Oral Presentation International Congress on Neuronal Ceroid Lipofuscinoses 2025

Two year results of first-in-human intracisternal TTX-181 investigational AAV9 gene therapy in a child with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) (127791)

Carolina Fischinger de Souza 1 2 3 , Alessandra Pereira 1 3 , Jorge Bizzi 1 3 , Ana Lucia Staub 1 , Tamires Alves 1 , Juliana Duarte 1 , Christina Ohnsman 4 , Roberto Giugliani 1 3
  1. Hospital de Clinicas de Porto Alegre, Brazil, Porto Alegre, Please Select, Brazil
  2. Casa Dos Raros, Porto Alegre, Please Select, Brazil
  3. Hospital Moinhos De Vento , Porto Alegre, Please Select, Brazil
  4. Tern Therapeutics, Washington, DISTRICT OF COLUMBIA, United States

CLN2 Batten disease is a lysosomal disease caused by biallelic mutations in the CLN2 gene encoding tripeptidyl peptidase 1 (TPP1).  Insufficient TPP1 enzyme causes accumulation of lysosomal storage material resulting in progressive neurological and retinal degeneration. Treatment with biweekly intracerebroventricular (ICV) enzyme replacement therapy (ERT) with recombinant human TPP1 (cerliponase alfa) slows loss of ambulation but does not stop or reverse most manifestations of the disease. TTX-181 is an investigational one-time gene therapy comprised of a recombinant AAV9 vector containing a human CLN2 transgene designed to induce sustained secretion of TPP1 in the central nervous system. A 5-year-old child with CLN2 received 1.25 x 1011 genome copies/gram of brain mass of intracisternal TTX-181 under a single-patient investigator-initiated study. Assessments included safety and tolerability, seizure frequency, anti-epileptic medication use, ERT use, CLN2 Clinical Rating Scale Expanded Language and Motor (CRS-LX and -MX), and Mullen Scales of Early Learning (MSEL). Cerebrospinal fluid (CSF) was collected for TPP1 assay via indwelling ICV port immediately before ERT infusions at 34 days prior to TTX-181 administration, immediately prior to the administration procedure, and at subsequent regular intervals. TTX-181 was well tolerated with no serious adverse events through the 2-year study period. TPP1 in CSF was 23- to 54-fold higher than baseline and sustained over 2 years, with associated 90% reduction in seizure frequency, withdrawal of two anti-epileptic medications by 5 months, increased ERT intervals, and ultimately, ERT discontinuation at 16 months. While motor and language decline were observed on CLN2 CRS-LX and -MX, stabilization or small increases in age-equivalent fine motor, receptive and expressive language skills were observed at 2 years compared with baseline on MSEL.  Loss of gross motor skills were observed on MSEL. These results support further clinical testing of TTX-181 to better characterize safety, efficacy, dose level, and optimal age of administration.