B3 - Lysosomal Storage Diseases
50: AAV-Ep+ in Preclinical Studies for Late Infantile Neuronal Ceroid Lipofuscinosis
Type: Oral Abstract Session
Presentation Details
Session Title: Lysosomal Storage Disorders
Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL) is a childhood neurodegenerative disease that appears between 2-4 years of age and progresses with visual, motor, and mental decline, with a life expectancy of less than two decades. Most cases of LINCL are caused by deficiency in the soluble lysosomal enzyme tripeptidyl peptidase (TPP1) as a result of mutations in the CLN2 gene. We have previously demonstrated that gene therapy-mediated enzyme replacement of TPP1 produced significant clinical benefits in a LINCL canine model. In these experiments, therapeutic amelioration of LINCL pathology was achieved using wild-type AAV to target ependymal cells resulting in secretion of TPP1 into the cerebrospinal fluid. We hypothesized that a more efficient delivery vector with improved tropism for ependymal cells and parenchymal neurons could enhance the efficacy of this TPP1 gene therapy strategy and help facilitate the translation of this successful therapeutic approach to humans. To achieve this, we applied a peptide-modified AAV vector screening methodology developed in our lab to identify new vectors with improved tropism for ependymal cells in non-human primates (NHPs). We found AAV-Ep+, which showed a cumulative rank enrichment of ~30,000 from the last rounds of screening. To characterize the transduction efficiency of AAV-Ep+ in ependyma cells of NHP brain, AAV-Ep+.mRuby3 was bilaterally injected in the lateral ventricles of a cynomolgus monkey. Ependymal cell transduction was highly efficient, with mRuby3 expression detected in 76-99% of cells across different regions of the brain ventricle system. Moreover, at this dose, AAV-Ep+ shows low levels of off-target transduction in peripheral tissues and dorsal root ganglia. We next tested AAV-Ep+ in a TPP1-deficient mouse model. Brain TPP1 levels in mice treated with AAV-Ep+ were up to 11-fold higher than mice treated similarly with wtAAV. Furthermore, extended lifespan and improved disease phenotypes were achieved to a significantly greater degree than the highest doses of WT serotypes tested. In summary, AAV-Ep+ results in broad and robust transduction of brain ependyma cells in non-human primates. Utilized as a vector to deliver gene therapy in a LINCL model, AAV-Ep+ increases recombinant TPP1 biodistribution and rescues phenotypes at doses significantly lower than conventional serotypes. AAV-Ep+ is a promising candidate for improving the translatability and applicability of gene therapy for LINCL and other diseases amenable to ependymal cell targeted treatments.
Luis Tecedor1, Yonghong Chen1, David E. Leib2, Paul T. Ranum3, Bryan P. Simpson2, Megan S. Keiser4, Melanie McFadden1, Alexis Mackiewicz1, Brian Lewandowski1, Elena Lysenko1, Jang-Ho Cha5, Beverly L. Davidson1
1Children's Hospital of Philadelphia, Philadelphia, PA,2Latus Bio, Philadelphia, PA,3Latus Bio, Saint Paul, MN,4Ohio State University Wexner Medical Center, Columbus, OH,5Latus Biosciences, Arlington, MA"
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