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.

The Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS)

“…In our experience, the rare nature of INAD make it a challenging diagnosis, and families are often on a diagnostic odyssey despite parental and medical awareness the child is not developing normally. This delay between symptom onset and diagnosis is in line with other pediatric genetic diseases (2,11,(13)(14)(15)(16)(17)(18)(19).…”

“…however longitudinal monitoring which includes rate of progression to assess whether underlying genotype is affecting the phenotype should be performed at a future date to con rm this prior observation. Mechanistically regarding genotype-phenotype correlations in biochemical genetics, more severe mutations tend to result in less functional enzyme and thus infer a more severe phenotype; this is observed in other genetic disorders of enzymatic function and metabolism (2,(20)(21)(22)(23)(24).…”

“…Infantile neuroaxonal dystrophy (INAD, NBIA2A; MIM# 256600) is a major subtype of PLA2G6-associated neurodegeneration (PLAN), a heterogenous group of clinical disorders with varying severity comprising INAD, atypical neuroaxonal dystrophy (NBIA2B; MIM# 610217) and adult-onset dystonia-parkinsonism (PARK14; MIM# 612953). PLAN is caused by biallelic pathogenic variants in PLA2G6, and the speci c phenotype of PLAN is based on various clinical, genotype-phenotype, neurophysiologic, radiographic, and laboratory features (1,2).…”

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

“…There is some basis to recommend DHA supplements, especially given their low toxicity [ 124 ]. A clinical trial using deutered polyunsaturated fatty acids is underway to assess efficacy; they may be able to partially rescue the locomotor problems and restore mitochondrial potential, by inhibiting lipid peroxidation [ 125 , 126 ]. In addition, early anti-inflammatory therapy may help to slow down the progression of cerebellar atrophy in PLAN patients.…”

The Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS)

“…Infantile neuroaxonal dystrophy (INAD, NBIA2A; MIM# 256600) is a major subtype of PLA2G6associated neurodegeneration (PLAN), a heterogenous group of clinical disorders with varying severity comprising INAD, atypical neuroaxonal dystrophy (NBIA2B; MIM# 610217) and adult-onset dystonia-parkinsonism (PARK14; MIM# 612953). PLAN is caused by biallelic pathogenic variants in PLA2G6, and determining the specific phenotype of PLAN is based on various clinical, genotypephenotype, neurophysiologic, radiographic, and laboratory features (1,2).…”