Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes

Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes

Accepted Manuscript Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes Stefan Groeneweg, Robin P. ...

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Accepted Manuscript Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes Stefan Groeneweg, Robin P. Peeters, Theo J. Visser, W. Edward Visser PII:

S0303-7207(17)30116-8

DOI:

10.1016/j.mce.2017.02.029

Reference:

MCE 9856

To appear in:

Molecular and Cellular Endocrinology

Received Date: 9 January 2017 Revised Date:

17 February 2017

Accepted Date: 18 February 2017

Please cite this article as: Groeneweg, S., Peeters, R.P., Visser, T.J., Visser, W.E., Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes, Molecular and Cellular Endocrinology (2017), doi: 10.1016/j.mce.2017.02.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Thyroid hormone analogue therapy in RTH syndromes

Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes Stefan Groeneweg, Robin P. Peeters, Theo J. Visser, W. Edward Visser

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Department of Internal Medicine and Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands

All authors have nothing to disclose

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To whom correspondence should be addressed: W. Edward Visser, PhD, The Rotterdam Thyroid Center & Department of Internal Medicine, Erasmus Medical Center, room Ee502, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands, Tel: +31 10 7043363; E-mail: [email protected]

Abbreviations

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Keywords: thyroid hormone, thyroid hormone analogues, resistance to thyroid hormone, RTHbeta, AHDS, MCT8, Triac, Tetrac, DITPA

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TH, thyroid hormone; T3, 3,3’,5-triiodothyronine; TR, T3-receptors; RTH, resistance to thyroid hormone; Triac, 3,3’,5-triiodothyroacetic acid; DITPA, 3,5-diiodothyropropionic acid; Tetrac, 3,3’,5,5’-tetraiodothyroacetic acid; T4, thyroxine; DIO, deiodinase; rT3, 3,3’,5’-triiodothyronine; MCT8, monocarboxylate transporter; SBP2, SECIS-binding protein 2; D, dextro; TTR, transthyretin; L, levo; LBD, ligand binding domain; FT4, free T4; PTU. Propylthiouracil; GC-1, 3,5-dimethyl-4-(4-hydroy-3-isopropylbenzyl)-phenoxy acetic acid; AHDS, Allan-HerndonDudley syndrome; TFTs, thyroid function tests; BBB, blood-brain-barrier; KO, knock-out; OATP, organic anion transporting polypeptide; DKO, double knock-out; SHBG, sex hormonebinding globulin.

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Abstract Thyroid hormone (TH) is crucial for normal development and metabolism of virtually all tissues. TH signaling is predominantly mediated through binding of the bioactive hormone 3,3’,5triiodothyronine (T3) to the nuclear T3-receptors (TRs). The intracellular TH levels are

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importantly regulated by transporter proteins that facilitate the transport of TH across the cell membrane and by the three deiodinating enzymes. Defects at the level of the TRs, deiodinases and transporter proteins result in resistance to thyroid hormone (RTH) syndromes. Compounds with thyromimetic potency but with different (bio)chemical properties compared to T3 may hold

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therapeutic potential in these syndromes by bypassing defective transporters or binding to mutant TRs. Such TH analogues have the potential to rescue TH signaling. This review describes the

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role of TH analogues in the treatment of RTH syndromes. In particular, the application of 3,3’,5triiodothyroacetic acid (Triac) in RTH due to defective TRβ and the role of 3,5diiodothyropropionic acid (DITPA), 3,3’,5,5’-tetraiodothyroacetic acid (Tetrac) and Triac in

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MCT8 deficiency will be highlighted.

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1. Introduction Thyroid hormone (TH) is crucial for normal development and metabolism of virtually all

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tissues. Its important developmental role is best illustrated by the severe consequences of

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untreated congenital hypothyroidism which results in growth impairment and intellectual

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disability (Grüters and Krude, 2012). The thyroid gland mainly produces the inactive prohormone

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thyroxine (T4) and to a lesser extent the bioactive hormone 3,3’,5-triiodothyronine (T3). The

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main effects of TH are exerted through binding of T3 to its nuclear receptor (thyroid hormone

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receptor, TR), which functions as a ligand-dependent transcription factor. The main receptor

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isoforms are TRα1 and 2 and TRβ1 and 2, which differ in their tissue distribution (Cheng et al.,

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2010). TRα1 and TRβ1 and 2 are bona fide T3-interacting receptors. The amount of T3 available

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for receptor binding is importantly determined by the intracellular deiodinases (DIO1-3), which

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facilitate the activation of T4 to T3 (DIO1 and DIO2) and/or the inactivation of T4 to 3,3’,5’-

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triiodothyronine (rT3) and of T3 to 3,3’-diiodothyronine (3,3’-T2; DIO1 and DIO3). In addition,

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decarboxylation of the alanine side-chain, resulting in the formation of iodothyronamines, and

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subsequent oxidative deamination, resulting in the formation of iodothyroacetic acids, comprise

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another mechanism of iodothyronine metabolism (Wood et al., 2009; Hoefig et al., 2016).

