# Targeted replacement of defective lysosomal enzymes in the lung and brain

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2020 · $402,899

## Abstract

SUMMARY
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.

## Key facts

- **NIH application ID:** 9898422
- **Project number:** 5R01HL098416-10
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** SILVIA MURO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,899
- **Award type:** 5
- **Project period:** 2010-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898422

## Citation

> US National Institutes of Health, RePORTER application 9898422, Targeted replacement of defective lysosomal enzymes in the lung and brain (5R01HL098416-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9898422. Licensed CC0.

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