Brain delivery and efficacy of an intravenously-administered lysosomal enzyme using a blood-brain barrier transport vehicle

Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.

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Characterization of the Blood–Brain Barrier Integrity and the Brain Transport of SN-38 in an Orthotopic Xenograft Rat Model of Diffuse Intrinsic Pontine Glioma

Pharmaceutics ◽

10.3390/pharmaceutics12050399 ◽

2020 ◽

Vol 12 (5) ◽

pp. 399 ◽

Cited By ~ 2

Author(s):

Catarina Chaves ◽

Xavier Declèves ◽

Meryam Taghi ◽

Marie-Claude Menet ◽

Joelle Lacombe ◽

...

Keyword(s):

Blood Brain Barrier ◽

Diffuse Intrinsic Pontine Glioma ◽

Brain Barrier ◽

Brain Delivery ◽

Pontine Glioma ◽

Anticancer Drug Delivery ◽

Blood Brain ◽

The Brain

The blood–brain barrier (BBB) hinders the brain delivery of many anticancer drugs. In pediatric patients, diffuse intrinsic pontine glioma (DIPG) represents the main cause of brain cancer mortality lacking effective drug therapy. Using sham and DIPG-bearing rats, we analyzed (1) the brain distribution of 3-kDa-Texas red-dextran (TRD) or [14C]-sucrose as measures of BBB integrity, and (2) the role of major ATP-binding cassette (ABC) transporters at the BBB on the efflux of the irinotecan metabolite [3H]-SN-38. The unaffected [14C]-sucrose or TRD distribution in the cerebrum, cerebellum, and brainstem regions in DIPG-bearing animals suggests an intact BBB. Targeted proteomics retrieved no change in P-glycoprotein (P-gp), BCRP, MRP1, and MRP4 levels in the analyzed regions of DIPG rats. In vitro, DIPG cells express BCRP but not P-gp, MRP1, or MRP4. Dual inhibition of P-gp/Bcrp, or Mrp showed a significant increase on SN-38 BBB transport: Cerebrum (8.3-fold and 3-fold, respectively), cerebellum (4.2-fold and 2.8-fold), and brainstem (2.6-fold and 2.2-fold). Elacridar increased [3H]-SN-38 brain delivery beyond a P-gp/Bcrp inhibitor effect alone, emphasizing the role of another unidentified transporter in BBB efflux of SN-38. These results confirm a well-preserved BBB in DIPG-bearing rats, along with functional ABC-transporter expression. The development of chemotherapeutic strategies to circumvent ABC-mediated BBB efflux are needed to improve anticancer drug delivery against DIPG.

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Peptide decorated glycolipid nanomicelles for drug delivery across the blood–brain barrier (BBB)

Biomaterials Science ◽

10.1039/c9bm00955h ◽

2019 ◽

Vol 7 (10) ◽

pp. 4017-4021 ◽

Cited By ~ 4

Author(s):

S. Meenu Vasudevan ◽

N. Ashwanikumar ◽

G. S. Vinod Kumar

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Delivery ◽

Blood Brain

Schematic summary of the development of peptide decorated glycolipid nanomicelles for brain delivery by crossing Blood Brain Barrier (BBB).

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miR-143 regulates lysosomal enzyme transport across blood-brain barrier and improves CNS treatment for Hurler syndrome

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2019.11.328 ◽

2020 ◽

Vol 129 (2) ◽

pp. S125-S126

Author(s):

Dao Pan ◽

Yi Lin ◽

Xiaohong Wang ◽

Kevin Rose ◽

Mei Dai ◽

...

Keyword(s):

Blood Brain Barrier ◽

Lysosomal Enzyme ◽

Brain Barrier ◽

Hurler Syndrome ◽

Blood Brain ◽

Enzyme Transport

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Nose-to-Brain Delivery

Pharmaceutics ◽

10.3390/pharmaceutics12020138 ◽

2020 ◽

Vol 12 (2) ◽

pp. 138 ◽

Cited By ~ 2

Author(s):

Paolo Giunchedi ◽

Elisabetta Gavini ◽

Maria Cristina Bonferoni

Keyword(s):

Side Effects ◽

Blood Brain Barrier ◽

Neurological Diseases ◽

Systemic Administration ◽

Brain Barrier ◽

Brain Delivery ◽

Special Issue ◽

Drug Bioavailability ◽

Blood Brain ◽

The Brain

Nose-to-brain delivery represents a big challenge. In fact there is a large number of neurological diseases that require therapies in which the drug must reach the brain, avoiding the difficulties due to the blood–brain barrier (BBB) and the problems connected with systemic administration, such as drug bioavailability and side-effects. For these reasons the development of nasal formulations able to deliver the drug directly into the brain is of increasing importance. This Editorial regards the contributions present in the Special Issue “Nose-to-Brain Delivery”.

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