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Importantly, some of these metabolic intermediates have been found to exert biological effects, of

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which the thyromimetic effects of 3,3’,5-triiodothyroacetic acid (Triac) have been most

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extensively studied (Groeneweg et al., 2017 submitted). The transport of TH across the plasma

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membrane by membrane transporter proteins is another crucial step that governs intracellular TH

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concentrations (Hennemann et al., 2001). Many transporters have been shown to facilitate TH

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transport, of which the monocarboxylate transporter (MCT)8 is the most specific TH transporter

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identified to date (reviewed in Visser et al., 2007; Bernal et al., 2015; Kinne et al., 2010). Thus,

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cellular TH action requires adequate function of (1) TH transporter proteins, (2) deiodinases and

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(3) nuclear receptors.

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Defects in any of these processes give rise to distinct clinical syndromes, collectively

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called disorders of TH signaling or resistance to thyroid hormone (RTH) syndromes (Refetoff et

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al. 2014 and Dumitrescu and Refetoff, 2013). So far, clinical phenotypes have been associated

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with mutations in TRβ (reviewed in Dumitrescu and Refetoff, 2013), TRα (Bochukova et al.,

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2012; Van Mullem et al., 2012) and MCT8 (Friesema et al., 2004; Dumitrescu et al., 2004). No

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mutations in deiodinases have been identified yet, although mutations in SECIS-binding protein 2 3

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(SBP2) and selenocysteine transfer RNA, both required for the adequate production of

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deiodinases and other selenoproteins, have been reported (reviewed in Fu and Dumitrescu, 2014;

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Schoenmakers et al., 2016). Compounds with thyromimetic potency but with different (bio)chemical properties

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compared to T3 may hold therapeutic potential in RTH syndromes by bypassing defective

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transporters or binding to mutant TRs. The application of bioactive TH metabolites or synthetic

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TH analogues has been studied in many different contexts (e.g. heart failure or primary

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hypothyroidism). This review will focus on the (putative) application of these compounds in the

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treatment of RTH syndromes.

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2. Properties of TH analogues used in RTH syndromes

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The TH analogues studied in the context of RTH syndromes (RTH-β and MCT8

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deficiency) are 3,3’,5-triiodothyroacetic acid (Triac), 3,3’,5,5’-tetraiodothyroacetic acid

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(Tetrac),3,5-diiodothyropropionic acid (DITPA) and dextro(D)-T4 (choloxin). Tetrac and Triac

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are naturally occurring metabolites of TH in humans, although present at ~50-fold lower

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concentrations than T4 and T3, respectively (Crossley and Ramsden, 1979, Gavin et al., 1980,

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Menegay et al., 1989). Their major serum binding protein is transthyretin (TTR) and free

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fractions of Triac and Tetrac are lower than those of T3 and T4, respectively. Nevertheless, they

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have shorter half-lives, amounting to 6 h for Triac and 3-4 days for Tetrac compared with 1 day

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for T3 and 7 days for T4. Binding assays have shown a similar affinity of Triac and T3 for TRα1,

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whereas Triac shows a 3-6-fold higher affinity for TRβ than T3 (Takeda et al., 1995, Messier et

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al., 2000). Early studies have investigated the therapeutic potential of Triac in myxedematous

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patients or to reduce goiter size (e.g. Trotter 1956, Lerman and Pitt-Rivers 1956, Brenta et al.,

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2003). The synthetic TH analogue DITPA binds with similar affinity to both TR isoforms,

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although its affinity is ~350-fold less than T3 (Pennock et al., 1992). In humans, DITPA has been

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studied in the context of heart failure (Goldman et al., 2009, Ladenson et al., 2010, Talukder et

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al., 2011). D-T4 predominantly exerts its effects after conversion to D-T3, that binds to the

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nuclear TRs with an almost equal affinity as levo(L)-T3 (Latham et al. 1981). Nevertheless, the

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biological activity of the D-enantiomer is much lower compared to the L-enantiomer. Hence, D-

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T4 has to be administrated in a 25-40-fold higher dose than L-T4 to obtain a similar degree of

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TSH suppression (Gorman et al. 1979). In humans, the application of D-T4 has been

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predominantly studied in hypercholesterolemia (e.g. Bantle et al. 1984, Brun et al. 1981).

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Numerous factors determine the ultimate thyromimetic effect of TH analogues at the tissue

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levels, including 1) their affinity for plasma proteins, 2) their cellular uptake by transporters, 3)

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their metabolism by deiodinases and other enzymes, and 4) their affinity for TR isoforms.

