Project Details

Description

The overall objective of this proposal is to develop improved methods for the treatment of the neurodegenerative lysosomal storage disorder (LSD) late infantile neuronal ceroid lipofuscinosis (LINCL). LINCL is an autosomal recessive disease due to mutations in gene encoding the lysosomal protease tripeptidyl peptidase 1 (TPP1). In the absence of effective treatment, LINCL is characterized by increasingly severe seizures, dementia, loss of vision and motor skills, and early death, typically at 8-15 years of age. Previous NIH-supported research from our group provided a firm underpinning for development of Brineura, the first FDA-approved enzyme replacement therapy for a neurodegenerative LSD. This was a breakthrough but there is considerable room for improvement. The current approved therapy involves intracerebroventricular administration of recombinant human TPP1 to the brain via the cerebrospinal fluid (CSF), a delivery method that is invasive and carries risk of infectious and non-infectious complications when used for chronic treatment. More importantly, animal studies in mouse, dog and monkey indicate that the distribution of recombinant TPP1 is not uniform throughout the brain when it is administered to the CSF, with regions proximal to the CSF receiving most TPP1 while regions distal receiving little or none. In LINCL patients, a failure to adequately treat specific brain regions that are distal to the site of administration remains a cause for concern and could have significant and possibly fatal long-term consequences. This proposal aims to continue the trajectory of our LINCL research with an integrated effort to use existing and novel animal models to develop improved therapies. In Aim 1, we will continue development of recombinant TPP1 derivatives that can cross the blood brain barrier. Given that the brain is highly vascularized, bloodstream- mediated delivery will likely provide the most uniform distribution of TPP1 throughout the brain. Promising candidates will initially be evaluated in our LINCL mouse model. In Aim 2, in which we will identify candidate CSF and blood biomarkers for LINCL that can be used for short-term monitoring of treatment efficacy. The previous aims will be integrated in Aim 3, in which chronic treatment studies will be conducted in the mouse model. These will provide proof-of-principle for effective IV-mediated treatment to be explored in larger animal models, and help validate candidate biomarkers. Convincing proof-of-principle for novel, improved treatment methods for LINCL will have significant translational implications for this disease. In addition, the majority of LSDs have a neurological component and are currently refractory to treatment. We envisage that any useful discoveries emerging from the proposed research will potentially also have a positive impact in these diseases.
StatusFinished
Effective start/end date4/1/985/31/22

Funding

  • National Institute of Neurological Disorders and Stroke: $50,000.00
  • National Institute of Neurological Disorders and Stroke: $344,335.00
  • National Institute of Neurological Disorders and Stroke: $259,281.00
  • National Institute of Neurological Disorders and Stroke: $30,000.00
  • National Institute of Neurological Disorders and Stroke: $130,000.00
  • National Institute of Neurological Disorders and Stroke: $50,000.00
  • National Institute of Neurological Disorders and Stroke: $369,313.00
  • National Institute of Neurological Disorders and Stroke: $369,313.00
  • National Institute of Neurological Disorders and Stroke: $429,000.00
  • National Institute of Neurological Disorders and Stroke: $369,313.00
  • National Institute of Neurological Disorders and Stroke: $429,000.00
  • National Institute of Neurological Disorders and Stroke: $345,625.00
  • National Institute of Neurological Disorders and Stroke: $360,634.00
  • National Institute of Neurological Disorders and Stroke: $350,175.00
  • National Institute of Neurological Disorders and Stroke: $267,061.00
  • National Institute of Neurological Disorders and Stroke: $275,073.00
  • National Institute of Neurological Disorders and Stroke: $313,031.00
  • National Institute of Neurological Disorders and Stroke: $347,813.00
  • National Institute of Neurological Disorders and Stroke: $204,408.00

ASJC

  • Clinical Neurology
  • Neurology
  • Molecular Biology
  • Biotechnology

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