deficient activity in peripheral blood and other body tissues and fluids; however, its activity in CSF was recently determined. We aim to quantify the TPP1 activity of the infused patient´s CSF to follow-up the variations along the treatment. Methods: TPP1 activity was quantified in CSF from 27 controls (lumbar puncture samples provided by the Central Laboratory of the Children?s Hospital) and 5 CLN2 disease patients from Argentina under treatment in our centre at Cordoba. CSF samples were collected before each infusion. Results: Controls showed a TPP1 activity of 19.36-379.5 nmol/24h/mg prot. (226.68 ± 89.6 nmol/24h/mg prot.). Case 1: activity range of 6.26-5630.69 nmol/24h/mg prot. with a marked activity decrease between infusions. Case 2: TPP1 activity ranged 0-3239.1 nmol/24h/mg prot. Case 3: TPP1 activity ranged 0-6.98 nmol/24h/mg prot. Case 4: activity range was 1.52-802.84 nmol/24h/mg prot. Case 5: currently only one sample was collected showing 268.63 nmol/24h/mg prot. Discussion: TPP1 activity in infused patient? CSF showed a broad range of variation despite all received the same dose of enzyme. Cases 1 and 2 showed along the progression of infusions highly variable TPP1 activity values, probably due to variations in the periods between infusions. Moreover, samples of the same time of treatment from two subjects showed highly different TPP1 activity values, suggesting that individuals do not respond the same way to therapy. The TPP1 activity assay could be an efficient biomarker; however, further studies are needed to understand the variations of TPP1 activity along Cerliponase alfa therapy.Lay abstractCerliponase alfa intrathecal infusion was implemented since 2017 at Cordoba as a enzyme replacement therapy for CLN2 disease. TPP1/CLN2 deficiency in peripheral blood is the hallmark of CLN2 disease. However, its activity in cerebrospinal fluid (CSF) was recently determined. In this study, we measured the TPP1/CLN2 activity from 5 patients? CSF along the Cerliponase alfa treatment. We showed that TPP1/CLN2 activity has a broad range, both among patients and infusions. We suggest that this variation may be caused by an irregular attendance of patients to infusions, and by a different response of patients to treatment. The TPP1/CLN2 activity assay could be an efficient biomarker; however, further studies are needed to understand the variations of TPP1 activity along Cerliponase alfa therapy.