The Protein Translocation Defect of MCT8L291R Is Rescued by Sodium Phenylbutyrate

Braun, Doreen; Schweizer, Ulrich

doi:10.1159/000507439

Cited by 6 publications

(1 citation statement)

References 45 publications

(75 reference statements)

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“…Since the first compassionate use trial with LT4 and PTU (propylthiouracil) in 2008, 19 the development of therapies for MCT8 deficiency has recently gained momentum. Treatment strategies range from symptomatic interventions, 15,20 replacement therapies 19,[21][22][23][24][25][26] and chaperone rescue 27 to gene-modifying approaches. 28,29 Clinical outcome measures for all these studies vary widely, often consisting of surrogate parameters.…”

Section: Introductionmentioning

confidence: 99%

Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review

Wilpert,

Tonduti,

Vaia

et al. 2023

NDT

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Introduction The SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients’ perspective and identify clinical endpoints that are clinically relevant to their daily life. Methods We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials. Results We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5–9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints. Discussion We recommend that future trials should define a relevant improvement in “development” and/or other patient-relevant outcomes compared to natural history as treatment goals.

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Section: Introductionmentioning

confidence: 99%

Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review

Wilpert,

Tonduti,

Vaia

et al. 2023

NDT

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Circular PCR as an efficient and precise umbrella of methods for the generation of circular dsDNA with staggered nicks: Mechanism and types

Ferro-Gallego,

Vila-Sanjurjo,

Valderrama Pereira

et al. 2024

Biology Methods and Protocols

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Here, we introduce the highly versatile circular PCR (CiPCR) technique, propose a mechanism of action, and describe a number of examples demonstrating the versatility of this technique. CiPCR takes place between two fragments of dsDNA with two homologous regions, as long as one of the fragments carries said regions at its 3´ and 5´ ends. Upon hybridization, elongation by a polymerase occurs from all 3´ ends continuously until a 5´ end is reached, leading to stable circular dsDNA with staggered nicks. When both dsDNA fragments carry the homology at their 3´ and 5´ ends (Type I CiPCR), all four 3' ends effectively prime amplification of the intervening region and CiPCR products can function as template during the reaction. In contrast, when only one of the two dsDNA fragments carries the homologous regions at its 3´ and 5´ ends and the other carries such regions internally (Type II CiPCR), only two 3´ ends can be amplified and CiPCR products possess no template activity. We demonstrate the applicability of both CiPCR types via well-illustrated experimental examples. CiPCR is well adapted to the quick resolution of most of the molecular cloning challenges faced by the biology/biomedicine laboratory, including the generation of insertions, deletions, and mutations.

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Glycerol Phenylbutyrate Treatment of 2 Patients With Monocarboxylate Transporter 8 Deficiency

Zung,

Sonntag,

Schweizer

et al. 2024

The Journal of Clinical Endocrinology &Amp; Metabolism

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Abstarct Context Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. Objective We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. Methods We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, Vital signs, anthropometric measurements and neurocognitive functions. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P321L mutation. The effects of GPB were compared to the effects of DITPA and TRIAC, thyromimetic medications that the patients received in the past. Results NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment reduced high T3 and increased low T4 levels. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, in hyperreflexia score and in cognitive functions. Serum metabolites did not exceed the toxic range but elevated liver transaminases were observed. Conclusions In the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body-mass index, with minor neuro-developmental changes.

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The Protein Translocation Defect of MCT8L291R Is Rescued by Sodium Phenylbutyrate

Cited by 6 publications

References 45 publications

Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review

Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review

Circular PCR as an efficient and precise umbrella of methods for the generation of circular dsDNA with staggered nicks: Mechanism and types

Glycerol Phenylbutyrate Treatment of 2 Patients With Monocarboxylate Transporter 8 Deficiency

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