WO2010060934A2 - Protéines cnnm et utilisations de celles-ci - Google Patents
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- WO2010060934A2 WO2010060934A2 PCT/EP2009/065848 EP2009065848W WO2010060934A2 WO 2010060934 A2 WO2010060934 A2 WO 2010060934A2 EP 2009065848 W EP2009065848 W EP 2009065848W WO 2010060934 A2 WO2010060934 A2 WO 2010060934A2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4738—Cell cycle regulated proteins, e.g. cyclin, CDC, INK-CCR
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/16—Ophthalmology
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/18—Dental and oral disorders
Definitions
- the present invention relates proteins from the group consisting of CNNMl, CNNM2, CNNM3 and CNNM4 , its derivatives or fragments thereof for use as a medicament.
- Cone-rod dystrophies are inherited dystrophies of the retina characterized by the accumulation of deposits mainly localized to the cone-rich macular region of the eye. Dystrophy can be limited to the retina or be part of a syndrome.
- syndromic cone-rod dystrophies are genetically heterogeneous with mutations in genes encoding structural, cell adhesion and transporter proteins.
- CNNM4 conserved domain proteins 4 gene
- Cone-rod dystrophy is a generic term that designs a clinically and genetically heterogeneous group of diseases of the retina.
- the macula is characteristically affected first by typical decreased visual acuity and loss of sensitivity in the central visual field, in contrary to rod-cone dystrophy which is best represented by retinitis pigmentosa leading to loss of peripheral vision and night blindness.
- CRD can be non syndromic and due to mutations in genes implicated, among others, in photoreceptor development, synaptic transmission or structure; in retinoid metabolism or in opsin trafficking 1 .
- CRD also occurs in syndromic forms as in Bardet-Biedl 2 , thiamine responsive megaloblastic anemia (Rogers syndrome) 3 or spinocerebellar atexia type 7 4 . In rare instances, it has been associated with dysmorphic syndromes or metabolic dysfunctions 1 . Recently, a new autosomic recessive syndrome associating CRD and amelogene- sis imperfecta (AI) has been described 5 and mapped to human chromosome 2qll 6;7 (OMIM: 217080) . For the first time, we herein report on two additional families and show that mutations in the CNNM4 gene, a metal ion transporter encoding gene, cause this condition. Straight-forward applications of this finding are also discussed.
- the pedigree consisted of two families. Blood was collected from family members after informed consent and DNA was isolated from peripheral leukocytes with the Nucleon-Bacc2 (Am- ersham Biosciences) . The affected family members had a complete eye and dental evaluation, including best corrected Snellen visual acuity (BCVA) , slit lamp examination, funduscopy, Goldmann perimetry, electroretinography (ERG) , optical coherence tomography (OCT), fundus colour pictures and autofluorescence . Affected members were carefully assessed by a dentist. The parents and unaffected siblings had complete physical evaluation, including best vision and fundus evaluation and dental inspection. The protocol of the study adhered to the provisions of the Declaration of Helsinki.
- Genome scan Linkage analysis was performed at the University of Lausanne Affymetrix GeneChip platform applying the human mapping 5OK Xbal array according to the manufacturer's protocols on fam- ily A. Data were acquired with Affymetrix GCOS v.1.2 software. An in-house software was implemented in order to display continuous homozygosity regions among the affected individuals. Genes in the interval defined by the homozygous SNPs were identified in Ensembl and evaluated for potential implication based on expression and previous implication in inherited diseases.
- RT- PCR of mouse Cnnm4 was performed on RNA extracted from teeth of 2 -day old C57B1 / 6 mice us ing the fol low ⁇ ing primers : 5 ' - CTCTA GGAGG CACTC TTCTGC- 3 ' and 5 ' -ATCCT CAGCC AGCCA TGC- 3 ' .
- primers were designed for RT-PCR as well as real-time PCR and are described in Table 2. Genomic DNA contamination was checked as described 8 .
- cnnm4 MO ATTTT GCCAC TGTCC ACTCA CTGTA
- control-MO ct-MO
- ATaTT cCCAC TcTCC ACTgA CTcTA ATaTT cCCAC TcTCC ACTgA CTcTA
- Toluidine Blue-staining Embryos were fixed in 4% PFA overnight. Standard Technovit 8100 embedding protocol was used, embryos were sectioned on microtome (5 ⁇ m thick sections) and stained with toluidine blue. For cell count, sections including the optic nerve were used as well as one before and one after. The eyes from 6 wild type, cnnm4 MO- and ct-MO-injected embryos were screened. Zebrafish do not have buccal teeth, but instead have two sets of pharyngeal teeth.
- Embryos were evaluated at 5 dpf and the number of ganglion cells was counted on toluidine blue-stained sections containing the optic nerve. The number of GCL from wt embryo was set to 1 and the counts in the morphants and rescued embryos were compared.