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3. TH analogues and RTHβ 3.1 Background and rationale of TH analogue therapy

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Heterozygous mutations of TRβ are the common genetic cause of RTHβ (Weiss et al.,

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2016). So far, over 3000 cases have been identified and about 132 distinct pathogenic mutations

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have been identified in the TRβ gene (Weiss et al., 2016). These mutations generally cluster

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within three distinct hot spots (Figure 1). Mutant receptors exhibit a diminished T3 binding

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affinity and/or impaired interaction with co-regulators involved in the mediation of T3 action and

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generally display a dominant negative effect over the wild-type receptor (Hayashi et al., 1995,

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Yoh et al., 1997, Liu et al., 1998). Biochemical hallmarks of RTHβ are the presence of elevated

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serum (free) T4, T3 and rT3 levels accompanied by non-suppressed or elevated serum TSH

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levels. The clinical features of RTHβ comprise a combination of hypothyroid and thyrotoxic

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symptoms, resulting from the tissue-specific distribution of the TR isoforms. T3 action is reduced

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in tissues that predominantly express the (mutant) TRβ isoform, most importantly the pituitary

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and liver (Refetoff et al., 1993, Forrest et al., 1996). In contrast, tissues that predominantly

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express TRα, such as the heart and brain, are exposed to the high serum TH levels which may

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result in tachycardia, hyperactivity, anxiety and learning disabilities (Refetoff et al., 1993, Forrest

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et al., 1996).

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Given the large variation in the severity of clinical symptoms, the need for treatment is

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assessed on an individual basis (reviewed in Dumitrescu and Refetoff, 2013). In most patients the

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increased endogenous TH levels provide an adequate compensation for the reduced TH

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sensitivity in the TRβ expressing tissues and, thus, treatment is not needed. In contrast, some

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patients have persistent symptoms such as tachycardia and atrial fibrillation due to apparent TH

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excess in TRα-expressing tissues. Symptomatic treatment such as beta-blockers for tachycardia

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can alleviate such symptoms.

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The major objective in the treatment of RTHβ is to maintain an acceptable balance

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between over-stimulation of TRα-expressing tissues and under-stimulation of the TRβ-expressing

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tissues. The ideal treatment should therefore aim to selectively potentiate T3 action in the TRβ-

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expressing tissues, while keeping the TRα-expressing tissues euthyroid. This led to the

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consideration of TH analogues with preferential affinity for TRβ in the treatment of RTHβ. In

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this context, Triac has been most widely studied in humans.

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3.2 Triac

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As mentioned earlier, Triac may preferentially act through the TRβ isoform (Takeda et

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al., 1995, Messier et al., 2001, Martinez et al., 2009). This is supported by a lower EC50 value for

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TRβ compared to TRα mediated transcriptional activation by Triac (Martinez et al., 2009). These

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findings are further strengthened by X-ray crystallography studies demonstrating that the

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interaction of Triac with the ligand binding domain (LBD) of TRβ is energetically more

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favorable than its interactions with TRα (Martinez et al., 2009). This is mainly driven by a single

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amino acid difference between TRα (Ser277) and β (Asn331) at the LBD, leading to a relative

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displacement of the β-hairpin of the TRβ LBD which potentiates direct substrate contacts

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(Wagner et al., 2001, Martinez et al., 2009). Importantly, Triac was shown to exhibit a higher

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affinity than T3 for several TRβ mutants, resulting in greater transcriptional activation in cells

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expressing the mutant receptor alone or in combination with wild-type TRβ (Takeda et al., 1995,

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Messier et al., 2001). Together, these studies suggest that Triac is able to trans-activate specific

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mutant TRβ proteins more potently than T3 and, thus, diminish the dominant negative effect.

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These in vitro observations are in line with case reports and case series in clinically

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suspicious and/or genetically confirmed RTHβ patients. An overview of these reports is provided

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in Table 1. The location of the mutations identified in these patients is indicated in the schematic

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representation of TRβ (Figure 1) and follows the distribution across the well-defined hotspots

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cluster 1 (9 cases), cluster 2 (4 cases) and cluster 3 (2 cases), with the exception of the p.R383H

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mutant which is located outside these clusters (Clifton-Bligh et al., 1998).

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In the patients with mutations that fall within cluster 1 and 2, increasing doses of Triac

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(generally up to 2000 µg/day divided in 2-3 doses, corresponding to 25–35 µg/kg body weight

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(BW) · day, were shown to effectively reduce basal and TRH-induced serum TSH levels by up to

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90 percent, resulting in a subsequent decrease of serum (F)T4 and (F)T3 levels. In most cases, a 6

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(partial) alleviation of the thyrotoxic symptoms including tachycardia, excessive perspiration and

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behavioral problems were reported and in several cases Triac treatment effectively reduced goiter

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volume (summarized in Table 1). A few studies provided biochemical parameters that reflect TH

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action at the tissue level, with a decrease in cholesterol levels being the most consistent

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observation. Hence, the putative negative effects of the relatively high doses Triac on the TRα-

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expressing tissues, including the bone, are difficult to evaluate based on the currently available

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literature.

