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Linear Cyclodextrin Polymer Prodrugs as Novel Therapeutics for Niemann-Pick Type C1 Disorder.

ABSTRACT: Niemann-Pick Type C1 disorder (NPC) is a rare lysosomal storage disease characterized by the accumulation of cholesterol in lysosomes. NPC has no FDA approved treatments yet, however 2-hydroxypropyl-?-cyclodextrin (HP?CD) has shown efficacy for treating the disease in both mouse and feline NPC models and is currently being investigated in late stage clinical trials. Despite promising results, therapeutic use of HP?CD is limited by the need for high doses, ototoxicity and intrathecal administration. These limitations can be attributed to its poor pharmacokinetic profile. In the attempt to overcome these limitations, we have designed a ?-cyclodextrin (?CD) based polymer prodrugs (ORX-301) for an enhanced pharmacokinetic and biodistribution profile, which in turn can potentially provide an improved efficacy at lower doses. We demonstrated that subcutaneously injected ORX-301 extended the mean lifespan of NPC mice at a dosage 5-fold lower (800?mg/kg, body weight) the HP?CD dose proven efficacious (4000?mg/kg). We also show that ORX-301 penetrates the blood brain barrier and counteracts neurological impairment. These properties represent a substantial improvement and appear to overcome major limitations of presently available ?CD-based therapy, demonstrating that this novel prodrug is a valuable alternative/complement for existing therapies.

SUBMITTER: Kulkarni A

PROVIDER: S-EPMC6015065 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Linear Cyclodextrin Polymer Prodrugs as Novel Therapeutics for Niemann-Pick Type C1 Disorder.

Kulkarni Aditya A Caporali Paola P Dolas Atul A Johny Soniya S Goyal Sandeep S Dragotto Jessica J Macone Alberto A Jayaraman Ramesh R Fiorenza Maria Teresa MT

Scientific reports 20180622 1

Niemann-Pick Type C1 disorder (NPC) is a rare lysosomal storage disease characterized by the accumulation of cholesterol in lysosomes. NPC has no FDA approved treatments yet, however 2-hydroxypropyl-β-cyclodextrin (HPβCD) has shown efficacy for treating the disease in both mouse and feline NPC models and is currently being investigated in late stage clinical trials. Despite promising results, therapeutic use of HPβCD is limited by the need for high doses, ototoxicity and intrathecal administrati ...[more]

PMID: 29934581

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Project description:OBJECTIVES:The aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ß-cyclodextrin) may be more appropriately monitored and understood. DESIGN:Fifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients. RESULTS:Over half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4 kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function. CONCLUSIONS:This is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype.

Dataset Information

Linear Cyclodextrin Polymer Prodrugs as Novel Therapeutics for Niemann-Pick Type C1 Disorder.

Publications

Linear Cyclodextrin Polymer Prodrugs as Novel Therapeutics for Niemann-Pick Type C1 Disorder.

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