- ARVO Association for Research in Vision and Ophthalmology
- the OCT device that was used is not sensitive enough to evaluate any ganglion cell loss. However, if present, such a loss would be associated with reduced night vision, a sign often present in rod cone dystrophies.
- Fullfield photopic ERGs performed according to protocols recommended by the International Society for Clinical Electrophysiol- ogy of Vision (ISCEV) was non recordable. Under scotopic conditions, b-wave amplitudes were markedly reduced in patient II.1 and severely reduced in patient II.4. A slightly delayed culmination time of the b-wave was observed in both patients. During the 7 years follow-up of patient II.1, the remaining scotopic bwave dropped by 40% of the lower limit for the age. At the same time, both children were followed by a dentist for AI (Fig. Ih) .
- patient II.4 had a mandibular cyst which contained the 2 lower incisives and 1 premolar.
- Family B is a 5-generation consanguineous family originating from Lebanon (Fig. Ib) .
- Two sisters and 1 cousin were affected with a disease very closely resembling patients from family A.
- a bilateral nystagmus was noted by the parents.
- their major complaints were the presence of photophobia and difficulties to see in darkness.
- the decidual and permanent teeth were yellow/brown showing no enamel layer with numerous carious lesions in the 2 sisters, consistent with a hypoplastic, hypomineralized AI.
- ERG examination of patient V.6 at 2 years according to ISCEV standards showed that the scotopic reponse was within normal while the photopic response was severely attenuated.
- Arginine 236 is located between the first and second transmembrane domains of the protein and is totally conserved among species as far as C. elegans . It is also fully conserved in human and mouse paralogs (Fig. 6) . Both these mutations were analyzed in ethnically matched control individuals and in 1248 index patients with various forms of retinal degeneration. The C heterozygous duplication was observed in one control individual coming from the same geographical region as family A. No mutation was observed in the screened cohort of patients .
- Cnnm4 was evaluated by immunohistology on postnatal day 2 (P2) and on 2-month-old (2M) C57B1/J6 mice. At 2M, strong expression was observed in the different parts of the eye (Fig. 2) .
- Cnnm4 expression is mainly observed in the epithelium surrounding the nuclei, in the keratocytes and in the endoderm.
- Cnnm4 expression was concentrated in the ganglion cell layers, the inner (IPL) and outer plexiform layers (OPL) and the inner and outer photoreceptor segments (Fig. 2) where it is mainly localized to the cytoplasm compartment, surrounding the nucleus.
- IPL and OPL consist mainly of connecting fibrils and dendrites from ganglion, bipolar, amacrine, Muller and horizontal cells and rod and cone photoreceptors.
- the nuclei of the inner and outer cell layers as well as the retinal pigment epithelium also expressed Cnnm4, but at a lower level. This expression is consistent with the observation that Cnnm4 is localized in dendrites and soma of cultured neurons 13 .
- AI describes a group of inherited disorders primarily affecting the formation of enamel, a tissue with low protein and high mineral content.
- ameloblasts secrete the 4 major matrix proteins and proteases: amelogenin, ameloblastin, enamelin and enamelysin. While this part of tooth development is relatively well characterized, not much is known on the maturation of enamel, during which the protein content is slowly being reduced and the mineral content is increased in order to produce enamel, the strongest tissue of the body 14 ' '15 .
- CNNM4 is implicated in ion transport 13 ' '16 , possibly magnesium, the hypoplastic/ hypomineralised form of AI present in both families could result from aberrant mineralization of enamel.
- CNNM4 is characterized by an " Egyptian conserved domain" that is evolutionarily conserved in species ranging from bacteria to mammals 16 , including zebrafish.
- dpf day post fertilization
- dpf transient tachycardia was observed in most of the embryos treated with MO. This tachycardia was not observed anymore at 5 dpf.
- the eyes of the morphants showed a reduction of approximately 35% of the number of ganglion cells on toluidine blue- stained sections. This reduction was rescued by about 50% with injection of human CNNM4 mRNA (Fig. 4) .
- CNNM proteins are also known under the name of ACDPl to -4 and cyclin Ml to -4.
- CNNM4 is also sometimes referred to as FLJ42791 or KIAA1592.
- CNNM shall be construed as to comprise all these different denominations.
- the 775-amino acid CNNM4 protein has four transmembrane domains, a sequence motif present in cyclin box, a cNMP-binding domain (cyclic nucleotide- monophosphatebinding domain) , two cystathionine-beta-synthase (CBS) domains and a DUF21 domain 16 .
- CBS domains are small intracellular modules, usually found in two or four copies and whose function is still debated 17 .
