WO2023177314A1 - A low molecular weight compound for use in the treatment of spinocerebellar ataxia type 3 - Google Patents
A low molecular weight compound for use in the treatment of spinocerebellar ataxia type 3 Download PDFInfo
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- WO2023177314A1 WO2023177314A1 PCT/PL2023/050017 PL2023050017W WO2023177314A1 WO 2023177314 A1 WO2023177314 A1 WO 2023177314A1 PL 2023050017 W PL2023050017 W PL 2023050017W WO 2023177314 A1 WO2023177314 A1 WO 2023177314A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
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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
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
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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
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the subject of the invention is a low molecular weight compound for use in the treatment of spinocerebellar ataxia type 3.
- the invention concerns the field of treatment of spinocerebellar attack type 3, caused by the presence of mutant ataxin protein 3.
- Neurodegenerative diseases such as polyglutamine diseases, Alzheimer's disease, and Parkinson's disease often share clinical and molecular symptoms. Many of them have similar genetic etiology, including gene mutations that cause abnormal protein function. These functions lead to protein aggregation and accumulation in neurons, neuronal degeneration, defective neurotransmission and excitotoxicity, energy deficits, abnormal intracellular signaling, transcriptional changes, and inflammatory changes (McLoughlin, H.S. et al., 2020. Pathogenesis of SC A3 and implications for other polyglutamine diseases. Neurobiology of Disease 134, 104635.).
- SCA3 Spinocerebellar ataxia 3
- MBD Machado-Joseph disease
- SCA3 Neurological features, pathogenesis and animal models. Cerebellum 7, 125-137.
- Pathological changes include dysfunction and loss of neurons in the deep cerebellar nuclei, the nuclei of the bridge, as well as the nuclei of the vestibular and cranial nerves, the spinocerebellar segment (Clarke's column), and anterior horns (Rub, U. et al., 2013. Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. Prog. Neurobiol. 104, 38-66).
- Spinocerebellar ataxia type 3 is a progressive neurodegenerative disease for which there is no effective causal therapy underlying the mechanism of the disease. Most of the available therapies are associated with alleviating individual symptoms of the disease. Currently, tested drugs include neurotransmitter modulators, ion transport inhibitors, growth factors, histone deacetylase inhibitors and autophagy enhancers, and tests using adipocyte-derived stem cells and umbilical cord blood.
- proteasome has been identified in nuclear inclusions of ataxin 3 and has been shown to inhibit aggregation of mutant ataxin 3 (Chai, Y. et al., 1999. Evidence for Proteasome Involvement in Polyglutamine Disease: Localization to Nuclear Inclusions in SCA3/MJD and Suppression of Polyglutamine Aggregation in vitro. Human Molecular Genetics 8, 673-682).
- proteasome inhibitors have been used in the treatment of cancer.
- the publication No. EP2619184B1 disclosed the use of bortezomib in the treatment of neurodegenerative diseases.
- the invention aims to provide an effective and causal drug in the therapy of spinocerebellar ataxia type 3, which reduces the level of mutant ataxin 3 in cells.
- the subject of the invention is a low molecular weight compound for use in the treatment of spinocerebellar ataxia type 3, which is selected from bortezomib, carfilzomib, VLX1570, or oprozomib with the following chemical formulas: oprozomib
- the action of the low molecular weight compounds, according to the present invention consists in the inhibition of the proteasome.
- the level of pathogenic mutant ataxin 3 protein in the cells of patients with spinocerebellar ataxia type 3 is significantly reduced.
- Figs. 1A and IB depict the diagrams of the applied methods of administration of low molecular weight compounds, which reflect the possible scheme of administration in patients with spinocerebellar ataxia type 3.
- the first method (Fig. 1A) consisted in continuous exposure of cells to low molecular weight compounds. The tested compounds were administered in a given concentration to a culture medium with a reduced amount of FBS (2%). At 48 hours, the medium was exchanged for fresh medium containing low molecular weight compounds at a given concentration after 48 hours. After another 24 hours, the cells were lyzed. This method was equivalent to the continuous delivery of therapeutics to patients, while the potential administration to patients is not limited below or above 72 hours.
