The lysosomal storage (LSDs) disorders comprise ~50 fatal diseases due to genetic lysosomal enzyme deficiency, which affects most tissues and associates to broad inflammatory phenotype. Treatment is by enzyme replacement therapy (ERT), where recombinant enzymes are i.v. infused in hospitals, with high burden to patients and the health system (?$150,000/patient- year). Still, ERT success is restricted to a few diseases that affect the liver, spleen, and kidneys, since the enzymes access these blood clearance organs. Yet, delivery to tissues separated from the blood by a tight endothelial barrier (mainly the brain, to some extent the lungs) is hindered. An example is that of types A-B NPD, a sphingomyelin storage due to acid sphingomyelinase (ASM) deficiency, which leads to premature death. NPD-A has a strong neurological involvement, not improved by ERT. NPD-B mainly affects the lungs and, although helped by ERT, high and frequent dosage causes immune reactions and resistance, along with other side effects. Our original award focused on targeting recombinant ASM to ICAM-1, a protein overexpressed in inflammation and associated to a new route of transport across the endothelium and into lysosomes of tissue cells. Through the previous period we successfully achieved our goals and improved: brain and lung targeting, transport across the endothelium, uptake in subjacent tissue cells, lysosomal enzyme activity, and substrate reduction (38 articles, 5 journal covers and/or editorials, 17 awards). To move this promising platform toward translation, we now will focus on: (a) enzyme encapsulation in biodegradable polymer nanocarriers and safer targeting moieties to minimize immune recognition, (b) incorporation of anti-phagocytic signals to minimize clearance, (c) tuning of the formulation parameters to optimize the balance between brain-lung targeting and explore combination therapy for enhanced effects, and (e) optimization of carrier degradation within lysosomal to avoid ?polymer storage? upon chronic treatment. We have key results supporting these new directions and completion of a renewed project will significantly advance the opportunity for a more effective and safer treatment of NPD, and likely other LSDs.

Public Health Relevance

The proposed research is relevant to public health and the NIH mission because it focuses on an unsolved medical problem: the safe and effective delivery of therapeutic enzymes for the treatment of fatal lysosomal disorders, such as the case of types A-B Niemann-Pick disease (NPD), in which we focus. Enzyme therapy is approved for NPD lung condition, but high and frequent dosage cause immune effects and resistance, and it is of no use (is not approved) for the brain condition. Through our original award we successfully enhanced the targeting of the enzyme to the lungs and brain, and in this renewal we will advance our platform toward translation by improving the therapeutic potential, lowering frequency of administration, and minimizing side effects, for a clinically relevant therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL098416-07
Application #
9324409
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Vuga, Louis Justine
Project Start
2010-04-01
Project End
2021-03-31
Budget Start
2017-04-06
Budget End
2018-03-31
Support Year
7
Fiscal Year
2017
Total Cost
$374,584
Indirect Cost
$124,584
Name
University of Maryland College Park
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Kim, Joshua; Sinha, Sauradeep; Solomon, Melani et al. (2017) Co-coating of receptor-targeted drug nanocarriers with anti-phagocytic moieties enhances specific tissue uptake versus non-specific phagocytic clearance. Biomaterials 147:14-25
Garnacho, Carmen; Dhami, Rajwinder; Solomon, Melani et al. (2017) Enhanced Delivery and Effects of Acid Sphingomyelinase by ICAM-1-Targeted Nanocarriers in Type B Niemann-Pick Disease Mice. Mol Ther 25:1686-1696
Solomon, Melani; Muro, Silvia (2017) Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives. Adv Drug Deliv Rev 118:109-134
Manthe, Rachel L; Muro, Silvia (2017) ICAM-1-Targeted Nanocarriers Attenuate Endothelial Release of Soluble ICAM-1, an Inflammatory Regulator. Bioeng Transl Med 2:109-119
Garnacho, Carmen; Muro, Silvia (2017) ICAM-1 targeting, intracellular trafficking, and functional activity of polymer nanocarriers coated with a fibrinogen-derived peptide for lysosomal enzyme replacement. J Drug Target 25:786-795
Serrano, Daniel; Manthe, Rachel L; Paul, Eden et al. (2016) How Carrier Size and Valency Modulate Receptor-Mediated Signaling: Understanding the Link between Binding and Endocytosis of ICAM-1-Targeted Carriers. Biomacromolecules 17:3127-3137
Ghaffarian, Rasa; Herrero, Edgar PĂ©rez; Oh, Hyuntaek et al. (2016) Chitosan-Alginate Microcapsules Provide Gastric Protection and Intestinal Release of ICAM-1-Targeting Nanocarriers, Enabling GI Targeting In Vivo. Adv Funct Mater 26:3382-3393
Long, Yan; Xu, Miao; Li, Rong et al. (2016) Induced Pluripotent Stem Cells for Disease Modeling and Evaluation of Therapeutics for Niemann-Pick Disease Type A. Stem Cells Transl Med 5:1644-1655
Ghaffarian, Rasa; Roki, Niksa; Abouzeid, Abraham et al. (2016) Intra- and trans-cellular delivery of enzymes by direct conjugation with non-multivalent anti-ICAM molecules. J Control Release 238:221-230
Rappaport, Jeff; Manthe, Rachel L; Solomon, Melani et al. (2016) A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders. Mol Pharm 13:357-368

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