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The response on Triac treatment of two cases with a mutation located within cluster 3,

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which predominantly entails the hinge region of the receptor, clearly differed. The first case

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(p.V264D) was refractory to Triac treatment, i.e. hardly showed any changes in serum TSH and

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free (F)T4 levels or clinical improvements (Persani et al., 1998). Also in another case (p.R243Q)

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only modest clinical improvement was observed upon long-term Triac treatment (5.5 years),

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although some reduction of serum TSH and FT4 levels was reported (Guran et al., 2009).

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The number of reports on Triac treatment in RTHβ patients is limited and they reveal great

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differences in dosing, duration of follow-up and treatment outcomes. Nevertheless, the picture

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emerges that Triac has beneficial effects in a subset of RTHβ patients, especially those with

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mutations within cluster 1 and 2. The abovementioned limitations prevented a more detailed

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comparison of the response to Triac treatment among the cases within cluster 1 and 2. Clinical

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trials and long-term follow-up studies are required to describe the positive and adverse effects of

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Triac at the tissue level in RTHβ in more detail. It would be of clinical relevance to document the

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effects of Triac in RTHβ patients using established treatment protocols and well-defined outcome

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measures.3.3 D-T4

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Several case reports and series explored the use of D-T4 (2000-8000 µg/day) alone or in

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combination with anti-thyroid drugs, with the primary aim to control the thyrotoxic symptoms of

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RTHβ patients. In several RTHβ cases in which D-T4 was used as a monotherapy, a decrease in

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serum TSH levels and subsequent improvement of some clinical parameters have been found, but

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the effects on objective markers reflecting tissue TH action were limited or have not been

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reported (Hamon et al., 1988; Pohlenz and Knöbl 1996, Sarkissian et al., 1999). Importantly, in

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these cases serum sex hormone-binding globulin (SHBG) levels, reflecting TH action in the liver,

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remained stable or even decreased below the reference range, suggesting that D-T4 was 7

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ineffective to restore TH action in the liver. Dorey et al. (1990) studied the effect of D-T4 alone

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or in combination with propythiouracil (PTU) and found the strongest reduction in serum TSH

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levels when using D-T4 monotherapy in a daily dose of 2 mg and reported serum SHBG and

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ferritin levels as well as echocardiographic parameters to be within the normal range at the end of

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the study (at least 16 months of follow-up). In contrast, other reports have shown that D-T4

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treatment had no effects or weaker effects compared to other interventions (Schwartz and Bercu,

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1992, Lind and Eber, 1986). It is unclear to what extent the observed thyromimetic effects can be

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attributed to the presence of 2-3% L-T4 in most D-T4 preparations (Young et al. 1984). Taken

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together, the role of D-T4 in the treatment of RTHβ is unclear and therefore its application in

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clinical practice is not recommended.

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3.4 TH analogue treatment during pregnancy

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Monitoring and treatment of RTHβ patients during pregnancy is of particular importance

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as TH is crucial for development (discussed in Weiss et al., 2016). One case reported on the use

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of Triac in an RTHβ patient during pregnancy, because of signs of hypothyroidism in the fetus

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that was heterozygous for the same p.T337A mutation. However, the benefits of such an

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approach for the fetus are highly controversial (Asteria et al., 1999; Weiss and Refetoff 1999).

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Therefore, treatment with TH analogues in pregnant RTHβ patients aiming to positively

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influence fetal development is not recommended. If therapeutic interventions are required, the

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use of PTU or L-T4 is strongly preferred (Weiss et al., 2010).

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3.5 Prospectives

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The development of TH analogues that specifically stimulate the (mutant) TRβ isoform

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appears to be a promising treatment option to be further explored. Importantly, detailed structural

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insights into wild-type and mutant receptors in complex with different analogues are

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indispensable to generate tailor-made TH analogues (Wagner et al., 2001, Martinez et al., 2009).

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From these and other studies, it becomes increasingly clear which properties of the T3 molecule

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should be preserved in the analogue to selectively bind to one of the TR isoforms. Over the last

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decades different TH analogues have been developed with even greater isoform specificity and

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higher affinity for the wild-type TRβ receptor than Triac, including 3,5-dimethyl-4-(4-hydroy-3-

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isopropylbenzyl)-phenoxy acetic acid (GC-1), eprotirome (KB2115) and KB141 (Malm et al.,

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2007, Chielline et al., 1998, Grover et al., 2005). However, the applicability of these analogues

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in RTHβ appears limited by their restricted tissue availability (Gloss et al., 2005, Baxter et al.,

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2004, Grover et al., 2003) or the occurrence of tissue toxicity (Sjouke et al., 2014). Several

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studies reported on the synthesis of ligands that could effectively activate specific mutant TRβ

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proteins by varying different moieties of the substrate molecule (Hashimoto et al., 2005; Hassan

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and Koh 2006; Hassan and Koh 2008). Although this class of tailored-made analogues appear

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very promising, they have not been used in clinical practice thus far.