- the second method (Fig. 1A) consisted in continuous exposure of cells to low molecular weight compounds. The tested compounds were administered in a given concentration to a culture medium with a reduced amount of FBS (2%). At 48 hours, the medium was exchanged for fresh medium containing low molecular weight compounds at a given concentration after 48 hours. After another
- IB consisted in administering low-molecular compounds alternately with a medium not containing low molecular weight compounds.
- the cells were exposed to therapeutic substances for 24 hours and then cultured for 2 days in a medium without low molecular weight compounds. After 10 days, the cells were lyzed.
- This method simulated administration at time intervals, but the reported treatment times and breaks in the treatment of patients are not limited above or below to the mentioned number of hours.
- GAPDH - Glyceraldehyde 3-phosphate dehydrogenase a control protein used to normalize the level of protein expression
- MG132 - the name of the reference proteasome inhibitor the use of the drug is not limited to patients with the number of CAG repeats or PolyQ sequences mentioned before.
- the therapy can be used in patients with fewer or more CAG repeats in the ATXN-3 gene and with more or fewer glutamines in the polyglutamine sequence in the ataxin-3 protein.
- Fibroblasts from patients with spinocerebellar ataxia type 3 were cultured in EMEM (Lonza) supplemented with 10% FBS (fetal bovine serum; EurX), antibiotics (Sigma- Aldrich). Treatment of fibroblast cells was carried out using low molecular weight compounds. The cells were sown on 60 mm dishes for 24 hours before transfection. After 24 hours, fibroblast cells reached approx. -60% confluence. Mixtures for treatment were prepared in EMEM supplemented with 2% FBS with low molecular weight compounds in DMSO.
- the cells were treated in two regimes; first approach: Fibroblasts grew for 24 hours after passage (-60% confluence). The culture medium was then changed to an EMEM supplemented with 2% FBS with proteasome inhibitors in DMSO, the medium was changed 48 hours after the first dose of proteasome inhibitor to a fresh medium containing proteasome inhibitors at the same concentration for a further 24 hours, after which the cells were collected for Western blot analysis. In the second approach, the cells were grown for 10 days.
- the cells were placed on a 60 mm plate 24 hours after passage (the cells had a confluence of -30%) and then incubated for 24 hours with proteasome inhibitors, after which the medium was changed to a normal medium (EMEM (Lonza) supplemented with 10% FBS (fetal bovine serum; EurX), antibiotics (Sigma-Aldrich)) for 48 hours.
- EMEM fetal bovine serum
- FBS fetal bovine serum
- antibiotics Sigma-Aldrich
- the cells were lysed in a buffer containing 60 mM TRIS, 2% SDS, 10% sucrose, and 2 mM PMSF.
- the protein concentration was estimated using the BCA protein determination kit (Pierce) and 20 pg of the total protein was diluted in a 2-mercaptoethanol sample buffer and boiled at 95°C for 5 min.
- the proteins were separated by SDS-PAGE gel electrophoresis ( 5% stacking gel/12% resolving gel), transferred onto nitrocellulose, and stained with Ponceau S. solution.
- Blots were blocked with 5% skimmed milk in PBS/0.05% Tween 20 and then incubated overnight at 4°C with the following primary antibodies: anti-ataxin-3 1:2000; ProteinTech, anti-GAPDH 1:10 000 (Merck Millipore). The blots were probed with suitable anti-rabbit antibodies conjugated with HRP 1:2000 (Jackson ImmunoResearch). The immunoreaction was detected using the ECL substrate (ThermoFisher Scientific).
- Lysates of cells treated for 72 hours were analyzed using the western blot technique to determine the amount of mutant ataxin protein 3 after treatment with low molecular weight compounds. Analyses showed that bortezomib, carfilzomib, and VLX1570 at concentrations of 10 nM statistically significantly reduced the level of mutant protein in fibroblast cells (fig. 2A). Cell lysates treated at 10 days were also analyzed using the western blot technique to determine the amount of mutant ataxin protein 3 after treatment with low molecular weight compounds. The analysis again showed that bortezomib, carfilzomib, and VLX1570 at 10 nM lowered statistically significant level of mutant protein in fibroblast cells (Fig. 2B).
