US20130227717A1 - Hdac inhibitors to treat charcot-marie-tooth disease - Google Patents
Hdac inhibitors to treat charcot-marie-tooth disease Download PDFInfo
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- US20130227717A1 US20130227717A1 US13/877,648 US201113877648A US2013227717A1 US 20130227717 A1 US20130227717 A1 US 20130227717A1 US 201113877648 A US201113877648 A US 201113877648A US 2013227717 A1 US2013227717 A1 US 2013227717A1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
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- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61P25/00—Drugs for disorders of the nervous system
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Definitions
- the present disclosure relates to diseases in the peripheral nervous system, particularly hereditary neuropathies, most particularly, Charcot-Marie-Tooth (CMT) disease. It is shown that this disease is associated with decreased acetylated tubulin levels, which can be overcome by inhibition of histone deacetylases (HDACs). Using HDAC inhibitors, it is shown herein that the symptoms of the CMT phenotype can be overcome both in vitro and in vivo. Also provided herein are two different mouse models of CMT disease.
- CMT Charcot-Marie-Tooth
- CMT Charcot-Marie-Tooth
- CMT Charcot-Marie-Tooth
- CMT patients show slowly progressive distal muscle weakness and atrophy, foot deformities, steppage gait, distal sensory loss, and decreased or absent deep tendon reflexes 1, 2 .
- Electrophysiologically, CMT is divided into three groups: demyelinating CMT (type 1), CMT characterized by axonal loss (type 2), and intermediate forms demonstrating signs of both demyelination and axonal loss.
- distal HMN Hereditary Motor Neuropathy
- CMT and distal HMN have been associated with approximately 40 causative genes (for an overview, see the World Wide Web at molgen.ua.ac.be/CMTMutations) and the pattern of inheritance can be autosomal dominant, autosomal recessive or X-linked 1, 2 .
- the underlying pathological mechanism for most of the mutated genes remains unknown.
- HSPB1 27 kDa small heat-shock protein (HSPB1, also called HSP27) on chromosome 7q11.23 were previously identified as a cause of CMT2 and/or distal HMN2 3, 4 .
- HSPB1 is a member of the small heat-shock proteins that contain a highly conserved ⁇ -crystallin domain.
- HSPB1 shows chaperone activity by binding to misfolded and/or (partially) denatured proteins and preventing them from forming toxic aggregates 5, 6 .
- HSPB1 also plays a crucial role in diverse cellular processes such as modulation of the intracellular redox state, the assembly of cytoskeletal structures, cell differentiation, and inhibition of apoptosis by interacting with pro-apoptotic signaling proteins 5-7 .
- CMT Charcot-Marie-Tooth
- HSPB1 small heat-shock protein
- distal HMN distal hereditary motor neuropathy
- HDAC6 histone deacetylase 6
- ⁇ -tubulin deacetylation corrected the axonal transport defects induced by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice.
- the findings demonstrate the pathogenic role of ⁇ -tubulin deacetylation in mutant HSPB 1-induced neuropathies and offers perspectives for HDAC6 inhibitors as a therapeutic strategy against hereditary axonopathies (see also d'Ydewalle et al., Nat. Med. 2011; 17(8):968-74; ref 47), but also against induced peripheral neuropathies, such as chemotherapy-induced peripheral neuropathy.
- HDAC6 histone deacetylase 6
- HDAC inhibitors particularly HDAC6 inhibitors
- HDAC inhibitors are provided for use in treatment of neuropathies. It is to be understood that this applies to the other methods described herein as well, and the equivalent phrasing will thus not always be repeated.
- the methods of treating Charcot-Marie-Tooth disease by inhibiting HDAC function, particularly HDAC6 function are used to treat Charcot-Marie-Tooth disease characterized by at least one mutation in the HSPB1 gene or protein.
- the mutation in the HSPB1 gene or protein is a mutation in the alpha-crystallin domain of HSPB1, particularly of residue S135, most particularly a S135F point mutation.
- the mutation in the HSPB1 gene or protein is a mutation in the C-terminal tail of HSPB1, particularly of residue P182, most particularly, a P182L point mutation.
- the HDAC function can be inhibited by using or administering a HDAC inhibitor, such as a pan-HDAC inhibitor, a non-selective inhibitor of type II HDACs, a selective inhibitor of type II HDACs, a selective inhibitor of type IIb HDACs or a selective inhibitor of HDAC6.
- a HDAC inhibitor such as a pan-HDAC inhibitor, a non-selective inhibitor of type II HDACs, a selective inhibitor of type II HDACs, a selective inhibitor of type IIb HDACs or a selective inhibitor of HDAC6.
- the selective HDAC6 inhibitor is selected from tubacin and tubastatin A.
- the methods of treating Charcot-Marie-Tooth disease by inhibiting HDAC function result in improvement of at least one of the symptoms of Charcot-Marie-Tooth disease, particularly an improvement in motor function.
- the methods provided herein result in reinnervation, i.e., in the growth of new, functional axons in the place of axons that were lost as result of the neuropathy.
- non-human transgenic animal models are provided that can serve as a model to study CMT disease.
- these animals are mice.
- the transgenic non-human animals are characterized by at least one mutation in the HSPB1 gene.
- the mutation is neuron-specific.
- the at least one mutation in the HSPB1 gene or protein is a mutation in the alpha-crystallin domain of HSPB1, particularly of residue S135, most particularly, a S135F point mutation.