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4. TH analogues and RTHα

Mutations in the TRα isoform have been recently identified (Bochukova et al., 2012; Van

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Mullem et al., 2012). The resulting phenotype has been coined RTHα, predominantly

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characterized by abnormal bone development, constipation, anemia and various degrees of

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neurocognitive impairments (Moran and Chatterjee, 2015). These clinical features are

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accompanied by subtle changes in thyroid parameters, including low-normal serum (F)T4 and

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high-normal serum (F)T3 concentrations in the context of normal TSH levels. Several lines of

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evidence suggest that treatment with supra-physiological doses of LT4 may have beneficial

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effects on several parameters including body length. So far, the use of TRα-specific TH

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analogues has not been reported, but is an approach worthwhile to explore in future studies.

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5. TH analogues and the Allan-Herndon-Dudley syndrome (AHDS) 5.1 Background and rationale of TH analogue therapy The only TH transporter that is currently linked to clinical disease is MCT8 (Friesema et

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al., 2004; Dumitrescu et al., 2004). Mutations in MCT8 result in AHDS, characterized by severe

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intellectual disability and abnormal serum thyroid function tests (TFTs), including elevated

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serum T3, reduced rT3 and low or low-normal (F)T4 levels in the presence of a normal to high-

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normal TSH. MCT8 has been found to be essential for TH transport across the blood-brain-

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barrier (BBB) and into neuronal cells (Wirth et al., 2009; Ceballos et al., 2009). Serum TFTs in

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the Mct8 knock-out (KO) mice resemble those observed in human AHDS patients (Trajkovic et

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al., 2007, Trajkovic et al., 2010). Unfortunately, Mct8 KO mice do not display a neurological

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phenotype, most likely due to the compensatory role of the T4 transporter organic anion

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transporting polypeptide (OATP) 1C1 at the BBB in mice (Dumitrescu et al., 2006, Trajkovic et

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al., 2007). Indeed, the Mct8/Oatp1c1 double KO (DKO) mice show severe neuromotor

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abnormalities that to some extent resemble those observed in athyroid Pax-8 KO mice (Mayerl et

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al., 2014). The current paradigm of AHDS holds that tissues that depend on MCT8 for cellular TH

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supply are hypothyroid, most importantly the brain, whereas tissues that rely on other

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transporters such as liver and heart are exposed to the high serum T3 levels which results in a

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local thyrotoxicity (Figure 2A). Currently no effective therapy is available that restores TH

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signaling in all tissues. Although block-and-replace therapy with PTU and L-T4 has been shown

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to effectively restore serum TFTs and several biochemical markers that reflect TH state in the

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peripheral tissues, no effects on TH signaling in the brain are to be expected given the important

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role of MCT8 in the transport of T4 across the BBB (Visser et al., 2013). A potential therapy

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comprises a TH analogue that crosses the BBB and enters target cells independently from MCT8,

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but exerts similar effects as TH once inside the cell (Figure 2B). The hypothesis underlying the

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mechanism of these analogues consist of the simultaneous inhibition of TSH secretion and hence

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endogenous TH production and secretion, while providing adequate thyromimetic effects in all

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body tissues, including the brain (Figure 2B). Alternatively, reintroduction of wild-type MCT8

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with gene-therapy could be an effective therapeutic strategy.

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5.2 DITPA

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The first studies exploring the application of TH analogues in AHDS were carried out

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with DITPA. Administration of DITPA (300-1000 µg/ 100 g BW · day) to Mct8 KO and control

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mice results in similar tissue availability of DITPA in the liver and brain, suggesting an Mct8-

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independent cellular entry in these tissues (Di Cosmo et al., 2009a). In this dose range, DITPA

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effectively reduces serum TSH and subsequently T4, T3 and rT3 levels in Mct8 KO and control

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animals (Di Cosmo et al., 2009a, Ferrara et al., 2015). Moreover, DITPA is able to, at least

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partially, restore the abnormal expression levels of several well-known T3-responsive genes and

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deiodinase activity in the liver and brain of hypothyroid control and Mct8 KO mice in a dose-

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dependent way (Di Cosmo et al., 2009a). Especially the reduction in Dio1 activity may further

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contribute to the reduction of elevated serum T3 levels as observed in AHDS (Di Cosmo et al.,

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2009 and Di Cosmo et al., 2015). Of note, the thyromimetic potency of DITPA appears to be

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tissue-specific, which may be attributed to a tissue-specific bio-availability of DITPA.