- Lysates of cells treated for 72 hours were analyzed using the western blot technique to determine the amount of mutant ataxin protein 3 after treatment with low molecular weight compounds. Analyses showed that oprozomib at 25 nM statistically significantly reduces mutant ataxin 3 (Fig. 2C).
- the studied low molecular weight compounds significantly reduced the amounts of mutant ataxin protein 3 in the cells of patients with spinocerebellar ataxia type 3.
- Therapy with low-molecular compounds, according to the invention is a very beneficial solution for the patient due to lower costs of treatment, and easier way of administration (e.g. oral or injection).
Abstract
A low molecular weight compound for use in the treatment of spinocerebellar ataxia type 3, which is selected from bortezomib, carfilzomib, VLX1570, or oprozomib.
Description
A low molecular weight compound for use in the treatment of spinocerebellar ataxia type 3
The subject of the invention is a low molecular weight compound for use in the treatment of spinocerebellar ataxia type 3. The invention concerns the field of treatment of spinocerebellar attack type 3, caused by the presence of mutant ataxin protein 3.
Neurodegenerative diseases such as polyglutamine diseases, Alzheimer's disease, and Parkinson's disease often share clinical and molecular symptoms. Many of them have similar genetic etiology, including gene mutations that cause abnormal protein function. These functions lead to protein aggregation and accumulation in neurons, neuronal degeneration, defective neurotransmission and excitotoxicity, energy deficits, abnormal intracellular signaling, transcriptional changes, and inflammatory changes (McLoughlin, H.S. et al., 2020. Pathogenesis of SC A3 and implications for other polyglutamine diseases. Neurobiology of Disease 134, 104635.). Spinocerebellar ataxia 3 (SCA3), also called Machado-Joseph disease (MJD), is a neurodegenerative disease caused by a mutation in the ATXN3 gene. A mutation in a gene produces an abnormal protein that tends to form inclusions inside the brain. Patients with spinocerebellar ataxia type 3 suffer from motor and mental impairments such as gait ataxia, spasticity, eye movement disorders, and dementia (Riess, O. et al., 2008. SCA3: Neurological features, pathogenesis and animal models. Cerebellum 7, 125-137. Pathological changes include dysfunction and loss of neurons in the deep cerebellar nuclei, the nuclei of the bridge, as well as the nuclei of the vestibular and cranial nerves, the spinocerebellar segment (Clarke's column), and anterior horns (Rub, U. et al., 2013. Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. Prog. Neurobiol. 104, 38-66).
Spinocerebellar ataxia type 3 is a progressive neurodegenerative disease for which there is no effective causal therapy underlying the mechanism of the disease. Most of the available therapies are associated with alleviating individual symptoms of the disease. Currently, tested drugs include neurotransmitter modulators, ion transport inhibitors, growth factors, histone deacetylase inhibitors and autophagy enhancers, and tests using adipocyte-derived stem cells and umbilical cord blood. Substances such as acetyl-DL-leucine (various ataxias), Ceftriaxone (various ataxias), Trans -resveratrol, Trehalosa, valproic acid, Tandospirone, BHV-4157, Cabaletta, and others have been clinically tested (Chen, Y.-S. et al., 2020. Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado-Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies. Int. J. Mol. Sci. 21, 3063). One of the ways to reduce mutant ataxin-3 aggregation is targeted elevated expression of the ubiquitin-proteasome pathway (UPS). The proteasome has been identified in nuclear inclusions
of ataxin 3 and has been shown to inhibit aggregation of mutant ataxin 3 (Chai, Y. et al., 1999. Evidence for Proteasome Involvement in Polyglutamine Disease: Localization to Nuclear Inclusions in SCA3/MJD and Suppression of Polyglutamine Aggregation in vitro. Human Molecular Genetics 8, 673-682). Drugs such as rho kinase inhibitor (Hl 152), catapol, puerarin, and daidzein (the latter are active components of medicinal herbs, Rehmannia glutinosa and Pueraria lobata, respectively) have been proposed as potential inducers of the mutant ataxin-3 protein removal by UPS (Chen, I.-C. et al., 2019. Targeting Ubiquitin Proteasome Pathway with Traditional Chinese Medicine for Treatment of Spinocerebellar Ataxia Type 3. Am. J. Chin. Med., 47, 63-95; Wang, Z., 2018. Experimental and Clinical Strategies for Treating Spinocerebellar Ataxia Type 3. Neuroscience, 371, 138-154).
