Enzyme replacement with transferrin receptor-targeted α-L-iduronidase rescues brain pathology in mucopolysaccharidosis I mice

Kida, Sachiho; Koshimura, Yuri; Yoden, Eiji; Yoshioka, Atsushi; Morimoto, Hideto; Imakiire, Atsushi; Tanaka, Noboru; Tanaka, Shingo; Mori, Akira; Ito, Jun; Inoue, Asuka; Yamamoto, Ryûji; Minami, Kohtaro; Hirato, Tohru; Takahashi, Ken­ichi; Sonoda, Hidenori

doi:10.1016/j.omtm.2023.05.010

Cited by 13 publications

(10 citation statements)

References 35 publications

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“…Increases in LAMP-1 are used as a diagnostic marker for lysosomal storage disorders, such as MPS I. 37,38 Human CD3 staining within heterozygous and untreated mice showed no notable positive staining. The treated MPS I group had rare CD3 positive cells with lymphocyte morphology scattered throughout the sinusoids and portal triads (black arrows and insets) (Figure 4E) .…”

Section: Resultsmentioning

confidence: 99%

“…In fact, ongoing research is exploring the use of fusion IDUA proteins, such as IDUA-antibody fusion proteins or melanotransferrin linked peptide sequence to help shuttle IDUA across the BBB. 38,50,51 These innovative approaches hold promise for enhancing the delivery of the IDUA enzyme into the brain and CNS, potentially resulting in therapeutic IDUA levels and neurocognitive improvements. Employing these methods in engineered Tm cells would likely offer improved delivery across the BBB as well.…”

Section: Discussionmentioning

confidence: 99%

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Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders

Laoharawee,

Kleinboehl,

Jensen

et al. 2024

Preprint

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Enzymopathy disorders are the result of missing or defective enzymes. Amongst these enzymopathies, mucopolysaccharidosis type I, is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), ultimately causes toxic build-up of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T cells (Tm) migrate throughout the body's tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS. Our study indicates that genetically engineered Tm holds great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders

Laoharawee,

Kleinboehl,

Jensen

et al. 2024

Preprint

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“…We chose TfR1 as a target because of its high expression on the human BBB; its ability to mediate constitutive, ligand-independent receptor-mediated transcytosis (RMT) across the CNS vasculature (8)(9)(10)(11)(12); and its track record as a target to increase the delivery of biologics into the CNS of mice (13)(14)(15), nonhuman primates (NHPs) (16)(17)(18), and humans as investigational therapies (19)(20)(21)(22) and as an approved antibody-based therapeutic for Mucopolysaccharidosis type II (23). We first screened 7-mer-modified AAV9 capsid libraries for their ability to bind to human TfR1 in vitro.…”

Section: Introductionmentioning

confidence: 99%

An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery

Huang,

Chan,

Lou

et al. 2023

Preprint

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Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an AAV capsid, BI-hTFR1, that binds human Transferrin Receptor (TfR1), a protein expressed on the blood-brain barrier (BBB). BI-hTFR1 was actively transported across a human brain endothelial cell layer and, relative to AAV9, provided 40–50 times greater reporter expression in the CNS of humanTFRCknock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliverGBA1, mutations of which cause Gaucher disease and are linked to Parkinson’s disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9. These findings establish BI-hTFR1 as a promising vector for human CNS gene therapy.

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“…Although the BBB limits the transport of macromolecules between the blood and brain, certain endogenous peptides and proteins are capable of crossing via specific receptors expressed on the endothelial cell surface by receptor-mediated transcytosis . By exploiting this endogenous transport system, the delivery of intravenously injected protein drugs to the brain has been previously examined. − Pabinafusp alfa, a BBB-penetrating IDS-targeted transferrin receptor (TfR) generated by fusion with an antihuman TfR antibody, was successfully delivered to neurons in the brains of cynomolgus monkeys and MPS II model mice. It preserved neurological function in mice as determined by several experimental tests. ,, Pabinafusp alfa has been evaluated in clinical studies and is currently available for the treatment of patients with all types of MPS II in Japan, including the neuronopathic type. − …”

Section: Introductionmentioning

confidence: 99%

“… 8 By exploiting this endogenous transport system, the delivery of intravenously injected protein drugs to the brain has been previously examined. 9 − 21 Pabinafusp alfa, a BBB-penetrating IDS-targeted transferrin receptor (TfR) generated by fusion with an antihuman TfR antibody, was successfully delivered to neurons in the brains of cynomolgus monkeys and MPS II model mice. It preserved neurological function in mice as determined by several experimental tests.…”

Section: Introductionmentioning

confidence: 99%

Transferrin Receptor-Targeted Iduronate-2-sulfatase Penetrates the Blood-Retinal Barrier and Improves Retinopathy in Mucopolysaccharidosis II Mice

Imakiire,

Morimoto,

Suzuki

et al. 2023

Mol. Pharmaceutics

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Mucopolysaccharidoses (MPSs) make up a group of lysosomal storage diseases characterized by the aberrant accumulation of glycosaminoglycans throughout the body. Patients with MPSs display various signs and symptoms, such as retinopathy, which is also observed in patients with MPS II. Unfortunately, retinal disorders in MPS II are resistant to conventional intravenous enzyme-replacement therapy because the blood-retinal barrier (BRB) impedes drug penetration. In this study, we show that a fusion protein, designated pabinafusp alfa, consisting of an antihuman transferrin receptor antibody and iduronate-2-sulfatase (IDS), crosses the BRB and reaches the retina in a murine model of MPS II. We found that retinal function, as assessed by electroretinography (ERG) in MPS II mice, deteriorated with age. Early intervention with repeated intravenous treatment of pabinafusp alfa decreased heparan sulfate deposition in the retina, optic nerve, and visual cortex, thus preserving or even improving the ERG response in MPS II mice. Histological analysis further revealed that pabinafusp alfa mitigated the loss of the photoreceptor layer observed in diseased mice. In contrast, recombinant nonfused IDS failed to reach the retina and hardly affected the retinal disease. These results support the hypothesis that transferrin receptor-targeted IDS can penetrate the BRB, thereby ameliorating retinal dysfunction in MPS II.

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Enzyme replacement with transferrin receptor-targeted α-L-iduronidase rescues brain pathology in mucopolysaccharidosis I mice

Cited by 13 publications

References 35 publications

Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders

Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders

An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery

Transferrin Receptor-Targeted Iduronate-2-sulfatase Penetrates the Blood-Retinal Barrier and Improves Retinopathy in Mucopolysaccharidosis II Mice

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