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Importantly, administration of the lowest dose DITPA (300 µg/100 g BW· day) to Mct8 KO mice

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has only minor effects on TH markers in the brain, whereas it already normalizes the

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hypermetabolic state as well as the abnormal serum TFTs (Ferrare et al., 2015). In mice, DITPA

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(300 µg/100 g BW · day) was shown to cross the placenta in pregnant dams that were rendered

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hypothyroid and have significant effects on the expression of TH-dependent genes in the fetal

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mouse cerebral cortex (Ferrara et al., 2014). Obviously, the interpretation of studies performed in

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Mct8 KO mice are complicated by the lack of neurological derangements in this animal model.

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In line with the preclinical data, treatment of 4 AHDS patients, initiated at 8.5-25 months

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of age, with increasing doses of DITPA (up to 2000-2400 µg/kg BW · day in 3 divided doses)

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normalized the high serum T3 levels in all 4 patients. However, several markers of peripheral TH

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action, including serum SHBG, heart rate and body weight showed variable responses among the

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patients (Verge et al., 2012). No effects were observed on neuropsychological functioning. It is

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yet unclear to what extent DITPA rescues brain development in human AHDS subjects should

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administration be started early after birth.

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5.3 Triac and Tetrac

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Recently, the therapeutic potential of the naturally occurring TH metabolite Triac has also

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been studied. In vitro studies have shown that cellular uptake of Triac is MCT8 independent

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(Kersseboom et al., 2014, Groeneweg et al., 2014). Similar to T3, Triac is efficiently metabolized

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by DIO1 and DIO3 and regulates the expression of TH-responsive neuronal genes (Kersseboom

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et al., 2014). Importantly, administration of Triac from postnatal day 1 largely prevents the

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abnormal brain development in Pax8 KO mice, evidenced by (near-) normal Purkinje cell

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morphology, myelination and parvalbumin expression in the cerebral cortex, all known to be TH-

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dependent processes (Kersseboom et al., 2014). These effects are also observed in Mct8/Pax8

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DKO mice, illustrating that Mct8 is not required for this response (Kersseboom et al., 2014).

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Triac administration to Mct8/Oatp1c1 DKO mice rescued disrupted brain development.

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The abnormal Purkinje cell layer is restored upon Triac treatment (40 µg/100 g BW · day)

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between postnatal day 1 to 12 and also myelination is largely improved (Kersseboom et al.,

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2014). A recent study in Mct8 KO mice reported a reduction in expression levels of some

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positively regulated TH-responsive genes upon low dose (3 µg/100 g BW · day) Triac treatment

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(Bárez-López et al., 2016). However, Mct8 KO mice do not properly replicate the neurological

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phenotype observed in AHDS patients and hence it can be argued to what extent these findings 11

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can be extrapolated to models that are more reminiscent to the human condition (Visser et al.,

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2016). The positive findings of Triac on brain development are corroborated by studies in

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chicken in which Mct8 was silenced (Delbaere et al., 2017), showing that Triac is able to restore

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the abnormal Purkinje cell development in the cerebellum. In addition, Triac was shown to

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potentiate myelination in the mct8 -/- zebrafish model (Zada et al., 2016).

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Due to its short half-life time, Triac requires multiple daily doses to acquire stable serum

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levels. For this reason, the therapeutic potency of its more stable precursor Tetrac has also been

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explored (Horn et al., 2013). Similar to T3 and Triac, Tetrac (40 µg/100 g BW · day)

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administration to Pax8 KO mice starting at postnatal day 1 results in (near complete)

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normalization of the development of the cerebellum and striatum, whereas only partial

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normalization is observed in the inhibitory parvalbuminergic neurons of the cerebral cortex (Horn

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et al., 2013).

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Although these findings overall indicate that Triac and Tetrac can replace TH during brain

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development in various brain areas, differences may exist in its thyromimetic potency among

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distinct neuronal populations. In addition, little is known about the effects Triac and Tetrac on

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brain development once administration is initiated at a later developmental stage. Additional

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studies in models that better replicate the TH status in the brain of human AHDS patients are

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required to determine the therapeutic potential of Triac when administered at a later

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developmental age.

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The putative role of Triac as a therapy for AHDS patients is currently under investigation

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in a prospective interventional cohort study, the Triac Trial (NTC02060474). This study

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primarily aims to normalize the high serum T3 levels and reduce the hypermetabolic state in the

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peripheral tissues, since this accounts for high co-morbidity. Although Tetrac would be an

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interesting alternative, such studies are hampered by the absence of marketing authorization for

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Tetrac and the limited experience with its administration to human subjects.

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5.4 Prospectives

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Ongoing studies will reveal if Triac is an effective treatment for the peripheral phenotype

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of AHDS. Early treatment is advantageous in many respects, possibly including the

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neurocognitive phenotype. This calls for programs for early diagnosis of AHDS. Theoretically, 12

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prenatal delivery of a TH analogue that is able to cross the placenta such as DITPA or Triac to

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mothers who are pregnant of an AHDS child might be of benefit. (Ferrara et al., 2014, Asteria et

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al., 1999, Cortelazzi et al., 1999). However, the medical and ethical considerations should be

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realized if such a situation occurs.