So far, proteasome inhibitors have been used in the treatment of cancer. The publication No. EP2619184B1 disclosed the use of bortezomib in the treatment of neurodegenerative diseases.
The invention aims to provide an effective and causal drug in the therapy of spinocerebellar ataxia type 3, which reduces the level of mutant ataxin 3 in cells. The subject of the invention is a low molecular weight compound for use in the treatment of spinocerebellar ataxia type 3, which is selected from bortezomib, carfilzomib, VLX1570, or oprozomib with the following chemical formulas:
oprozomib
The action of the low molecular weight compounds, according to the present invention, consists in the inhibition of the proteasome. As a result, the level of pathogenic mutant ataxin 3 protein in the cells of patients with spinocerebellar ataxia type 3 is significantly reduced.
The invention was presented in the examples and figures.
In the course of the study, it determined the effectiveness of bortezomib, carfilzomib, VLX1570, and oprozomib on the reduction of the level of mutant ataxin protein 3 in the cell culture of fibroblasts derived from SC A3 patients. The study was conducted with reference to the reference proteasome inhibitor Mg 123.
Figs. 1A and IB depict the diagrams of the applied methods of administration of low molecular weight compounds, which reflect the possible scheme of administration in patients with spinocerebellar ataxia type 3. The first method (Fig. 1A) consisted in continuous exposure of cells to low molecular weight compounds. The tested compounds were administered in a given concentration to a culture medium with a reduced amount of FBS (2%). At 48 hours, the medium was exchanged for fresh medium containing low molecular weight compounds at a given concentration after 48 hours. After another 24 hours, the cells were lyzed. This method was equivalent to the continuous delivery of therapeutics to patients, while the potential administration to patients is not limited below or above 72 hours. The second method (Fig. IB) consisted in administering low-molecular compounds alternately with a medium not containing low molecular weight compounds. The cells were exposed to therapeutic substances for 24 hours and then cultured for 2 days in a medium without low molecular weight compounds.
After 10 days, the cells were lyzed. This method simulated administration at time intervals, but the reported treatment times and breaks in the treatment of patients are not limited above or below to the mentioned number of hours. Figs. 2A, 2B, and 2C depict the results of experimental studies. In Figs. 2A, 2B, and 2C, the following abbreviations have the following meanings: GAPDH - Glyceraldehyde 3-phosphate dehydrogenase, a control protein used to normalize the level of protein expression; wtATXN3 - normal ataxin protein 3 containing 18 CAG repeats; mutATXN3 - mutant ataxin 3 protein containing 69 CAG repeats; MG132 - the name of the reference proteasome inhibitor. However, the use of the drug is not limited to patients with the number of CAG repeats or PolyQ sequences mentioned before. The therapy can be used in patients with fewer or more CAG repeats in the ATXN-3 gene and with more or fewer glutamines in the polyglutamine sequence in the ataxin-3 protein.
Fibroblasts from patients with spinocerebellar ataxia type 3 (GM06153, 18/69 CAG) (Coriell Cell Repositories) were cultured in EMEM (Lonza) supplemented with 10% FBS (fetal bovine serum; EurX), antibiotics (Sigma- Aldrich). Treatment of fibroblast cells was carried out using low molecular weight compounds. The cells were sown on 60 mm dishes for 24 hours before transfection. After 24 hours, fibroblast cells reached approx. -60% confluence. Mixtures for treatment were prepared in EMEM supplemented with 2% FBS with low molecular weight compounds in DMSO. The cells were treated in two regimes; first approach: Fibroblasts grew for 24 hours after passage (-60% confluence). The culture medium was then changed to an EMEM supplemented with 2% FBS with proteasome inhibitors in DMSO, the medium was changed 48 hours after the first dose of proteasome inhibitor to a fresh medium containing proteasome inhibitors at the same concentration for a further 24 hours, after which the cells were collected for Western blot analysis. In the second approach, the cells were grown for 10 days. The cells were placed on a 60 mm plate 24 hours after passage (the cells had a confluence of -30%) and then incubated for 24 hours with proteasome inhibitors, after which the medium was changed to a normal medium (EMEM (Lonza) supplemented with 10% FBS (fetal bovine serum; EurX), antibiotics (Sigma-Aldrich)) for 48 hours. Scheme was repeated for up to 10 days and the cells were collected for a Western blot.