- the mutation in the HSPB1 gene or protein is a mutation in the C-terminal tail of HSPB1, particularly of residue P182, most particularly, a P182L point mutation.
- the non-human transgenic animal models recapitulate at least one of the symptoms of Charcot-Marie-Tooth disease observed in humans.
- FIG. 1 Neuronal expression of human mutant HSPB1 in mice leads to progressive motor defects and decreased muscle strength.
- Panel a Western blots of sciatic nerve, DRG, spinal cord and brain homogenates isolated from two-month-old non transgenic (Nontg) mice or mice expressing WT or mutant (S135F or P182L) HSPB1 probed with an antibody to the HA tag of the 27-kDa human HSPB1.
- Glyceraldehyde-3-phosphate dehydrogenase (Gapdh) staining confirmed equal loading.
- MW molecular weight.
- Panel b Six-month-old mice expressing WT or mutant HSPB1 lifted by the tail showing normal spreading of the limbs (WT) or limb-clasping behavior (S135F and P182L).
- Panels d and e Age-dependent measurements of grip strength normalized to body weight of all paws combined (Panel d) or forepaws only (Panel e) using a dynamometer with a grid or a triangular bar, respectively. AU, arbitrary units.
- FIG. 2 No effect on survival and more severe motor phenotype in mutant HSPB1 P182L .
- FIG. 3 Mice expressing mutant HSPB1 show steppage gait and clawed hindpaws.
- Panel a Typical gait patterns of eight-month-old transgenic mice monitored with the semiautomated Catwalk system. Colored bars represent the time a paw makes contact with the floor plate. LH, left hindpaw; LF, left forepaw; RH, right hindpaw; RF, right forepaw. Asterisks mark hesitations in the gait pattern observed for both mutant HSPB1 mouse lines. Scale bar, 10 cm.
- Panels b-f Quantification of various parameters obtained from the gait analysis with the Catwalk.
- Blue asterisks indicate differences between P182L and WT.
- Red asterisks indicate differences between S135F and WT.
- the lines represent the span in which the data points are significantly different. Tukey's HSD test was used for post hoc analysis. Data are presented as means ⁇ s.e.m.
- Panel g Typical example of a mutant HSPB1 P182L -expressing mouse showing clawed hindpaws.
- FIG. 4 Mutation-dependent pure motor or sensorimotor axonal loss and denervation of neuromuscular junctions in mice expressing mutant HSPB1.
- Panel a Relative difference in response latencies on a hot plate between mice expressing HSPB1 WT , HSPB1 S135F and HSPB1 P182L .
- Panels b-d Determination of the amplitude and the latency of the CMAPs in mice expressing HSPB1 WT , HSPB1 S135F or HSPB1 P182L .
- Panel b CMAP amplitudes as a function of age.
- Panel c Linear curve fitting of the CMAP data points (R 2 S135F : 0.99 and R 2 P182L : 0.94).
- Panel d CMAP latencies as a function of age.
- Panels e and f Age-dependent measurements of amplitudes (Panel e) and latencies (Panel f) of SNAPs. Blue asterisks indicate difference between P182L and WT. Red asterisks indicate difference between S135F and WT. Line represents the span in which the data points are significantly different compared to WT. Tukey's HSD test was used to analyze post hoc.
- Panel g Toluidine blue staining of semithin distal sciatic nerve sections of ten-month-old HSPB1 WT -expressing (left) and mutant HSPB1-expressing (middle and right) mice, showing axonal loss in the mutant lines. No signs of demyelination were observed. Scale bars, 40 ⁇ m.
- Panel h Correlation between myelin thickness and axonal diameter confirming the absence of demyelination in HSPB1 WT -expressing (left) and mutant HSPB1-expressing (middle and right) mice.
- Panel i Quantification of the number of axons in distal parts of the sciatic nerve.
- FIG. 5 Mutant HSPB1-induced neuropathy caused no proximal axonal loss, but is characterized by muscle denervation.
- Panel a Toluidine blue staining of semi-thin proximal sciatic nerve sections of ten-month-old HSPB1 WT (left panel) and mutant HSPB1 (middle and right panel) mice showing no axonal loss. No signs of demyelination were observed. Scale bar 40 ⁇ m.
- Panel b Correlation of myelin thickness and axonal diameter confirming the absence of demyelination in HSPB1WT (left panel) and mutant HSPB1 (middle and right panel) mice.
- Panel c Quantification of the number of axons in proximal parts of the sciatic nerve. One-way ANOVA. P>0.05.
- Panel d Fluorescent micrograph of acetylcholine-receptor clusters stained with ⁇ -bungarotoxin (in red) and terminal axon branch stained with neurofilament heavy chain (Nf200; in green) from a 25 ⁇ m thick longitudinal section of gastrocnemius muscle of a ten-month-old HSPB1 S135F animal. Scale bar: 20 ⁇ m.
- Panel e Quantification of the number of acetylcholine-receptor clusters per terminal axon branch visible within a field of view. One-way ANOVA. *P ⁇ 0.05; ** P ⁇ 0.001; *** P ⁇ 0.0001.
- FIG. 6 Mutant HSPB1 mice show axonal transport defects and decreased acetylated tubulin levels.