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Since AHDS is a monogenetic disorder, gene therapy is an attractive alternative to

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explore. In mice, i.v. administration of AAV9-MCT8 increases functional MCT8 expression at

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the BBB and brain T3 levels in Mct8 KO mice (Iwayama et al., 2016). Further studies are

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warranted to optimize the gene delivery strategy and assess its safety.

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6. TH analogues and defects of deiodination

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Mutations in SBP2 and selenocysteine transfer RNA disturb deiodination of TH and

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several of its metabolites and produce a typical biochemical thyroid fingerprint (elevated serum

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T4 and rT3 and low to low-normal T3 levels in the presence of normal or slightly elevated TSH

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levels). However, it is unclear which features, if any, can be attributed to defective TH signaling.

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Several reports mention beneficial effects of L-T3 treatment on body height (Di Cosmo et al.,

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2009b, Azevedo et al., 2010, Hamajima et al., 2012), although in other cases spontaneous catch-

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up growth was reported (Dumitrescu et al., 2005, Schoenmakers et al., 2010). Therefore, the role

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of L-T3 or TH analogues in the treatment of these disorders seems to be limited.

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7. Concluding remark

The thyromimetic action and hence applicability of TH analogues is importantly

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determined by their receptor isoform specificity, tissue availability and metabolic clearance.

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These analogue specific properties largely determine their applicability in the treatment of RTHβ

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syndromes. In humans, Triac has a role in the treatment of RTHβ, in particular for patients

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harboring mutations in clusters 1 or 2 of TRβ. Advancing insight into the protein structure of the

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TR isoforms and substrate-receptor interactions will provide novel opportunities to design tailor-

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made isoform or mutant specific TH analogues. The role of DITPA and Triac has been explored

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in animal models of AHDS. The efficacy of Triac therapy in AHDS patients is currently

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explored.

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Acknowledgements: this work was supported by a grant from the Netherlands Organisation for Health Research and Development (project number 113303005) (to WEV) and from the Sherman Foundation (to WEV).

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Conflict of interest: The authors declare that they have no conflicts of interest.

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Legends to the figures

Figure 1

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Schematic representation of the TRβ protein. The 3 hotspots for mutations are indicated as cluster 3 (residue 234-282), containing part of the hinge region and ligand binding domain (LBD), cluster 2 (310-353) and cluster 1 (429-460), both containing part of the LBD. The location of the mutations identified in RTH-β patients who have been treated with Triac (summarized in Table 1) are indicated with a dot. Green dots represent cases with a favorable response to Triac

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treatment and red dots represent cases that showed no response to Triac treatment.

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Figure 2

(A) Schematic representation of a T3 target cell that relies on MCT8 for its T3 uptake. The proposed mechanism of TH analogues in case of defective MCT8 entails cellular uptake in an MCT8-independent way, binding to the TR and preferably degradation through similar pathways as TH. (B) Schematic representation of the current paradigm of MCT8 deficiency and the

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proposed working mechanism of TH analogues (colored in green) at systemic level. In AHDS, the MCT8-dependent tissues (e.g the brain), are hypothyroid, whereas tissues that rely on other transporters (e.g. heart, liver and kidney), are exposed to the high serum T3 levels, resulting in tissue thyrotoxicity. Proper TH analogues reduce TSH secretion by the pituitary and thereby

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reduce the endogenous production of TH. The subsequent decrease in serum T3 levels results in a net decrease in TH action in MCT8-independent tissues. Simultaneously, the TH analogue

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exhibits its thyromimetic function in MCT8-dependent tissues and hence restores TH signaling.

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Figure 1

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Figure 2

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Table 1 Overview of case reports of RTH-β patients treated with Triac Effects

Reference(s)

F

4 months

TSH↓, fT4↓, PR↓

n.a.

n.a.

NA

2100 µg

58 weeks

TSH↓, ↓ goiter size

3

n.a.

n.a.

NA

2100 µg

25 weeks

TSH↓, fT4↓, ↓ goiter size

4

F

n.a.

38

1400 µg

3 months

TSH↓

5

M

n.a.

38

1400 µg

3 months

TSH↓

6

M

n.a.

2

1400 µg

4 months

7

M

n.a.

25

3000 µg

7 days

8

F

n.a.

37

3500 µg

28 weeks

Not effective; combined with carbimazole TRH-induced TSH secretion ↓ TSH↓, fT4↓, ↓ goiter size

9

M

n.a.

42

6 weeks

TSH↓, fT4↓

1012 13

F/ M F/ M

n.a.

n.a.

n.a.

variou s

2800-4200 µg 2100-2800 µg n.a.

>3 months n.a.

14

F

n.a.

10

700 µg

15

F

n.a.

