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Cited by 111Lysosomal Storage Disorders ResearchRNA Interference and Gene DeliveryNanoparticle-Based Drug Delivery

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Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as Compared to Enzyme Replacement Therapy

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DeRosa, Frank, Smith, Lianne, Shen, Yinghua, Huang, Yan, Pan, Jing, Xie, Hongsheng, Yahalom, Barak, Heartlein, Michael W.·2019·Molecular Therapy
DOI 10.1016/j.ymthe.2019.03.001PMC PMC6453518
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Abstract

Fabry disease is a lysosomal storage disorder caused by the deficiency of α-galactosidase A. Enzyme deficiency results in a progressive decline in renal and cardiac function, leading to cardiomyopathy and end-stage renal disease. Current treatments available, including enzyme replacement therapies, have provided significant benefit to patients; however, unmet medical needs remain. mRNA therapy, with drug-like properties, has the unique ability to produce therapeutic proteins endogenously. Here we describe the sustained delivery of therapeutic human α-galactosidase protein in vivo via nanoparticle-formulated mRNA in mouse and non-human primate, with a demonstration of efficacy through clinically relevant biomarker reduction in a mouse Fabry disease model. Multi-component nanoparticles formulated with lipids and lipid-like materials were developed for the delivery of mRNA encoding human α-galactosidase protein. Upon delivery of human GLA mRNA to mice, serum GLA protein levels reached as high as ∼1,330-fold over normal physiological values.