- Panel a Representative fluorescent micrograph of a cultured DRG neuron loaded with a selective mitochondrial marker (MitoTracker-Red; left) and typical kymographs obtained from DRG neurons isolated from ten-month-old mice (top right, HSPB1WT; bottom right, HSPB1S135F). Stationary mitochondria are visible as straight vertical lines, whereas moving mitochondria are deflected either to the left (retrograde) or to the right (anterograde).
- Left scale bar 40 ⁇ m. In right images, time (t) scale bar: 50 seconds; distance (d) scale bar: 25 ⁇ m.
- Panel f Western blots from sciatic nerves of ten-month-old mice expressing HSPB1 WT or mutant HSPB1 probed with antibodies to acetylated tubulin.
- FIG. 7 Tubastatin A dose-dependently rescued axonal transport and increased acetyl-tubulin levels in vitro.
- Panels a and b Axonal transport of mitochondria was assessed in DRG neurons isolated from symptomatic (eight-month-old) HSPB1 S135F mice after 12 hours incubation with various concentrations (0, 0.25, 0.50 or 1.00 ⁇ M) of Tubastatin A.
- Panel a Quantification of the total number of mitochondria at various concentrations of Tubastatin A. One-way ANOVA. P>0.05.
- Panel b Quantification of the number of moving mitochondria at different concentrations of Tubastatin A. One-way ANOVA. *P ⁇ 0.05; **P ⁇ 0.001; P ⁇ 0.0001.
- FIG. 8 HDAC6 inhibition rescues axonal transport defects and restores the CMT2 phenotype.
- Panels a and b Axonal transport of mitochondria measured in DRG neurons isolated from ten-month-old HSPB1 S135F -expressing mice after 12 hours of treatment with TSA (0.4 ⁇ M), tubacin (2 ⁇ M), tubastatin A (1 ⁇ M) or an equivalent amount of DMSO.
- Total number of (Panel a) and number of moving (Panel b) mitochondria (per 200 seconds and per 100 ⁇ m) were quantified.
- n 20 to 30 cells isolated from three different mice for each condition. *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.0001.
- Panel g Motor performance on an accelerating rotarod of HSPB1 S135F -expressing mice treated for three weeks with TSA or tubastatin A.
- One-way ANOVA was used to analyze the data in Panels a, b, and e through i. Data are presented as means ⁇ s.e.m.
- FIG. 9 TSA or tubastatin A treatment leads to muscle reinnervation and rescues axonal transport defects.
- Panels a and b Effect of vehicle (DMSO), TSA or tubastatin A treatment on the innervation level of the gastrocnemius muscle in symptomatic, eight-month-old HSPB1 S135F -expressing mice.
- DMSO vehicle
- TSA or tubastatin A treatment on the innervation level of the gastrocnemius muscle in symptomatic, eight-month-old HSPB1 S135F -expressing mice.
- HDAC histone deacetylases, enzymes responsible for reversible protein deacetylation (EC number 3.5.1).
- HDAC family members eighteen HDAC family members have been identified. They can be divided into two categories, i.e., zinc-dependent enzymes (Class I, Class II and Class IV) and nicotinamide adenine dinucleotide-dependent enzymes (Class III: sirtuins).
- Class I HDACs include HDAC1, HDAC2, HDAC3 and HDAC8 and show homology to the yeast protein-reduced potassium deficiency 3.
- Class II HDACs include HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10 and are homologous to the yeast enzyme HDA1.
- Class II HDACs are further grouped into two subclasses, IIa (HDAC4, HDAC5, HDAC7, and HDAC9) and IIb (HDAC6 and HDAC10), according to their sequence homology and domain organization.
- HDAC11 the most recently identified member, is classified into the new Class IV of HDACs.
- Sirtuins including human sirtuin (SIRT)1-7 show distinct homology with the yeast enzyme Sir2.
- HDAC inhibitor is used herein to refer to a molecule capable of inhibiting the deacetylase function of one or more HDACs.
- HDAC inhibitors are well known in the art and include, but are not limited to, trifluoroacetylthiophene-carboxamides, tubacin, tubastatin A, WT 161, PCI-34051, MC1568, MC1575, suberoylanilide hydroxamic acid (also known as vorinostat or SAHA), Trichostatin A, sodium butyrate, valproic acid, M344, Sriptaid, Trapoxin, Depsipeptide (also known as Romidepsin), MS275 (Entinostat), 4-phenylimidazole, MC1293, droxinostat, curcumin, belinostat (PXD101), panobinostat (LBH589), MGCD0103 (mocetinostat), parthenolide and givinostat (ITF2357)
- a “selective HDAC inhibitor” or “specific HDAC inhibitor” is an inhibitor that selectively inhibits certain HDACs, while it does not inhibit others, or inhibits others to a much lower extent. For instance, a selective HDAC6 inhibitor will inhibit HDAC6, but not other HDACs; or it will be more active toward HDAC6. A selective class II HDAC inhibitor will typically inhibit class II HDACs, but not class I HDACs (or only to a much lower extent).
- a selective HDAC inhibitor will be two times more active toward the targeted HDAC(s) than to those non targeted, or four times more active, or six times more active, or eight times more active, or ten times more active, or 20 times more active, or even 50 times more active, or more.
- selective HDAC6 inhibitors include, but are not limited to, tubacin, tubastatin A, WT161, pyridylalanine-containing hydroxamic acids (Schäfer et al., Chem. Med. Chem. 2009; 4(2):283-90), C3 ethyl-substituted SAHA (Choi et al., Bioorg. Med. Chem. Lett. 2011; 21(20):6139-42).
