title: Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA.
abstract: Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive, neurodegenerative lysosomal storage disease affecting the CNS and is fatal by age 8 to 12 years. A total average dose of 2.5 10(12) particle units of an adeno-associated virus (AAV) serotype 2 vector expressing the human CLN2 cDNA (AAV2 CU h-CLN2) was administered to 12 locations in the CNS of 10 children with LINCL. In addition to safety parameters, a neurological rating scale (primary variable) and three quantitative magnetic resonance imaging (MRI) parameters (secondary variables) were used to compare the rate of neurological decline for 18 months in treated subjects compared with untreated subjects. Although there were no unexpected serious adverse events that were unequivocally attributable to the AAV2 CU hCLN2 vector, there were serious adverse effects, the etiology of which could not be determined under the conditions of the experiment. One subject died 49 days postsurgery after developing status epilepticus on day 14, but with no evidence of CNS inflammation. Four of the 10 subjects developed a mild, mostly transient, humoral response to the vector. Compared with control subjects, the measured rates of decline of all MRI parameters were slower, albeit the numbers were too small for statistical significance. Importantly, assessment of the neurologic rating scale, which was the primary outcome variable, demonstrated a significantly reduced rate of decline compared with control subjects. Although the trial is not matched, randomized, or blinded and lacked a contemporaneous placebo/sham control group, assessment of the primary outcome variable suggests a slowing of progression of LINCL in the treated children. On this basis, we propose that additional studies to assess the safety and efficacy of AAV-mediated gene therapy for LINCL are warranted.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Worgall
authors.forename: Dolan
authors.initials: D
authors.lastname: Sondhi
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hackett
authors.forename: Barry
authors.initials: B
authors.lastname: Kosofsky
authors.forename: Minal V
authors.initials: MV
authors.lastname: Kekatpure
authors.forename: Nurunisa
authors.initials: N
authors.lastname: Neyzi
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Dyke
authors.forename: Douglas
authors.initials: D
authors.lastname: Ballon
authors.forename: Linda
authors.initials: L
authors.lastname: Heier
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Greenwald
authors.forename: Paul
authors.initials: P
authors.lastname: Christos
authors.forename: Madhu
authors.initials: M
authors.lastname: Mazumdar
authors.forename: Mark M
authors.initials: MM
authors.lastname: Souweidane
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000626:Aminopeptidases; D000914:Antibodies, Viral / Q000097:blood; D002490:Central Nervous System; D002648:Child; D002675:Child, Preschool; D018076:DNA, Complementary / Q000235:genetics; D000229:Dependovirus / Q000276:immunology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018450:Disease Progression; D010450:Endopeptidases / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000009:adverse effects / Q000276:immunology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009472:Neuronal Ceroid-Lipofuscinoses / Q000628:therapy*; D057057:Serine Proteases; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D000914:Antibodies, Viral; D018076:DNA, Complementary; D000091346:Tripeptidyl-Peptidase 1; D010450:Endopeptidases; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human