Plasma and Red Blood Cell Membrane Accretion and Pharmacokinetics of RT001 (bis-Allylic 11,11-D2-Linoleic Acid Ethyl Ester) during Long Term Dosing in Patients

Brenna, J. Thomas; James, Genevieve; Midei, Mark; Heerinckx, Frederic; Atwal, Paldeep S.; Milner, Peter M.; Schmidt, Karsten; Ploeg, Lex Van der; Fielding, Robert M.; Shchepinov, Mikhail S.

doi:10.1016/j.xphs.2020.08.019

Cited by 16 publications

(26 citation statements)

References 33 publications

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“…Finally, we found that treatment with deuterium-reinforced linoleic acid (RT-001), a polyunsaturated fatty acid (PUFA) with deuterium at its bis-allylic site to inhibit lipid peroxidation, provided the most pronounced rescue effect on RAG01 (440%, Fig. 6h ) 18 , 24 – 26 . In contrast, normal linoleic acid exhibited a toxicity effect to RAG01 at high concentrations, which suggested the likely involvement of lipid peroxidation in the compromised cell viability observed on patient cells ( Fig.…”

Section: Resultsmentioning

confidence: 98%

Characterization of a patient-derived variant of GPX4 for precision therapy

et al. 2021

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GPX4, as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia (SSMD). With structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants, and a deuterated PUFA were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations for therapeutic strategies targeting GPX4.

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Section: Resultsmentioning

confidence: 98%

Characterization of a patient-derived variant of GPX4 for precision therapy

et al. 2021

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“…In addition, future studies will further examine the mechanism(s) for improved deformability. Finally, as other clinical settings besides transfusion result from underlying mechanism(s) involving oxidative stress [e.g., hemolytic crises due to glucose-6-phosphate deficiency ( Gerli et al, 1982 ) or sickle cell disease ( Wu et al, 2016 )], and because deuterated fatty acids involve stable isotopes and are not radioactive, they may have other applications as therapeutics in other clinical scenarios ( Shchepinov, 2007 ; Brenna et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Deuterated Linoleic Acid Attenuates the RBC Storage Lesion in a Mouse Model of Poor RBC Storage

et al. 2022

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Background: Long-chain polyunsaturated fatty acids (PUFAs) are important modulators of red blood cell (RBC) rheology. Dietary PUFAs are readily incorporated into the RBC membrane, improving RBC deformability, fluidity, and hydration. However, enriching the lipid membrane with PUFAs increases the potential for peroxidation in oxidative environments (e.g., refrigerated storage), resulting in membrane damage. Substitution of bis-allylic hydrogens with deuterium ions in PUFAs decreases hydrogen abstraction, thereby inhibiting peroxidation. If lipid peroxidation is a causal factor in the RBC storage lesion, incorporation of deuterated linoleic acid (DLA) into the RBC membrane should decrease lipid peroxidation, thereby improving RBC lifespan, deformability, filterability, and post-transfusion recovery (PTR) after cold storage.Study Design and Methods: Mice associated with good (C57BL/6J) and poor (FVB) RBC storage quality received diets containing 11,11-D2-LA Ethyl Ester (1.0 g/100 g diet; deuterated linoleic acid) or non-deuterated LA Ethyl Ester (control) for 8 weeks. Deformability, filterability, lipidomics, and lipid peroxidation markers were evaluated in fresh and stored RBCs.Results: DLA was incorporated into RBC membranes in both mouse strains. DLA diet decreased lipid peroxidation (malondialdehyde) by 25.4 and 31% percent in C57 mice and 12.9 and 79.9% in FVB mice before and after cold storage, respectively. In FVB, but not C57 mice, deformability filterability, and post-transfusion recovery were significantly improved.Discussion: In a mouse model of poor RBC storage, with elevated reactive oxygen species production, DLA attenuated lipid peroxidation and significantly improved RBC storage quality.

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“…11,11-D2-octadeca-9 Z ,12 Z -enoic acid is a drug candidate (D2-linoleic acid; D2-Lin) produced by total organic synthesis. It has been used in ongoing human clinical and expanded use protocols as the first case of a novel class of oxidation-resistant, membrane-resident drugs . Ru catalysis has enabled scalable deuteration of the bis -allylic positions of highly unsaturated fatty acids (HUFA, ≥3 double bonds) and expands the range of D-reinforced PUFA drugs beyond the original D2-Lin.…”

Section: Introductionmentioning

confidence: 99%

“…11,11-D2-Lin inhibits H abstraction in tocopherol-mediated radical chain oxidation − Preliminary data from clinical trials show that D2-Lin consumed orally at multigram levels per day are safe, and early work indicates efficacy against infantile neuroaxonal dystrophy (INAD). , Strikingly, very recent data show that about 50% substitution of endogenous D0-DHA with D-DHA completely protects mouse retina against Fe-induced peroxidation that otherwise leads to blindness …”

Section: Introductionmentioning

confidence: 99%

Quantitative High-Field NMR- and Mass Spectrometry-Based Fatty Acid Sequencing Reveals Internal Structure in Ru-Catalyzed Deuteration of Docosahexaenoic Acid

et al. 2022

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Ru-based catalysis results in highly unsaturated fatty acid (HUFA) ethyl esters (EE) deuterated to various extents. The products carry 2H (D) mainly at their bis-allylic positions, where they are resistant to autoxidation compared to natural HUFA and are promising as neurological and retinal drugs. We characterized the extent of deuteration at each allylic position of docosa-4,7,10,13,16,19-hexaenoic acid deuterated to completion at bis-allylic and allylic positions (D-DHA) by two-dimensional (2D) and high-field (600 and 950 MHz) NMR. In separate experiments, the kinetics of docosahexaenoic acid (DHA) EE deuteration was evaluated using Paternò–Büchi (PB) reaction tandem mass spectrometry (MS/MS) analysis, enabling deuteration to be quantitatively characterized for isotopologues (D0–D14 DHA) at each internal allylic position. NMR analysis shows that the net deuteration of the isotopologue mixture is about 94% at the bis-allylic positions, and less than 1% remained as the protiated −CH2–. MS analysis shows that deuteration kinetics follow an increasing curve at bis-allylic positions with higher rate for internal bis-allylic positions. Percent D of bis-allylic positions increases linearly from D1 to D9 in which all internal bis-allylic positions (C9, C12, C15) deuterate uniformly and more rapidly than external bis-allylic positions (C6, C18). The mono-allylic positions near the methyl end (C21) show a steep increase of D only after the D10 isotopologue has been deuterated to >90%, while the mono-allylic position near the carboxyl position, C3, deuterates last and least. These data establish detailed methods for the characterization of Ru-catalyzed deuteration of HUFA as well as the phenomenological reaction kinetics as net product is formed.

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Plasma and Red Blood Cell Membrane Accretion and Pharmacokinetics of RT001 (bis-Allylic 11,11-D2-Linoleic Acid Ethyl Ester) during Long Term Dosing in Patients

Cited by 16 publications

References 33 publications

Characterization of a patient-derived variant of GPX4 for precision therapy

Characterization of a patient-derived variant of GPX4 for precision therapy

Deuterated Linoleic Acid Attenuates the RBC Storage Lesion in a Mouse Model of Poor RBC Storage

Quantitative High-Field NMR- and Mass Spectrometry-Based Fatty Acid Sequencing Reveals Internal Structure in Ru-Catalyzed Deuteration of Docosahexaenoic Acid

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