- WO2011/091213 describes reverse amide compounds that are also selective HDAC6 inhibitors; their use is also explicitly envisaged.
- selective type II HDAC inhibitors examples include, but are not limited to, MC1568 and MC1575.
- Droxinostat is an example of an inhibitor selective for HDAC3, 6 and 8.
- Bufexamac is an inhibitor selective for type IIb HDACs, i.e., HDAC6 and HDAC10 (Bantscheff et al., Nature Biotechnology 29, 255-265 (2011)).
- non-selective HDAC inhibitors include, but are not limited to, trichostatin A, SAHA and valproic acid.
- HDAC inhibitors to treat a peripheral neuropathy, particularly Charcot-Marie-Tooth disease (CMT).
- CMT Charcot-Marie-Tooth disease
- methods of treating a peripheral neuropathy, such as Charcot-Marie-Tooth disease by administering a HDAC inhibitor to the subject who has the neuropathy (particularly Charcot-Marie-Tooth disease).
- HDAC inhibitors are considered equivalent, but comply with the different requirements with patentability across jurisdictions. It is to be understood that embodiments envisaged for methods of treatment also apply for the use of a compound to treat the disease and vice versa.
- the findings herein are applicable to numerous neuropathies, as they address a fundamental underlying principle, rather than specific symptoms associated with a particular disease. That is, it is shown that restoring of muscle reinnervation is possible, through recreation of new neuromuscular junctions. Thus, any disease or disorder in which loss of neuromuscular junctions is one of the symptoms can, in principle, be treated in this way. This particularly applies to diseases that have this as a major phenotype, such as peripheral neuropathies (that don't have a central component), either hereditary (e.g., CMT) or induced (e.g., chemotherapy-induced peripheral neuropathy).
- CMT hereditary
- induced e.g., chemotherapy-induced peripheral neuropathy
- peripheral neuropathy Although all types of peripheral neuropathy will benefit, at least to some degree, from the treatment as described herein, most beneficial effects are to be expected when the disorder is an axonopathy, i.e., when axons are primarily affected. This is because the HDAC inhibition as proposed herein has direct effects on axonal transport, and not on the myelin sheaths. Thus, in myelinopathies (where the myelin is first affected and the axons are secondarily affected), an improvement of symptoms is also expected (because of the secondary involvement of axons), but not always a complete recovery. However, it should be stressed that complete recovery is possible for myelinopathies as well, although this might require a chronic treatment to sustain protection of the unsheathed axons.
- CMT1 the demyelinating form
- a most particularly envisaged subclass of CMT2 or distal HMN are the diseases caused by mutations in HSPB1 (entry 602195 in OMIM).
- the exact pathogenic mechanism by which mutations in HSPB1 cause CMT2F and/or distal HMN2B is unknown.
- mutant HSPB1 formed intracellular aggregates and inhibited cell division and/or caused neuronal death 3, 12, 13 .
- mutant HSPB1 disrupted the neurofilament network, thereby disturbing the intracellular distribution of specific cargoes 12, 13 .
- transgenic mouse models for mutant HSPB1-induced CMT2 and distal HMN we developed and characterized transgenic mouse models for mutant HSPB1-induced CMT2 and distal HMN.
- mutant HSPB1 mice expressing mutant HSPB1 selectively in neurons recapitulate all key features of CMT2 or distal HMN, depending on the mutation.
- Evidence is provided that mutant HSPB1 leads to severe axonal transport defects in a cell-autonomous way.
- HDAC6 histone deacetylase 6
- mice The data shows that the neuronal expression of human HSPB1 with the S135F mutation results in a CMT2 phenotype, while the P182L mutation leads to a distal HMN phenotype in mice.
- These two animal models recapitulate the key features of these two diseases and closely resemble human clinical symptoms.
- the phenotypes are characterized by disturbances of mitochondrial motility within the axons, which is accompanied by a decrease of acetylated ⁇ -tubulin levels.
- Pharmacological inhibition of HDAC6 rescues the CMT2 phenotype in mutant HSPB1 mice and restores the axonal transport defect in neurons.
- HSPB1 S135F and HSPB1 P182L mice develop an adult-onset, slowly progressing disease without an effect on survival. This is reminiscent of what is observed in CMT2 and distal HMN diseases that start in adulthood, progress slowly and have no major impact on the lifespan of the patients 3, 4, 8-11 .
- Both mutant HSPB1 lines also demonstrate several other key features of these axonal neuropathies. Axonal degeneration appears to be involved in a length-dependent way. Both mutant HSPB1 lines also show signs of distal axonal loss in motor nerve fibers upon electrophysiological assessment. No signs of demyelination of the motor nerve fibers were observed.
- HSPB1 mice have clawed hind paws. All these phenotypic characteristics accurately mimic what is seen in CMT2 and distal HMN. These patients show distal limb muscle weakening and atrophy as well as reduced or absent deep tendon reflexes leading to foot deformities (such as pes cavus and hammertoes) and steppage gait 3, 8-11 .
- HSPB1 P182L mice show an earlier reduction in general motor coordination and in muscle force compared to HSPB1 S135F mice. Furthermore, the reduction in both motor coordination and muscle force, as well as the disturbance in the hind paw angle, is always more pronounced in HSPB1 P182L mice than in the HSPB1 S135F mice.