- Proteins with CBS domains have been implicated as metabolic sensor (Cystathionine beta-synthase) , ATP binding (AMPactivated protein kinase) , nucleotide biosynthesis (inosine-5' -mono-phosphate dehydrogenase, IMPDH) and in intracellular trafficking and protein-protein interactions (CLC family) 17 .
- metabolic sensor Cystathionine beta-synthase
- AMPactivated protein kinase ATP binding
- IMPDH nucleotide biosynthesis
- IMPDH intracellular trafficking and protein-protein interactions
- CLC family protein-protein interactions
- CNNM4 is expressed in many tissues and recent studies on spinal cord dorsal horn neurons have shown that it is located on or close to the plasma membrane where it interacts with cytochrome oxydase 11 (COXIl) to regulate metal ion homeostasis 13 .
- COXIl cytochrome oxydase 11
- Metal ions are indispensable to many physiological processes, in particular to the visual cycle where, among other functions, magnesium is critical for adjusting the Ca 2+ sensitivity of the membrane guanylate cyclase 2d (GUCY2D) , an enzyme that produces cGMP in photoreceptor cells when stimulated by guanylyl cyclase- activating protein-1 (GCAPl) .
- GUI2D membrane guanylate cyclase 2d
- GCAPl guanylyl cyclase- activating protein-1
- GUCY2D Under physiological conditions, activation of photoreceptor GUCY2D is caused by Mg 2+ / Ca 2+ exchange in the EF-hands of GCAPl. Mutations in GUCY2D or GCAPl have been associated with rod-cone dystrophy 6 , Leber congenital amaurosis, a severe form of rod-cone dystrophy 21 and cone dystrophy, respectively 22 . Magnesium is also essential in enamel formation. It is found at high concentrations in enamel fluid surrounding the forming enamel crystals where it can compete with Ca ions for adsorption onto these crystals 23 .
- Releasing molecules and -devices useful in the context of the present invention are exhaustively known in the art, especially in ophthalmology, such as e.g. Vitrasert (FDA approved; Bausch and Lomb, Inc.), Retisert (FDA approved; Bausch and Lomb, Inc.), Medidur (FDA approved; Alimeira Sciences), Encapsulated Cell Technology (ECT, Neurotech) , Posurdex (Allergan, Inc.) .
- Vitrasert FDA approved; Bausch and Lomb, Inc.
- Retisert FDA approved; Bausch and Lomb, Inc.
- Medidur FDA approved; Alimeira Sciences
- Encapsulated Cell Technology ECT, Neurotech
- Posurdex Allergan, Inc.
- cell-penetrating peptides are described exhaustively and well known to the person of routine skill in the art, cf e.g. Bonny C, Oberson A, Negri S, Sauser C, Schorderet DF.
- Cell-permeable peptide inhibitors of JNK novel blockers of beta-cell death. Diabetes, 50:77-82, 2001.
- a suitable peptide is e.g. marketed by Xigen S. A. (Lausanne, Switzerland) under the tradename ICPTTM.
- NT 026970.9 (Sequence downloaded from Ensembl, Nov 23, 2008), Chromosome: NCBI36 : 2 : 96789766 : 96841955 : 1) SEQ ID #2: Human CNNM4 mRNA sequence (normal) , Accession # NM_020184.3; GI.94681045
- SEQ ID #4 Human CNNM4 mRNA sequence with dupC mutation
- SEQ ID #5 Human CNNM4 protein sequence with p.L438PfsX9 mutation; Duplication induces a frameshift mutation with a new putative stop codon (see SEQ ID # 17)
- SEQ ID #6 Human CNNM4 mRNA sequence with c.707G>A mutation
- SEQ ID #17 Mutated amino acids of SEQ ID #5; followed by STOP codon
- Figure 1 Pedigrees of family A (a) and B (b) . Filled symbols, affected individuals; open symbols, unaffected individuals, (c) Partial electropherograms of heterozygous (+/-) and homozygous
- OCT (patient II.4) showing decreased foveal and retinal thickness, loss of well defined retinal layers suggesting extensive loss of retinal cells and hyperreflectivity in the choroids due to the RPE and choriocapillaris atrophy, (h) Photograph of mouth
- FIG. 1 Cnnm4 immunostaining of cornea (a-c) and retina (d-f) of 2-month-old mouse retina.
- Cnnm4 is mainly expressed in the epithelium (epi) , surrounding the nuclei, in the keratocyte present in the stroma (st) and endothelium (en) .
- epi epithelium
- st stroma
- en endothelium
- immunostaining is mainly localized in the ganglion cell layer (arrow) , inner and outer plexi- form layers and the outer segments of the photoreceptors, (d) DAPI staining of the same slide, (f) negative control of immu- nostaining.
- epi epithelium
- st stroma
- en endothelium
- arrow ganglion cell layer
- asterisk inner cell layer
- filled triangle outer cell layer
- triangle retinal pigment epithelium.