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Figure 1 Quantification of Secreted Human α-Galactosidase Protein Levels (A) Quantification of secreted human α-galactosidase (hGLA) protein levels as measured via ELISA (N = 4 mice per group, error bars represent SD). The protein detected is a result of its production from hGLA mRNA delivered intravenously via a single dose of lipid nanoparticles (1.0 mg/kg encapsulated hGLA mRNA) over time (72 h). Aliquots of mouse serum were collected at the designated time points. (B) Comparison of hGLA protein levels after treatment with either hGLA mRNA LNPs (MRT) or direct injection of hGLA protein (ERT), as measured by ELISA. A prolonged exposure of hGLA protein is achieved when it is derived from hGLA mRNA. Aliquots of mouse serum were collected at the designated time points. All data are mean ± SD.
Figure 1 Quantification of Secreted Human α-Galactosidase Protein Levels (A) Quantification of secreted human α-galactosidase (hGLA) protein levels as measured via ELISA (N = 4 mice per group, error bars represent SD). The protein detected is a result of its production from hGLA mRNA delivered intravenously via a single dose of lipid nanoparticles (1.0 mg/kg encapsulated hGLA mRNA) over time (72 h). Aliquots of mouse serum were collected at the designated time points. (B) Comparison of hGLA protein levels after treatment with either hGLA mRNA LNPs (MRT) or direct injection of hGLA protein (ERT), as measured by ELISA. A prolonged exposure of hGLA protein is achieved when it is derived from hGLA mRNA. Aliquots of mouse serum were collected at the designated time points. All data are mean ± SD.CC BY-NC-ND · PubMed Central
Figure 2 Quantification of hGLA Protein Levels Quantification of hGLA protein levels in selected organs as measured by ELISA (N = 4 mice per group, error bars represent SD). The protein detected is a result of its production, over a period of 72 h, from hGLA mRNA delivered intravenously via a single dose of lipid nanoparticles (1.0 mg/kg encapsulated hGLA mRNA). Tissues were harvested at the designated time points, homogenized, and analyzed. All data are mean ± SD.
Figure 2 Quantification of hGLA Protein Levels Quantification of hGLA protein levels in selected organs as measured by ELISA (N = 4 mice per group, error bars represent SD). The protein detected is a result of its production, over a period of 72 h, from hGLA mRNA delivered intravenously via a single dose of lipid nanoparticles (1.0 mg/kg encapsulated hGLA mRNA). Tissues were harvested at the designated time points, homogenized, and analyzed. All data are mean ± SD.CC BY-NC-ND · PubMed Central
Figure 3 Detection of MRT-Derived Human GLA Protein within Liver and Kidney via Immunohistochemical Staining Positive staining in livers was observed in hepatocytes as well as sinusoidal cells. Successful detection of hGLA protein in kidneys was also observed. No positive detection of hGLA protein was observed in untreated control tissues. Scale bars, 700 μm (top) and 200 μm (bottom).
Figure 3 Detection of MRT-Derived Human GLA Protein within Liver and Kidney via Immunohistochemical Staining Positive staining in livers was observed in hepatocytes as well as sinusoidal cells. Successful detection of hGLA protein in kidneys was also observed. No positive detection of hGLA protein was observed in untreated control tissues. Scale bars, 700 μm (top) and 200 μm (bottom).CC BY-NC-ND · PubMed Central
Figure 4 Immunofluorescent Co-localization Studies Performed on Kidneys Immunofluorescent co-localization studies performed on kidneys of wild-type mice 24 h after treatment with hGLA MRT (1.0 mg/kg). MRT-derived hGLA protein was successfully detected within intracellular vesicles (green). Lysosomal-associated membrane protein LAMP-1 staining was achieved (red). Nuclei of cells were detected via DAPI staining (blue). An overlay of all three staining methods resulted in the successful determination of lysosomal localization of the hGLA protein within the kidneys (yellow). White arrows indicate intracellular vesicles. Scale bar, 50 μm.
Figure 4 Immunofluorescent Co-localization Studies Performed on Kidneys Immunofluorescent co-localization studies performed on kidneys of wild-type mice 24 h after treatment with hGLA MRT (1.0 mg/kg). MRT-derived hGLA protein was successfully detected within intracellular vesicles (green). Lysosomal-associated membrane protein LAMP-1 staining was achieved (red). Nuclei of cells were detected via DAPI staining (blue). An overlay of all three staining methods resulted in the successful determination of lysosomal localization of the hGLA protein within the kidneys (yellow). White arrows indicate intracellular vesicles. Scale bar, 50 μm.CC BY-NC-ND · PubMed Central
Figure 5 Quantification of Secreted hGLA Protein Levels in Male Marmosets Quantification of secreted hGLA protein levels in male marmosets as measured via ELISA (N = 2 marmosets, error bars represent SD). The protein detected is a result of its production from hGLA mRNA delivered intravenously via a single dose of lipid nanoparticles (0.10 mg/kg encapsulated hGLA mRNA). The dotted line represents pre-dose background levels due to cross-reactivity with monkey GLA protein. All data are mean ± SD.
Figure 5 Quantification of Secreted hGLA Protein Levels in Male Marmosets Quantification of secreted hGLA protein levels in male marmosets as measured via ELISA (N = 2 marmosets, error bars represent SD). The protein detected is a result of its production from hGLA mRNA delivered intravenously via a single dose of lipid nanoparticles (0.10 mg/kg encapsulated hGLA mRNA). The dotted line represents pre-dose background levels due to cross-reactivity with monkey GLA protein. All data are mean ± SD.CC BY-NC-ND · PubMed Central
Figure 6 Quantification of Gb3 and lyso-Gb3 Biomarkers in the Kidneys and Hearts of Treated GLA-KO Mice Levels of Gb3 and lyso-Gb3 were measured 1 week post-administration of either hGLA ERT or hGLA MRT (N = 4 mice per group, error bars represent SD). Enhanced biomarker reduction was observed for treatment with MRT as compared to ERT after a single-dose administration. Data were normalized to untreated mice and represented as a percentage of accumulated levels in untreated kidney and heart. Statistical analysis: ns, not significant; *p < 0.05 and ***p < 0.001. All data are mean ± SD.
Figure 6 Quantification of Gb3 and lyso-Gb3 Biomarkers in the Kidneys and Hearts of Treated GLA-KO Mice Levels of Gb3 and lyso-Gb3 were measured 1 week post-administration of either hGLA ERT or hGLA MRT (N = 4 mice per group, error bars represent SD). Enhanced biomarker reduction was observed for treatment with MRT as compared to ERT after a single-dose administration. Data were normalized to untreated mice and represented as a percentage of accumulated levels in untreated kidney and heart. Statistical analysis: ns, not significant; *p < 0.05 and ***p < 0.001. All data are mean ± SD.CC BY-NC-ND · PubMed Central
Figure 7 Quantification of Gb3 and lyso-Gb3 Biomarkers in the Kidneys and Hearts of Treated GLA-KO Mice after Multi-dose Regimens for hGLA ERT (Q1W × 8) and hGLA MRT (Q1M × 2) Levels of Gb3 and lyso-Gb3 were measured 1 week post-final administration of hGLA ERT and 28 days post-final administration of hGLA MRT (N = 5 mice per group, error bars represent SD). Similar biomarker reduction was observed for treatment with monthly MRT dosing as compared to weekly ERT dosing. Data were normalized to untreated mice and represented as a percentage of accumulated levels in untreated kidney and heart. Statistical analysis: ns, not significant; *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. All data are mean ± SD.
Figure 7 Quantification of Gb3 and lyso-Gb3 Biomarkers in the Kidneys and Hearts of Treated GLA-KO Mice after Multi-dose Regimens for hGLA ERT (Q1W × 8) and hGLA MRT (Q1M × 2) Levels of Gb3 and lyso-Gb3 were measured 1 week post-final administration of hGLA ERT and 28 days post-final administration of hGLA MRT (N = 5 mice per group, error bars represent SD). Similar biomarker reduction was observed for treatment with monthly MRT dosing as compared to weekly ERT dosing. Data were normalized to untreated mice and represented as a percentage of accumulated levels in untreated kidney and heart. Statistical analysis: ns, not significant; *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. All data are mean ± SD.CC BY-NC-ND · PubMed Central

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Metadata

Authors
DeRosa, F., Smith, L., Shen, Y., Huang, Y., Pan, J., Xie, H., Yahalom, B., & Heartlein, M. W.
Affiliations
  • Translate Bio (United States) (US)
  • Shire (United States) (US)
Corresponding author
Heartlein, Michael W.
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2019-04
Volume
27
Issue
4
Pages
878-889
ISSN
1525-0016 (ISSN-L)
DOI
10.1016/j.ymthe.2019.03.001
PMC
PMC6453518
OpenAlex
W2922121037
Cited by
111
References
68
Citations by year
2026: 7 · 2025: 14 · 2024: 18 · 2023: 21 · 2022: 19 · 2021: 14 · 2020: 13 · 2019: 5
FWCI
8.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Shire
Topics
  • Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
Fabry disease, alpha-galactosidase A, mRNA therapeutics, sustained protein delivery, enzyme replacement therapy, lysosomal storage disease, nonhuman primate model
MeSH terms
alpha-Galactosidase, Fabry Disease, Animals, Callithrix, Disease Models, Animal, Drug Compounding, Female, Humans, Kidney, Lipids, Liver, Male, RNA, Messenger, Drug Delivery Systems, Treatment Outcome, Mice, Knockout, Mice, Nanoparticles, Gene Knockout Techniques, Enzyme Replacement Therapy

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