- the severity of the motor phenotype in HSPB1 P182L mice is also reflected in the electrophysiological findings. HSPB1 P182L mice have a more pronounced age-dependent reduction in CMAP amplitudes compared to HSPB1 S135F mice.
- mice have a mixed sensorimotor polyneuropathy, while the HSPB1 P182L mice have a pure motor neuropathy. This is indicated by the observation that HSPB1 S135F mice show prolonged response latencies to increased temperature, while the HSPB1 P182L , mice did not. Electrophysiological findings confirm this difference as only the HSPB1 S135F mice have reduced SNAP amplitudes. Furthermore, loss of small sensory axons was observed in HSPB1 S135F mice, while these sensory axons were spared in HSPB1 P182L mice.
- Thy 1.2 expression cassette that selectively drives the expression of the transgene in postnatal neurons and that motor neurons can only be cultured from embryos.
- cultured DRG neurons only show a phenotype when isolated from symptomatic animals and thus indicates that only studying neurons from sick animals is useful.
- the fact that both mutations are situated in different domains of the HSPB1 proteins seems to imply that different cell types show a different sensitivity to the negative effects of these mutated proteins.
- mutations situated in the C-terminal part of the protein mainly affect motor axons, while mutations in the N-terminal region and in the ⁇ -crystallin domain are affecting in general both motor and sensory neurons.
- mutant HSPB1 can cause the phenotypes in a cell-autonomous way as expression of human HSPB1 is limited to neurons in the transgenic mice and this is sufficient to induce the CMT2 or distal HMN phenotypes.
- the cell-autonomous pathology of mutant HSPB1-induced CMT2 and distal HMN is in line with findings in other CMT2 models.
- Neuron-specific expression in mutant mitofusin 2 (MFN2) mice showed reduced mass of anterior hind limb muscles, ultimately resulting in limp hind paws 27 .
- Another mouse model with neuronal expression of mutant MFN2 showed locomotor impairment and gait defects 28 .
- mice The phenotypes in our transgenic mice are probably caused by a gain-of-function mechanism. This is in line with the dominant inheritance patterns of mutant HSPB1-induced CMT2 and distal HMN in humans. Furthermore, Hspb1-knockout mice are viable and do not show any overt phenotype (Huang et al., Genesis 2007; 45(8):487-501). These transgenic HSPB1 mouse models provide us the unique opportunity to study the pathological mechanism responsible for the observed phenotypes. As it was previously shown that the presence of HSPB1 P182L disturbed the intracellular distribution of specific proteins and organelles in transfected cortical neurons, we first concentrated on axonal transport 12 .
- axonal transport appears to play a crucial role in many neurodegenerative diseases 30 . Although no differences in axonal transport were found in cultured DRG neurons isolated from HSPB1 S135F mice before disease onset, mitochondrial transport was severely affected in DRG neurons isolated from symptomatic mutant HSPB1 S135F mice. This seems to be a common theme in CMT as alterations in mitochondrial transport were also observed in other CMT2 models. Mutations in mitochondrial proteins such as MFN2 (causing CMT2A) and ganglioside-induced differentiation-associated protein 1 (GDAP1, causing CMT2K) affected mitochondrial motility in transfected cell lines 31-33 .
- MFN2 causing CMT2A
- GDAP1 ganglioside-induced differentiation-associated protein 1
- Mutant MFN2 showed an increased tethering to the endoplasmic reticulum, which impaired axonal transport of mitochondria in transfected DRG neurons 31, 32 .
- Mutant GDAP1 also affected mitochondrial dynamics partially excluding mitochondria from axons 33 .
- Mutant NEFL also led to mitochondrial dysfunction prior to neurofilament network disruption 34 .
- other proteins involved in axonal transport are mutated in patients with CMT2 and/or distal HMN, including the small GTPase RAB7 (CMT2B), emphasizing the central role of axonal transport defects in CMT2 pathology 2 .
- Intracellular transport in particular, along extended processes such as axons, requires motor proteins that distribute their cargoes using guidance cues 16, 35, 36 .
- Acetylated ⁇ -tubulin is one of these cues 17, 35, 36 . This is especially true for mitochondrial transport, since moving mitochondria preferentially localize to acetylated microtubules 35 .
- disturbance of ⁇ -tubulin acetylation plays a role in neurodegenerative diseases such as familial dysautonomia and that increasing acetylated ⁇ -tubulin induces an increase in axonal transport 19, 20 .
- HDAC6 Restoring levels of acetylated ⁇ -tubulin by inhibiting HDAC6 (e.g., using TSA, tubacin or tubastatin A) rescued the axonal transport defects suggesting a key role for deacetylation in the mechanism of mutant HSPB1-induced CMT, as it has been shown in other neurodegenerative disorders including Huntington's disease, multiple sclerosis but also peripheral nerve injuries 37-39 .
- Pharmacological inhibition of HDAC6 also increased mitochondrial transport in hippocampal neurons indicating that HDAC6 regulates axonal transport 19 .
- TSA and tubastatin A treatment of mutant HSPB1 mice also partially restored the CMT2 phenotype both at the behavioral and electrophysiological levels, further indicating that reduced acetylated ⁇ -tubulin levels play an important role in mutant HSPB1-induced CMT2 pathology.