15

14 months 9 weeks

TSH ↓, T4 ↓, T3↓, no effect on SHBG Improvement of symptoms and signs of hyperthyroidism TSH ↓, fT4↓, PR↓, ↓ goiter size TSH↓, ↓goiter size

16

F

p.H435L

17

4 months

fT4 ↓, ↓ goiter size

17

F

p.H435Q

36

4 months

18

M

c.C1642A , p.P453T

TSH ↓, fT4↓, PR↓, tremor↓, ↓ goiter size TSH ↓, fT4 ↓, PR↓ improvement of nervousness, hyperkinetic behavior and heat intolerance TSH ↓, fT4↓, PR↓, ↓ goiter size

Beck-Peccoz et al. 1983 Faglia et al. 1987 Faglia et al. 1987 Salmela et al. 1988 Salmela et al. 1988 Hamon et al. 1988 Smallridge et al. 1989 Kunitake et al. 1989 Kunitake et al. 1989 Beck-Peccoz et al. 1990 Aguilar Diosdado et al. 1991 # Crinò et al. 1992 # Dulgeroff et al. 1992 Ueda et al. 1996 Ueda et al. 1996 Radetti et al. 1997

2

1400-2100 µg 700-2100 µg 1050-2100 µg 1400-1750 µg

24 months

20

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3-5

F

p.R320H

12

1000-2000 µg

2 weeks

21

M

∆430M

32

1000-2000 µg

2 weeks

19

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1

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Total daily dose 2000 µg

Duration

n.a.

Age in yrs 47

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Mutation

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Sex

EP

Case

F

n.a.

11-13

2100 µg

22 months

TSH ↓, FT4 ↓, improvement in clinical manifestations TSH ↓, FT4 ↓, improvement in clinical manifestations

Darendelier and Basx, 1997 # Persani et al. 1998 Persani et al. 1998

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Duration

Effects

Ref.

M

ND

2 weeks

TSH ↓, FT4 ↓, improvement in clinical manifestations Little-no effect on TSH and FT4 levels, no clinical improvement TSH ↓, FT4 ↓, FT3↓, cholesterol↓, ferritine↑ TSH ↓, T4 ↓, clinically euthyroid TSH ↓, insomnia↓, ↓heart rate, ↓ palpitations TSH ↓, fT4 ↓, improvement of hyperactivity TSH↓, PR↓, sweating ↓

Persani et al. 1998

23

M

p.V264D

27

1000-2000 µg

2 weeks

24

F

p.R383H

13

700 µg

3 years

25

F

T337A

29

2100 µg

3 years

26

M

p.R429Q

52

3 weeks

27

M

p.F455I

6-7

700-1400 µg 1400 µg

28

M

0

1400 µg

29

F

p.C436fs X p G344R

15

n.a.

12 months

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Total daily dose 1000-2000 µg

7 months

Persani et al. 1998

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22

Age in yrs 11

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Table 1 continued Case Sex Mutation

Clifton-Bligh et al., 1998 Asteria et al. 1999 Kong et al. 2005 Torre et al. 2005 # Wu et al. 2006

Slight reduction in TSH Santos et al., (co-administrated with 2008 # LT3) 30 F p.R243Q 13 n.a. 5.5 years Improvement of TSH and Guran et al. T4 levels, no clinical 2009 # improvements 31 M p.P453T 6-9 1500-3000 3 years TSH ↓, fT4 ↓, total Anzai et al. µg T4↓,↓PR improvement of 2012 hyperactivity, ↓goiter size 32 F pM313V 10 1000 µg 1 year TSH ↓, FT4 ↓, FT3↓, Stagi et al., cholesterol↓, insulin 2014 resistance ↓ 33 F p.P452R 20 1400 µg TSH ↓, T4 ↓, cholesterol Chatzitomaris ↓ et al. 2015 # 34 F ND 29 375 µg 6 months No effects on TFTs or Xue et al. goiter size 2015 Overview of main findings from case reports concerning Triac treatment in RTH patients. Explanations to the table: M, male; F, female; ↓ decrease; PR, pulse rate; n.a.: not available. ND no detectable mutation in the exons of the TRβ gene. Cases in which the effects of Triac were not further specified are excluded from this overview. References for which only the abstract was available to the authors are indicated with a #.

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EP

TE D

n.a.

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ACCEPTED MANUSCRIPT

Highlights 1. Thyroid hormone analogs may hold therapeutic potential in resistance to thyroid hormone

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(RTH) syndromes by bypassing defective transporters or binding to mutant thyroid hormone receptors (TRs).

2. In a subset of RTHβ patients, 3,3’,5-triiodothyroacetic acid (Triac) effectively binds mutant TRβ, ultimately resulting in alleviation of thyrotoxic symptoms

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3. 3,5-diiodothyropropionic acid (DITPA) partially restored peripheral thyrotoxicosis in

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monocarboxylate transport 8 (MCT8) deficiency in preclinical and clinical studies 4. Triac effectively rescues the neuromotor phenotype in Mct8 /Organic Anion Transporting

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Polypeptide deficient mice