- FIG. 3 Immunostaining of a lower incisive of a 2-day-old mouse. Cnnm4 is expressed in all tissues of the mandibula, including muscle and connective tissue (b) , DAPI staining of the same slide (a) , negative control of immunostaining (c) . At higher magnification (40Ox) , Cnnm4 is observed in the ameloblasts (filled triangle) and their cell body (open triangle) as well as in the odontoblasts (asterisk) (e) . (d) DAPI staining of the same slide, (f) negative control of hybridization .
- WT wild-type
- MO morpholino-treated embryos
- rescue mor- pholino-treated embryos injected with CNNM4 mRNA.
- Figure 5 Schematic representation of homozygous regions (black box) on human chromosomes.
- FIG. 7 Cnnm4 mRNA expression is at its highest levels in the mouse retina.
- Mouse Cnnml, -2, -3 and -4 mRNA expression was assessed by RT-PCR (panel A) and quantitative PCR (panel B) in mouse brain, retina, cornea, lens and rentinal pigment epithelium with attached choroids (RPE) samples. Pooled total RNA samples of 2 mice were used for each datapoint and quantitative results was performed on three samples in duplicate +/- SEM.
- RT-PCR For RT-PCR, amplified DNA fragments were analyzed on a 2% agarose gel and fragments of the expected size were detected, respectively 440 bp for Cnnml, 333 bp for Cnnm2, 195 bp for Cnnm3, 280 bp for Cnnm4 and 198 bp for the control gene RL8 (ribosomal protein L8), als indicated by the lkb Molecular Weight Marker (M; Roche, Basel, Switzerland) .
- M lkb Molecular Weight Marker
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Abstract
La présente invention concerne des protéines du groupe constitué de CNNM1, CNNM2, CNNM3 et CNNM4, des dérivés ou des fragments de celles-ci pour utilisation en tant que médicament, pour des applications de traitement et/ou de diagnostic. L’invention concerne en outre une séquence d’ADN génomique humain, ADNc ou ARNm codant pour une protéine fonctionnelle choisie dans le groupe constitué de CNNM1, CNNM2, CNNM3 et CNNM4 et des dérivés ou fragments fonctionnels de celles-ci.
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WO2003008557A2 (fr) * | 2001-07-19 | 2003-01-30 | University Of Florida | Activateurs de kinases dependant des cyclines |
WO2007130423A2 (fr) * | 2006-05-01 | 2007-11-15 | New York Society For The Ruptured And Crippled Maintaining The Hospital For Special Surgery | Marqueurs biologiques de tissu de plaie chronique et méthodes d'utilisation pour des critères de débridement chirurgical |
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WO2003008557A2 (fr) * | 2001-07-19 | 2003-01-30 | University Of Florida | Activateurs de kinases dependant des cyclines |
WO2007130423A2 (fr) * | 2006-05-01 | 2007-11-15 | New York Society For The Ruptured And Crippled Maintaining The Hospital For Special Surgery | Marqueurs biologiques de tissu de plaie chronique et méthodes d'utilisation pour des critères de débridement chirurgical |
Non-Patent Citations (5)
Title |
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DOWNEY L.M. ET AL.: "Identification of a locus on chromosome 2q11 at which recessive amelogenesis imperfecta and cone-rod dystrophy cosegregate." EUR. J. HUM. GENET., vol. 10, 2002, pages 865-869, XP002581334 * |
GOYTAIN ANGELA ET AL: "Functional characterization of ACDP2 (ancient conserved domain protein), a divalent metal transporter" PHYSIOLOGICAL GENOMICS, AMERICAN PHYSIOLOGICAL SOCIETY, US LNKD- DOI:10.1152/PHYSIOLGENOMICS.00058.2005, vol. 22, no. 3, 11 August 2005 (2005-08-11), pages 382-389, XP002535555 ISSN: 1094-8341 * |
GUO D. ET AL.: "Physical interaction and functional coupling between ACDP4 and te intracellular chaperone COXII, an implication of the role of ACDP4 in essentila metal ion transport and homeostasis." MOLECULAR PAIN, vol. 1, 15, April 2005 (2005-04), XP002581333 * |
MICHAELIDES M. ET AL.: "Progressive cone and cone-rod dystrophies : phenotypes and underlying molecular genetic basis." SURVEY OF OPHTHALMOLOGY, vol. 51, no. 3, 2006, pages 232-258, XP002581335 * |
WANG C-Y ET AL: "Molecular cloning and characterization of a novel gene family of four ancient conserved domain proteins (ACDP)" GENE, ELSEVIER, AMSTERDAM, NL LNKD- DOI:10.1016/S0378-1119(02)01210-6, vol. 306, 13 March 2003 (2003-03-13), pages 37-44, XP004416777 ISSN: 0378-1119 * |
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