- TSA brain-derived neurotrophic factor
- BDNF brain-derived neurotrophic factor
- TSA also has an important effect on histone acetylation, thereby influencing gene expression 25, 41, 42 .
- SMA spinal muscular atrophy
- an autosomal recessive motor neuron disease affecting children caused by insufficient SMN treatment with TSA increased the SMN protein expression leading to an improvement of motor performance and an increase in survival 25 .
- the HDAC inhibition that is described herein to treat peripheral neuropathy is particular inhibition of type II HDACs (i.e., using a type II HDAC inhibitor), more particularly of type IIb HDACs.
- the HDAC inhibitor is a selective inhibitor of type II HDACs.
- the HDAC inhibitor is a HDAC6 inhibitor. Even more particularly, the HDAC6 inhibitor is a selective HDAC6 inhibitor. A non-exhaustive list of HDAC and HDAC6 inhibitors that can be used is given above. According to specific embodiments, the HDAC inhibitor is a selective HDAC6 inhibitor selected from tubacin and tubastatin A.
- axonopathies i.e., disorders that are primarily characterized by dysfunctional axons, as opposed to demyelinating diseases, where the myelin sheath covering the axons is first affected.
- peripheral neuropathies i.e., peripheral neuropathies.
- neuropathies or axonopathies induced by external substances, such as drugs.
- chemotherapy-induced peripheral neuropathy CIPN
- vinka alkaloids e.g., vincristine, vinblastine, vindesine and vinorelbine
- platinum salts e.g., cisplatin, oxaliplatin
- taxanes e.g., paclitaxel, docetaxel
- epothilones ixabepilone and others
- bortezomib thalidomide and derivatives.
- transgenic animals expressing human mutant HSPB1 selectively in neurons has been developed. These mice demonstrate phenotypes that accurately replicate all key features of human symptoms of CMT2 and distal HMN.
- Mutant HSPB1 cells autonomously affect axonal transport and decrease acetylated ⁇ -tubulin levels. The reduction of acetylated ⁇ -tubulin levels is reversed by HDAC6 inhibition, which restores the defects in axonal transport and rescues the CMT2 phenotype behaviorally and electrophysiologically 47 .
- HDAC6 inhibition evidence is provided for the involvement of cytoskeletal changes in mutant HSPB1-induced CMT2 and distal HMN. Inhibition of HDAC6 may be a new therapeutic approach for both diseases, or for peripheral neuropathies in general.
- Transgenic mice were created using a Thy 1.2 expression cassette responsible for postnatal and neuron-specific expression of the transgene.
- the human wild-type (WT) or mutant (S135F and P182L) HSPB1 cDNA coupled to an N-terminal hemagglutinin (HA)-tag were cloned in this construct and transgenic animals were made using zygote injection.
- Western blot analysis revealed no human HSPB1 expression in non-neuronal tissues such as heart, liver and kidney (not shown). Brain, spinal cord, DRG and peripheral nerve expressed HA-tagged human HSPB1 ( FIG. 1 , Panel a). No significant differences in expression levels of HSPB1 were observed between the different transgenic mice (not shown).
- HSPB1 human WT or mutant HSPB1 was present only in the grey matter and in extended processes in the white matter (not shown).
- HSPB1 co-localized with the neuronal marker SMI-32 in ventral horn of transgenic mouse spinal cord, but not with glial fibrillary acidic protein (GFAP), confirming that human HSPB1 was exclusively expressed in neurons (not shown).
- GFAP glial fibrillary acidic protein
- mice were normal at birth and showed normal weaning and grooming behavior. The frequency of birth of all transgenic lines followed the normal Mendelian inheritance pattern indicating that there was no embryonic lethality. Furthermore, no differences in survival were observed between all genotypes (P>0.05; FIG. 2 , Panel a). However, at six months of age, all mutant (S135F and P182L) HSPB1 mice showed limb-clasping behavior when suspended by the tail, while non-transgenic and HSPB1 WT mice never did ( FIG. 1 , Panel b).
- mutant HSPB1-expressing mouse lines showed hesitations in placing their paws and had increased hind paw angles and decreased hind paw print areas, whereas forepaws were unaffected (P ⁇ 0.0001; FIG. 3 , Panels a-f).
- the decrease in hind paw print area is in line with the clawed hind paws observed in mutant HSPB1-expressing mice ( FIG. 3 , Panel g).
- These clawed hind paws were more pronounced in mice expressing HSPB1 P182L than in those expressing HSPB1 S135F and were not observed in mice expressing HSPB1 WT or non-transgenic mice.
- the P182L mutation in HSPB1 is associated with a pure motor neuropathy, while patients carrying the S135F mutation can also have sensory deficits, in particular, for pain and temperature 1, 2 . Therefore, tests were performed to see whether HSPB1 S135F and HSPB1 P182L mice showed signs of sensory impairment using the hotplate test.
- HSPB1 P182L did not show any differences in response latencies compared to HSPB1 WT mice ( FIG. 4 , Panel a), indicating that HSPB1 P182L mice have only impaired motor performance while the HSPB1 S135F mice have both motor and sensory deficits.
