Effective intravenous therapy for neurodegenerative disease with a therapeutic enzyme and a peptide that mediates delivery to the brain

Yu Meng, Istvan Sohar, David E. Sleat, Jason R. Richardson, Kenneth R. Reuhl, Robert Brian Jenkins, Gobinda Sarkar, Peter Lobel

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The blood-brain barrier (BBB) presents a major challenge to effective treatment of neurological disorders, including lysosomal storage diseases (LSDs), which frequently present with life-shortening and untreatable neurodegeneration. There is considerable interest in methods for intravenous delivery of lysosomal proteins across the BBB but for the most part, levels achievable in the brain of mouse models are modest and increased lifespan remains to be demonstrated. In this study, we have investigated delivery across the BBB using a mouse model of late-infantile neuronal ceroid lipofuscinosis (LINCL), a neurodegenerative LSD caused by loss of tripeptidyl peptidase I (TPP1). We have achieved supraphysiological levels of TPP1 throughout the brain of LINCL mice by intravenous (IV) coadministration of recombinant TPP1 with a 36-residue peptide that contains polylysine and a low-density lipoprotein receptor binding sequence from apolipoprotein E. Importantly, IV administration of TPP1 with the peptide significantly reduces brain lysosomal storage, increases lifespan and improves neurological function. This simple "mix and inject" method is immediately applicable towards evaluation of enzyme replacement therapy to the brain in preclinical models and further exploration of its clinical potential is warranted.

Original languageEnglish (US)
Pages (from-to)547-553
Number of pages7
JournalMolecular Therapy
Volume22
Issue number3
DOIs
StatePublished - 2014

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Neurodegenerative Diseases
Blood-Brain Barrier
Neuronal Ceroid-Lipofuscinoses
Lysosomal Storage Diseases
Peptides
Brain
Enzymes
Enzyme Replacement Therapy
Polylysine
LDL Receptors
Apolipoproteins E
Therapeutics
Nervous System Diseases
Intravenous Administration

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Effective intravenous therapy for neurodegenerative disease with a therapeutic enzyme and a peptide that mediates delivery to the brain. / Meng, Yu; Sohar, Istvan; Sleat, David E.; Richardson, Jason R.; Reuhl, Kenneth R.; Jenkins, Robert Brian; Sarkar, Gobinda; Lobel, Peter.

In: Molecular Therapy, Vol. 22, No. 3, 2014, p. 547-553.

Research output: Contribution to journalArticle

Meng, Yu ; Sohar, Istvan ; Sleat, David E. ; Richardson, Jason R. ; Reuhl, Kenneth R. ; Jenkins, Robert Brian ; Sarkar, Gobinda ; Lobel, Peter. / Effective intravenous therapy for neurodegenerative disease with a therapeutic enzyme and a peptide that mediates delivery to the brain. In: Molecular Therapy. 2014 ; Vol. 22, No. 3. pp. 547-553.
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