Mucopolysaccharidosis I-Hurler (MPS I-H) is a lysosomal storage disease caused by severe alpha-L-iduronidase deficiency that results in the lysosomal accumulation of glycosaminoglycans (GAGs). MPS I-H is caused by nonsense mutations (also known as premature termination codons or PTCs) in ~70% of patients of European descent. Nonsense suppression therapy is a novel approach to treat diseases by suppressing translation termination at PTCs in order to restore functional protein. We hypothesize that nonsense suppression therapy will reduce MPS I-H disease progression, particularly in tissues that do not respond well to current therapeutic approaches, including the brain, heart valves, cornea, and bone. PTC Therapeutics, Inc. has identified two new nonsense suppression drugs, PTC415 and PTC418, with better brain exposure compared to their previously developed nonsense suppression drug, PTC124. We hypothesize that PTC415 and PTC418 may moderate progression of MPS I-H to a greater degree than PTC124, particularly in the brain. To test this hypothesis, we will pursue the following Specific Aims:
Specific Aim 1 : Examine the effectiveness of two new nonsense suppression compounds with enhanced brain distribution in Idua-W402X mice. In this aim, we will investigate the efficacy and dose response of PTC415 and PTC418 compared to PTC124. We will first examine the ability of these drugs to restore alpha-L-iduronidase activity and reduce GAG accumulation in immortalized mouse embryonic fibroblasts (MEFs) derived from Idua-W402X mice. We will complement those in vitro studies with short-term in vivo dose response studies to determine the drug doses that most effectively restore alpha-L-iduronidase activity and reduce GAG accumulation in various tissues (including brain, heart, spleen, and liver) of Idua-W402X mice.
Specific Aim 2 : Determine whether long-term administration of nonsense suppression drugs can sustain GAG reduction and reduce progression of the MPS I-H phenotype in Idua-W402X mice. Based on the results of Aim 1, we will administer PTC415 or PTC418 to Idua-W402X mice for 28-week studies and then evaluate the ability of the drug to alleviate progression of the MPS I-H phenotype compared to PTC124. This will be accomplished using a battery of assays that we recently showed could provide good endpoints to assess long-term therapeutic benefit. The endpoints of this long-term in vivo study will be used to: 1) determine whether a partial restoration of alpha-L-iduronidase activity and a reduction of GAG storage can be sustained in a broad range of tissues;2) evaluate whether several progressive aspects of the MPS I-H phenotype are moderated in Idua-W402X mice, with a special focus on brain, heart, and bone defects;and 3) determine whether long-term administration is well tolerated. We anticipate that if one of these new nonsense suppression drugs is effective in moderating MPS I-H progression in Idua-W402X mice, we will pursue IND status for that drug as a treatment for MPS I-H.

Public Health Relevance

This application will test whether two new drugs that suppress translation termination at nonsense mutations can restore enough functional protein to reduce the disease progression of mucopolysaccharidosis I-Hurler (MPS I-H), a disease frequently caused by nonsense mutations. These drugs penetrate brain tissue and may relieve MPS I-H neurological defects. In addition, these drugs may also alleviate other MPS I-H defects that are resistant to current MPS I-H treatments.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Morris, Jill A
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University of Alabama Birmingham
Schools of Medicine
United States
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Xue, Xiaojiao; Mutyam, Venkateshwar; Thakerar, Amita et al. (2017) Identification of the amino acids inserted during suppression of CFTR nonsense mutations and determination of their functional consequences. Hum Mol Genet 26:3116-3129
Roy, Bijoyita; Friesen, Westley J; Tomizawa, Yuki et al. (2016) Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression. Proc Natl Acad Sci U S A 113:12508-12513
Keeling, Kim M (2016) Nonsense Suppression as an Approach to Treat Lysosomal Storage Diseases. Diseases 4:
Gunn, Gwen; Dai, Yanying; Du, Ming et al. (2014) Long-term nonsense suppression therapy moderates MPS I-H disease progression. Mol Genet Metab 111:374-381
Keeling, Kim M; Xue, Xiaojiao; Gunn, Gwen et al. (2014) Therapeutics based on stop codon readthrough. Annu Rev Genomics Hum Genet 15:371-94