- Nerve conduction studies are routinely done on CMT patients to discriminate demyelinating (type 1) from axonal (type 2) forms, as well as to assess whether patients show either a mixed sensorimotor (CMT2) or a pure motor neuropathy (distal HMN). Therefore, nerve conduction studies were performed on transgenic HSPB1 mice using sub-dermal electrodes, either at the level of the gastrocnemius muscle to measure compound muscle action potentials (CMAPs), or in the distal end of the tail to record sensory nerve action potentials (SNAPs). HSPB1 P182L and HSPB1 S135F mice showed a significant decrease in peak-to-peak amplitude of CMAPs at six and eight months of age, respectively (P ⁇ 0.0001; FIG.
- HSPB1 S135F mice CMAP amplitudes were significantly decreased compared to HSPB1 WT at the age of eight months, while SNAP amplitudes were already significantly lower at the age of six months. Since the recording electrodes for the SNAP amplitudes were placed more distally (4 cm distally from the base of the tail) compared to the electrodes for the CMAP amplitudes (at the level of the gastrocnemius muscle), it was concluded that the axonal neuropathy is length-dependent (i.e., longer axons are affected first). In conclusion, the electrophysiological findings confirm that HSPB1 S135F mice have a mixed sensorimotor polyneuropathy (CMT2), while HSPB1 P182L mice develop a pure motor neuropathy (distal HMN).
- CMT2 mixed sensorimotor polyneuropathy
- mice expressing mutant HSPB1 compared to HSPB1 WT -expressing mice ( FIG. 5 , Panels d and 3).
- HSPB1 WT -expressing mice had almost no visibly denervated neuromuscular junctions, whereas, of the remaining neuromuscular junctions, HSPB1 S135F -expressing and HSPB1 P182L -expressing mice showed a marked increase of denervated neuromuscular junctions ( FIG. 4 , Panel j).
- Both mutant HSPB1-expressing mouse lines showed atrophic muscle fibers in the gastrocnemius muscle accompanied by pyknotic nuclear clumps (data not shown). Fiber type grouping was observed in muscles from both mutant HSPB1-expressing mouse lines, whereas muscle fibers showed a normal “checkerboard” appearance in HSPB1 WT -expressing mice (not shown).
- histological examination of hind limb muscles and peripheral nerves confirms that HSPB1 S135F mice have a mixed sensorimotor axonal polyneuropathy (CMT2), while HSPB1 P182L mice develop a pure motor axonal neuropathy (distal HMN), which completely mimics human conditions. The defects are not due to demyelination, but to distal axonal loss.
- HSPB1 P182L DRG neurons did not show any difference in either total number of mitochondria or moving mitochondria, consistent with the pure motor phenotype of these mice (P>0.05; FIG. 6 , Panels b and c), and mitochondrial transport was also unaffected in DRG neurons isolated from presymptomatic mutant HSPB1 S135F -expressing mice ( FIG. 6 , Panels d and e). This shows that the disturbance of axonal transport in the isolated DRG neurons coincides with the presence of the sensory deficits in the transgenic mice.
- Mitochondria are mainly transported along microtubules consisting of polymerized tubulin 16 .
- Tubulin can undergo a variety of post-translational modifications such as tyrosination/detyrosination, glutamylation, glycylation and acetylation/deacetylation 17 .
- Acetylation/deacetylation of ⁇ -tubulin was focused on since this process is needed for intracellular trafficking of a wide range of proteins and organelles because it is considered as a recognition signal for the anchoring of molecular motor 17-19 .
- decreased levels of acetylated ⁇ -tubulin have been associated with neurodegenerative diseases 20, 21 .
- HDAC6 Inhibition Rescues Axonal Transport Defects in Cultured HSPB1 S135F Neurons
- HDAC6 Histone deacetylase 6
- HDAC6 a class II histone deacetylase
- Trichostatin A is a pan-HDAC inhibitor that selectively inhibits the deacetylating function of class I and class II (but not class III) HDACs, whereas both tubacin and tubastatin A ( FIG. 7 ) are highly selective HDAC6 inhibitors (refs. 24 and 46).
- TSA Trichostatin A
- tubacin or tubastatin A Treatment of DRG neurons isolated from symptomatic HSPB1 S135F -expressing mice with TSA, tubacin or tubastatin A increased total numbers of mitochondria FIG. 8 , Panel a) and restored the number of moving mitochondria ( FIG. 8 , Panel b). Tubacin and tubastatin A were more effective compared to TSA ( FIG. 8 , Panels a and b).
- TSA, but not tubastatin A also increased acetylated ⁇ -tubulin amounts in spinal cord ( FIG. 8 , Panels c, d, and f). Both TSA and tubastatin A did not affect overall ⁇ -tubulin abundance ( FIG. 8 , Panels c and d).
- TSA or tubastatin A treatment significantly increased the motor performance of HSPB1 S135F -expressing mice (P ⁇ 0.0001; FIG. 8 , Panel g).
- Treatment with either drug also increased electrophysiological parameters such as CMAP amplitudes as well as SNAP amplitudes ( FIG. 8 , Panels h and i).
- CMAP amplitudes as well as SNAP amplitudes
- FIG. 9 , Panel a the loss of acetylcholine-receptor clusters at the end plates in gastrocnemius muscle was restored
- FIG. 9 , Panel b the level of denervation of the remaining neuromuscular junctions was decreased.
- tubastatin A increased the total number of mitochondria ( FIG. 9 , Panel c). Moreover, the number of moving mitochondria was increased significantly after TSA or tubastatin A treatment (P ⁇ 0.0001; FIG. 9 , Panel d). Tubastatin A was more effective than TSA and resulted in a complete rescue of mitochondrial motility ( FIG. 9 , Panels c and d).
