CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis

Abstract

The neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited neurodegenerative diseases characterized by the progressive intralysosomal accumulation of autofluorescent material in many cells, visual defects, seizures, cognitive deficits, and premature death. Infantile neuronal ceroid lipofuscinosis (INCL) has the earliest onset ( approximately 1.5 years of age) and is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Currently there is no effective treatment for children with INCL. In this study, newborn PPT1-deficient mice received two (cortex), four (cortex and hippocampus), or six (cortex, hippocampus, and cerebellum) bilateral intracranial injections of AAV2-PPT1. The AAV-treated animals had localized increases in PPT1 activity, decreased autofluorescent material, improved histologic parameters, and increased brain mass. In addition, the treated animals had dose-dependent improvements in a battery of behavioral tests and improved interictal electroencephalographic tracings. However, there was neither a significant decrease in seizure frequency nor an increase in longevity even in INCL animals receiving six injections. These data suggest that early treatment of INCL using gene transfer techniques can be efficacious. However, higher levels or a broader distribution of PPT1 expression, or both, will be required for more complete correction of this neurodegenerative disease.

Synergistic effects of treating the spinal cord and brain in CLN1 disease

“…Based on a previous study that showed that intrathecal delivery of recombinant PPT1 enzyme could minimally improve the disease phenotype of Ppt1 −/− mice (31), we delivered AAV2/9-hPPT1 intrathecally to target the spinal cord. We also combined this approach with braindirected gene therapy (12,(24)(25)(26)(27).…”

“…Therefore, we tested whether intrathecal (IT) injections of an AAV2/9-hPPT1 vector, either alone or in combination with intracranial (IC) injections (12,(24)(25)(26)(27), would have any beneficial effect on disease progression and brain and spinal cord pathology.…”

“…PPT1-deficient mice (Ppt1 −/− ) exhibit a CLN1 disease-like phenotype including retinal dysfunction, progressive sensorimotor defects, seizures, and a shortened life span (10)(11)(12). These mice have been a powerful tool to study functional deficits, as well as pathology, in the forebrain and cerebellum.…”

“…Various experimental therapies have been tested to treat forebrain pathology in Ppt1 −/− mice, including antioxidants (19,20), enzyme replacement therapy (ERT) (21,22), human neuronal stem cells (23), and forebrain-directed gene therapy (12,(24)(25)(26)(27). Of these, adeno-associated virus (AAV) vector-mediated gene transfer has been the most promising (3,28).…”

Anxiolytic and Memory Enhancing Activity of L.SICERARIA in Rodents

“…After Lagenaria siceraria administration the animals used to cross the rod approximately in just 2 seconds as against the control reading which is approximately 9 seconds. This effect of Lagenaria siceraria on stationary rod activity may be due to its effects on neurotransmitter levels, especially acetylcholine (Ach) because the literature shows that the herbs which have been proven as memory enhancers have shown their effects by influencing cholinergic system and by changing neuronal morphology [25][26] .…”