RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development

Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Maurizi, Antonio [verfasserIn] Capulli, Mattia [verfasserIn] Patel, Rajvi [verfasserIn] Curle, Annabel [verfasserIn] Rucci, Nadia [verfasserIn] Teti, Anna [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	Osteopetrosis Autosomal dominant osteopetrosis type 2 Therapy Small interfering RNA Pre-clinical study

Übergeordnetes Werk:	Enthalten in: Bone - Amsterdam [u.a.] : Elsevier Science, 1985, 110, Seite 343-354
Übergeordnetes Werk:	volume:110 ; pages:343-354

DOI / URN:	10.1016/j.bone.2018.02.031

Katalog-ID:	ELV001927051

Internformat


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520			\|a Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7 G213R/WT ADO2 mice with Clcn7 G213R -specific siRNA and investigating the bone phenotype by μCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7 G213R siRNA is not only effective in pre-pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders.
650		4	\|a Osteopetrosis
650		4	\|a Autosomal dominant osteopetrosis type 2
650		4	\|a Therapy
650		4	\|a Small interfering RNA
650		4	\|a Pre-clinical study
700	1		\|a Capulli, Mattia \|e verfasserin \|4 aut
700	1		\|a Patel, Rajvi \|e verfasserin \|4 aut
700	1		\|a Curle, Annabel \|e verfasserin \|0 (orcid)0000-0002-9105-1131 \|4 aut
700	1		\|a Rucci, Nadia \|e verfasserin \|4 aut
700	1		\|a Teti, Anna \|e verfasserin \|0 (orcid)0000-0002-5887-4419 \|4 aut
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912			\|a GBV_ILN_4334
912			\|a GBV_ILN_4335
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4393
936	b	k	\|a 44.83 \|j Rheumatologie \|j Orthopädie
951			\|a AR
952			\|d 110 \|h 343-354