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007061939A2 (en) * | 2005-11-18 | 2007-05-31 | Gloucester Pharmaceuticals, Inc. | Metabolite derivatives of the hdac inhibitor fk228 |
US7244853B2 (en) * | 2001-05-09 | 2007-07-17 | President And Fellows Of Harvard College | Dioxanes and uses thereof |
WO2007130419A2 (en) * | 2006-05-04 | 2007-11-15 | Merck & Co., Inc. | Histone deacetylase inhibitors for the treatment of neurodegeneration |
US20080312175A1 (en) * | 2007-06-01 | 2008-12-18 | Duke University | Methods and compositions for regulating hdac4 activity |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2320331C2 (ru) * | 2002-03-04 | 2008-03-27 | МЕРК ЭйчДиЭйСи Рисерч, ЛЛС. | Способ индукции конечной дифференцировки |
WO2008062201A1 (en) | 2006-11-22 | 2008-05-29 | Karus Therapeutics Limited | Depsipeptides and their therapeutic use |
GB0715750D0 (en) | 2007-08-13 | 2007-09-19 | Karus Therapeutics Ltd | Chemical compounds |
JP2010540630A (ja) | 2007-10-04 | 2010-12-24 | メルク・シャープ・エンド・ドーム・コーポレイション | ヒストン脱アセチル化酵素阻害剤としてのn−ヒドロキシ−ナフタレンジカルボキサミド及びn−ヒドロキシ−ビフェニル−ジカルボキサミド化合物 |
EP2065038A1 (de) * | 2007-11-30 | 2009-06-03 | Pharnext | Neue therapeutische Ansätze zur Behandlung der Charcot-Marie-Tooth Krankheit |
GB0809329D0 (en) | 2008-05-22 | 2008-07-02 | Karus Therapeutics Ltd | Depsipeptides and their therapeutic use |
EP2293845A1 (de) | 2008-05-22 | 2011-03-16 | Karus Therapeutics Limited | Depsipeptide und ihre therapeutische verwendung |
WO2009141658A1 (en) | 2008-05-22 | 2009-11-26 | Karus Therapeutics Limited | Depsipeptides and their therapeutic use |
EP2391605B1 (de) | 2009-01-28 | 2017-11-08 | Karus Therapeutics Limited | Scriptaid-isostere und deren verwendung in der therapie |
GB0905970D0 (en) | 2009-04-06 | 2009-05-20 | Karus Therapeutics Ltd | Depsipeptides and their therapeutic use |
EP3091004B1 (de) | 2010-01-22 | 2017-12-13 | Acetylon Pharmaceuticals, Inc. | Umgekehrte amidverbindungen als proteindeacetylase-hemmer und verwendungsverfahren dafür |
CA2812855C (en) | 2010-10-08 | 2017-12-19 | Vib Vzw | Hdac inhibitors to treat charcot-marie-tooth disease |
-
2011
- 2011-10-06 CA CA2812855A patent/CA2812855C/en active Active
- 2011-10-06 AU AU2011311531A patent/AU2011311531B2/en active Active
- 2011-10-06 WO PCT/EP2011/067438 patent/WO2012045804A1/en active Application Filing
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- 2011-10-06 EP EP11767988.6A patent/EP2624832B1/de active Active
- 2011-10-06 ES ES11767988.6T patent/ES2647368T3/es active Active
- 2011-10-06 US US13/877,648 patent/US20130227717A1/en not_active Abandoned
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-
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- 2015-09-16 US US14/856,264 patent/US20160000766A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7244853B2 (en) * | 2001-05-09 | 2007-07-17 | President And Fellows Of Harvard College | Dioxanes and uses thereof |
WO2007061939A2 (en) * | 2005-11-18 | 2007-05-31 | Gloucester Pharmaceuticals, Inc. | Metabolite derivatives of the hdac inhibitor fk228 |
WO2007130419A2 (en) * | 2006-05-04 | 2007-11-15 | Merck & Co., Inc. | Histone deacetylase inhibitors for the treatment of neurodegeneration |
US20080312175A1 (en) * | 2007-06-01 | 2008-12-18 | Duke University | Methods and compositions for regulating hdac4 activity |
Non-Patent Citations (4)
Title |
---|
Houlden et al Neurology, 2008; 71: 1660-1668 * |
Kijima et al (J Hum Genet (2005) 50: 473-476 * |
Legace et al The Journal of Biological, 2004, 279, 18, 18851-18860 * |
Vasilescu et al Journal of Neurological Science, 1984, 63, 11-25 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9238028B2 (en) | 2010-10-08 | 2016-01-19 | Vib Vzw | HDAC inhibitors to treat charcot-marie-tooth disease |
WO2020018647A1 (en) * | 2018-07-17 | 2020-01-23 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Methods of treating pacs1 and pacs2 syndromes |
US11453661B2 (en) | 2019-09-27 | 2022-09-27 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
US11958845B2 (en) | 2019-09-27 | 2024-04-16 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
WO2023288110A1 (en) * | 2021-07-15 | 2023-01-19 | The United States Government As Represented By The Department Of Veterans Affairs | Romidepsin as a therapeutic agent for nerve-injury induced neuropathic pain and spasticity |
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