The cells were lysed in a buffer containing 60 mM TRIS, 2% SDS, 10% sucrose, and 2 mM PMSF. The protein concentration was estimated using the BCA protein determination kit (Pierce) and 20 pg of the total protein was diluted in a 2-mercaptoethanol sample buffer and boiled at 95°C for 5 min. The proteins were separated by SDS-PAGE gel electrophoresis ( 5% stacking gel/12% resolving gel), transferred onto nitrocellulose, and stained with Ponceau S. solution. Blots were blocked with 5% skimmed milk in PBS/0.05% Tween 20 and then
incubated overnight at 4°C with the following primary antibodies: anti-ataxin-3 1:2000; ProteinTech, anti-GAPDH 1:10 000 (Merck Millipore). The blots were probed with suitable anti-rabbit antibodies conjugated with HRP 1:2000 (Jackson ImmunoResearch). The immunoreaction was detected using the ECL substrate (ThermoFisher Scientific).
Lysates of cells treated for 72 hours were analyzed using the western blot technique to determine the amount of mutant ataxin protein 3 after treatment with low molecular weight compounds. Analyses showed that bortezomib, carfilzomib, and VLX1570 at concentrations of 10 nM statistically significantly reduced the level of mutant protein in fibroblast cells (fig. 2A). Cell lysates treated at 10 days were also analyzed using the western blot technique to determine the amount of mutant ataxin protein 3 after treatment with low molecular weight compounds. The analysis again showed that bortezomib, carfilzomib, and VLX1570 at 10 nM lowered statistically significant level of mutant protein in fibroblast cells (Fig. 2B).
Lysates of cells treated for 72 hours were analyzed using the western blot technique to determine the amount of mutant ataxin protein 3 after treatment with low molecular weight compounds. Analyses showed that oprozomib at 25 nM statistically significantly reduces mutant ataxin 3 (Fig. 2C).
The studied low molecular weight compounds significantly reduced the amounts of mutant ataxin protein 3 in the cells of patients with spinocerebellar ataxia type 3. Therapy with low-molecular compounds, according to the invention, is a very beneficial solution for the patient due to lower costs of treatment, and easier way of administration (e.g. oral or injection).
Claims
Claim
A low molecular weight compound for use in the treatment of spinocerebellar ataxia type 3, which is selected from bortezomib, carfilzomib, VLX1570, or oprozomib with the following chemical formulas:
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| PL440687A PL440687A1 (en) | 2022-03-18 | 2022-03-18 | Low molecular weight compound for use in treatment of spinocerebellar ataxia type 3 |
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| US20160051619A1 (en) * | 2005-03-22 | 2016-02-25 | President And Fellows Of Harvard College | Treatment of protein degradation disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20160051619A1 (en) * | 2005-03-22 | 2016-02-25 | President And Fellows Of Harvard College | Treatment of protein degradation disorders |
Non-Patent Citations (3)
| Title |
|---|
| ALBORNOZ NICOLAS ET AL: "Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 20, no. 14, 10 July 2019 (2019-07-10), pages 3379, XP093053799, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678303/pdf/ijms-20-03379.pdf> DOI: 10.3390/ijms20143379 * |
| PEREIRA SENA PRISCILA ET AL: "Pathophysiological interplay between O -GlcNAc transferase and the Machado-Joseph disease protein ataxin-3", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 118, no. 47, 16 November 2021 (2021-11-16), XP093053162, ISSN: 0027-8424, DOI: 10.1073/pnas.2025810118 * |
| Y. CHAI ET AL: "Evidence for Proteasome Involvement in Polyglutamine Disease: Localization to Nuclear Inclusions in SCA3/MJD and Suppression of Polyglutamine Aggregation in vitro", HUMAN MOLECULAR GENETICS, vol. 8, no. 4, 1 April 1999 (1999-04-01), GB, pages 673 - 682, XP055646297, ISSN: 0964-6906, DOI: 10.1093/hmg/8.4.673 * |
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