Indexfelder

author_variant	a m am m c mc r p rp a c ac n r nr a t at
matchkey_str	article:18732763:2018----::nitreecteayoatsmloiatseptoitp2oadt
hierarchy_sort_str	2018
bklnumber	44.83
publishDate	2018
allfields	10.1016/j.bone.2018.02.031 doi (DE-627)ELV001927051 (ELSEVIER)S8756-3282(18)30090-5 DE-627 ger DE-627 rda eng 610 DE-600 44.83 bkl Maurizi, Antonio verfasserin aut RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development 2018 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7 G213R/WT ADO2 mice with Clcn7 G213R -specific siRNA and investigating the bone phenotype by μCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7 G213R siRNA is not only effective in pre-pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders. Osteopetrosis Autosomal dominant osteopetrosis type 2 Therapy Small interfering RNA Pre-clinical study Capulli, Mattia verfasserin aut Patel, Rajvi verfasserin aut Curle, Annabel verfasserin (orcid)0000-0002-9105-1131 aut Rucci, Nadia verfasserin aut Teti, Anna verfasserin (orcid)0000-0002-5887-4419 aut Enthalten in Bone Amsterdam [u.a.] : Elsevier Science, 1985 110, Seite 343-354 Online-Ressource (DE-627)306320177 (DE-600)1496324-3 (DE-576)081952945 1873-2763 nnns volume:110 pages:343-354 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.83 Rheumatologie Orthopädie AR 110 343-354
spelling	10.1016/j.bone.2018.02.031 doi (DE-627)ELV001927051 (ELSEVIER)S8756-3282(18)30090-5 DE-627 ger DE-627 rda eng 610 DE-600 44.83 bkl Maurizi, Antonio verfasserin aut RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development 2018 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7 G213R/WT ADO2 mice with Clcn7 G213R -specific siRNA and investigating the bone phenotype by μCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7 G213R siRNA is not only effective in pre-pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders. Osteopetrosis Autosomal dominant osteopetrosis type 2 Therapy Small interfering RNA Pre-clinical study Capulli, Mattia verfasserin aut Patel, Rajvi verfasserin aut Curle, Annabel verfasserin (orcid)0000-0002-9105-1131 aut Rucci, Nadia verfasserin aut Teti, Anna verfasserin (orcid)0000-0002-5887-4419 aut Enthalten in Bone Amsterdam [u.a.] : Elsevier Science, 1985 110, Seite 343-354 Online-Ressource (DE-627)306320177 (DE-600)1496324-3 (DE-576)081952945 1873-2763 nnns volume:110 pages:343-354 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.83 Rheumatologie Orthopädie AR 110 343-354
allfields_unstemmed	10.1016/j.bone.2018.02.031 doi (DE-627)ELV001927051 (ELSEVIER)S8756-3282(18)30090-5 DE-627 ger DE-627 rda eng 610 DE-600 44.83 bkl Maurizi, Antonio verfasserin aut RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development 2018 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7 G213R/WT ADO2 mice with Clcn7 G213R -specific siRNA and investigating the bone phenotype by μCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7 G213R siRNA is not only effective in pre-pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders. Osteopetrosis Autosomal dominant osteopetrosis type 2 Therapy Small interfering RNA Pre-clinical study Capulli, Mattia verfasserin aut Patel, Rajvi verfasserin aut Curle, Annabel verfasserin (orcid)0000-0002-9105-1131 aut Rucci, Nadia verfasserin aut Teti, Anna verfasserin (orcid)0000-0002-5887-4419 aut Enthalten in Bone Amsterdam [u.a.] : Elsevier Science, 1985 110, Seite 343-354 Online-Ressource (DE-627)306320177 (DE-600)1496324-3 (DE-576)081952945 1873-2763 nnns volume:110 pages:343-354 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.83 Rheumatologie Orthopädie AR 110 343-354
allfieldsGer	10.1016/j.bone.2018.02.031 doi (DE-627)ELV001927051 (ELSEVIER)S8756-3282(18)30090-5 DE-627 ger DE-627 rda eng 610 DE-600 44.83 bkl Maurizi, Antonio verfasserin aut RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development 2018 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7 G213R/WT ADO2 mice with Clcn7 G213R -specific siRNA and investigating the bone phenotype by μCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7 G213R siRNA is not only effective in pre-pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders. Osteopetrosis Autosomal dominant osteopetrosis type 2 Therapy Small interfering RNA Pre-clinical study Capulli, Mattia verfasserin aut Patel, Rajvi verfasserin aut Curle, Annabel verfasserin (orcid)0000-0002-9105-1131 aut Rucci, Nadia verfasserin aut Teti, Anna verfasserin (orcid)0000-0002-5887-4419 aut Enthalten in Bone Amsterdam [u.a.] : Elsevier Science, 1985 110, Seite 343-354 Online-Ressource (DE-627)306320177 (DE-600)1496324-3 (DE-576)081952945 1873-2763 nnns volume:110 pages:343-354 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.83 Rheumatologie Orthopädie AR 110 343-354
allfieldsSound	10.1016/j.bone.2018.02.031 doi (DE-627)ELV001927051 (ELSEVIER)S8756-3282(18)30090-5 DE-627 ger DE-627 rda eng 610 DE-600 44.83 bkl Maurizi, Antonio verfasserin aut RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development 2018 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7 G213R/WT ADO2 mice with Clcn7 G213R -specific siRNA and investigating the bone phenotype by μCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7 G213R siRNA is not only effective in pre-pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders. Osteopetrosis Autosomal dominant osteopetrosis type 2 Therapy Small interfering RNA Pre-clinical study Capulli, Mattia verfasserin aut Patel, Rajvi verfasserin aut Curle, Annabel verfasserin (orcid)0000-0002-9105-1131 aut Rucci, Nadia verfasserin aut Teti, Anna verfasserin (orcid)0000-0002-5887-4419 aut Enthalten in Bone Amsterdam [u.a.] : Elsevier Science, 1985 110, Seite 343-354 Online-Ressource (DE-627)306320177 (DE-600)1496324-3 (DE-576)081952945 1873-2763 nnns volume:110 pages:343-354 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.83 Rheumatologie Orthopädie AR 110 343-354
language	English
source	Enthalten in Bone 110, Seite 343-354 volume:110 pages:343-354
sourceStr	Enthalten in Bone 110, Seite 343-354 volume:110 pages:343-354
format_phy_str_mv	Article
bklname	Rheumatologie Orthopädie
institution	findex.gbv.de
topic_facet	Osteopetrosis Autosomal dominant osteopetrosis type 2 Therapy Small interfering RNA Pre-clinical study
dewey-raw	610
isfreeaccess_bool	false
container_title	Bone
authorswithroles_txt_mv	Maurizi, Antonio @@aut@@ Capulli, Mattia @@aut@@ Patel, Rajvi @@aut@@ Curle, Annabel @@aut@@ Rucci, Nadia @@aut@@ Teti, Anna @@aut@@
publishDateDaySort_date	2018-01-01T00:00:00Z
hierarchy_top_id	306320177
dewey-sort	3610
id	ELV001927051
language_de	englisch
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author	Maurizi, Antonio
spellingShingle	Maurizi, Antonio ddc 610 bkl 44.83 misc Osteopetrosis misc Autosomal dominant osteopetrosis type 2 misc Therapy misc Small interfering RNA misc Pre-clinical study RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development
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topic_title	610 DE-600 44.83 bkl RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development Osteopetrosis Autosomal dominant osteopetrosis type 2 Therapy Small interfering RNA Pre-clinical study
topic	ddc 610 bkl 44.83 misc Osteopetrosis misc Autosomal dominant osteopetrosis type 2 misc Therapy misc Small interfering RNA misc Pre-clinical study
topic_unstemmed	ddc 610 bkl 44.83 misc Osteopetrosis misc Autosomal dominant osteopetrosis type 2 misc Therapy misc Small interfering RNA misc Pre-clinical study
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title	RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development
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title_full	RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development
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title_sort	rna interference therapy for autosomal dominant osteopetrosis type 2. towards the preclinical development
title_auth	RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development
abstract	Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7 G213R/WT ADO2 mice with Clcn7 G213R -specific siRNA and investigating the bone phenotype by μCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7 G213R siRNA is not only effective in pre-pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders.
abstractGer	Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7 G213R/WT ADO2 mice with Clcn7 G213R -specific siRNA and investigating the bone phenotype by μCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7 G213R siRNA is not only effective in pre-pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders.
abstract_unstemmed	Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7 G213R/WT ADO2 mice with Clcn7 G213R -specific siRNA and investigating the bone phenotype by μCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7 G213R siRNA is not only effective in pre-pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders.
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title_short	RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development
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up_date	2024-07-06T23:02:24.099Z
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RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development

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