Dataset Information

Treatment of infantile neuroaxonal dystrophy with RT001: A di-deuterated ethyl ester of linoleic acid: Report of two cases.

ABSTRACT:

Background

Infantile neuroaxonal dystrophy (INAD) is a rare, autosomal recessive disease due to defects in PLA2G6 and is associated with lipid peroxidation. RT001 is a di-deuterated form of linoleic acid that protects lipids from oxidative damage.

Methods

We evaluated the pharmacokinetics (PK), safety, and effectiveness of RT001 in two subjects with INAD (subject 1: 34 months; subject 2: 10 months). After screening and baseline evaluations, subjects received 1.8 g of RT001 BD. PK analysis and clinical evaluations were made periodically.

Main findings

Plasma levels of deuterated linoleic acid (D2-LA), deuterated arachidonic acid (D2-AA), D2-LA to total LA, and D2-AA to total AA ratios were measured. The targeted plasma D2-LA ratio (>20%) was achieved by month 1 and maintained throughout the study. RBC AA-ratios were 0.11 and 0.18 at 6 months for subjects 1 and 2; respectively. No treatment-related adverse events occurred. Limited slowing of disease progression and some return of lost developmental milestones were seen.

Conclusions

Oral RT001 was administered safely in two subjects with INAD. Early findings suggest that the compound was well tolerated, metabolized and incorporated in the RBC membrane. A clinical trial is underway to assess efficacy.

SUBMITTER: Adams D

PROVIDER: S-EPMC7358664 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Treatment of infantile neuroaxonal dystrophy with RT001: A di-deuterated ethyl ester of linoleic acid: Report of two cases.

Adams Darius D Midei Mark M Dastgir Jahannaz J Flora Christina C Molinari Robert J RJ Heerinckx Frederic F Endemann Sarah S Atwal Paldeep P Milner Peter P Shchepinov Mikhail S MS

JIMD reports 20200327 1

<h4>Background</h4>Infantile neuroaxonal dystrophy (INAD) is a rare, autosomal recessive disease due to defects in <i>PLA2G6</i> and is associated with lipid peroxidation. RT001 is a di-deuterated form of linoleic acid that protects lipids from oxidative damage.<h4>Methods</h4>We evaluated the pharmacokinetics (PK), safety, and effectiveness of RT001 in two subjects with INAD (subject 1: 34 months; subject 2: 10 months). After screening and baseline evaluations, subjects received 1.8 g of RT001 ...[more]

PMID: 32685351

Similar Datasets

Project description:BackgroundInfantile neuroaxonal dystrophy (INAD) is a rapidly progressive neurodegenerative disorder of early onset causing premature death. It results from biallelic pathogenic variants in PLA2G6, which encodes a calcium-independent phospholipase A2.ObjectiveWe aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings.Materials and methodsWe comprehensively analyzed the charts of 28 patients: 16 patients from Riyadh, Saudi Arabia, 8 patients from North and South America and 4 patients from Europe with a molecularly confirmed diagnosis of PLA2G6-associated neurodegeneration (PLAN) and a clinical history consistent with INAD.ResultsIn our cohort, speech impairment and loss of gross motor milestones were the earliest signs of the disease. As the disease progressed, loss of fine motor milestones and bulbar dysfunction were observed. Temporo-frontal function was among the last of the milestones to be lost. Appendicular spastic hypertonia, axial hypotonia, and hyperreflexia were common neurological findings. Other common clinical findings include nystagmus (60.7%), seizures (42.9%), gastrointestinal disease (42.9%), skeletal deformities (35.7%), and strabismus (28.6%). Cerebellar atrophy and elevations in serum AST and LDH levels were consistent features of INAD. There was a statistically significant difference when comparing patients with non-sense/truncating variants compared with missense/in-frame deletions in the time of initial concern (p = 0.04), initial loss of language (p = 0.001), initial loss of fine motor skills (p = 0.009), and initial loss of bulbar skills (p = 0.007).ConclusionINAD is an ultra-rare neurodegenerative disorder that presents in early childhood, with a relentlessly progressive clinical course. Knowledge of the natural history of INAD may serve as a resource for healthcare providers to develop a targeted care plan and may facilitate the design of clinical trials to treat this disease.

Project description:BackgroundINAD is an autosomal recessive neurogenetic disorder caused by biallelic pathogenic variants in PLA2G6. The downstream enzyme, iPLA2, plays a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids. The clinical presentation occurs between 6 months and 3 years with global developmental regression, hypotonia, and progressive spastic tetraparesis. Progression is often rapid, resulting in severe spasticity, visual impairment, and cognitive decline, with many children not surviving past the first decade of life. To date, no accepted tool for assessing the severity of INAD exists; other commonly used scales (e.g. CHOP-INTEND, Modified Ashworth, Hammersmith Functional Motor Scale) do not accurately gauge the current severity of INAD, nor are they sensitive/specific enough to monitor disease progression. Finally, these other scales are not appropriate, because they do not address the combination of CNS, peripheral nerve, and visual pathology that occurs in children with INAD.MethodsWe have developed and validated a structured neurological examination for INAD (scored out of 80). The examination includes six main categories of pediatric developmental evaluation: 1) gross motor-and-truncal-stability skills, 2) fine motor skills, 3) bulbar function, 4) ocular function, 5) temporo-frontal function, and, 6) Functional evaluation of the autonomic nervous system. A cohort of patients diagnosed with INAD were followed prospectively to validate the score against disease severity and disease progression.ResultsWe show significant correlation between the total neurological assessment score and months since symptom onset with a statistically significant (p = 6.7 × 10- 07) correlation between assessment score and disease onset. As hypothesized, the coefficient of months-since-symptom-onset is strongly negative, indicating a negative correlation between total score and months since symptom onset.ConclusionWe have developed and validated a novel neurological assessment score in INAD that demonstrates strong correlation with disease severity and disease progression.

Dataset Information

Treatment of infantile neuroaxonal dystrophy with RT001: A di-deuterated ethyl ester of linoleic acid: Report of two cases.

Background

Methods

Main findings

Conclusions

Publications

Treatment of infantile neuroaxonal dystrophy with RT001: A di-deuterated ethyl ester of linoleic acid: Report of two cases.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets