Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration

Mengbi Yang; Qian Zhang; Qianwen Wang; Kasper K. Sørensen; Josephine T. Boesen; Sum Yi Ma; Knud J. Jensen; Kin Ming Kwan; Jacky Chi Ki Ngo; Ho Yin Edwin Chan; Zhong Zuo

doi:10.1021/acs.molpharmaceut.8b00938

Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration

Mengbi Yang, Qian Zhang, Qianwen Wang, Kasper K. Sørensen, Josephine T. Boesen, Sum Yi Ma, Knud J. Jensen, Kin Ming Kwan, Jacky Chi Ki Ngo, Ho Yin Edwin Chan, Zhong Zuo

Department of Chemistry

2 Citations (Scopus)

Abstract

Polyglutamine diseases are a set of progressive neurodegenerative disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective therapeutics that can counteract the polyglutamine neurotoxicity. Two peptidylic inhibitors, QBP1 and P3, targeting the protein and RNA toxicities, respectively, have been previously demonstrated by us with combinational therapeutic effects on the Drosophila polyglutamine disease model. However, their therapeutic efficacy has never been investigated in vivo in mammals. The current study aims to (a) develop a brain-targeting delivery system for both QBP1 and L1P3V8 (a lipidated variant of P3 with improved stability) and (b) evaluate their therapeutic effects on the R6/2 transgenic mouse model of polyglutamine disease. Compared with intravenous administration, intranasal administration of QBP1 significantly increased its brain-to-plasma ratio. In addition, employment of a chitosan-containing in situ gel for the intranasal administration of QBP1 notably improved its brain concentration for up to 10-fold. Further study on intranasal cotreatment with the optimized formulation of QBP1 and L1P3V8 in mice found no interference on the brain uptake of each other. Subsequent efficacy evaluation of 4-week daily QBP1 (16 μmol/kg) and L1P3V8 (6 μmol/kg) intranasal cotreatment in the R6/2 mice demonstrated a significant improvement on the motor coordination and explorative behavior of the disease mice, together with a full suppression on the RNA- and protein-toxicity markers in their brains. In summary, the current study developed an efficient intranasal cotreatment of the two peptidylic inhibitors, QBP1 and L1P3V8, for their brain-targeting, and such a novel therapeutic strategy was found to be effective on a transgenic polyglutamine disease mouse model.

Original language	English
Journal	Molecular Pharmaceutics
Volume	15
Issue number	12
Pages (from-to)	5781-5792
Number of pages	12
ISSN	1543-8384
DOIs	https://doi.org/10.1021/acs.molpharmaceut.8b00938
Publication status	Published - 3 Dec 2018

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10.1021/acs.molpharmaceut.8b00938

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Yang, M., Zhang, Q., Wang, Q., Sørensen, K. K., Boesen, J. T., Ma, S. Y., Jensen, K. J., Kwan, K. M., Ngo, J. C. K., Chan, H. Y. E., & Zuo, Z. (2018). Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration. Molecular Pharmaceutics, 15(12), 5781-5792. https://doi.org/10.1021/acs.molpharmaceut.8b00938

Yang, M, Zhang, Q, Wang, Q, Sørensen, KK, Boesen, JT, Ma, SY, Jensen, KJ, Kwan, KM, Ngo, JCK, Chan, HYE & Zuo, Z 2018, 'Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration', Molecular Pharmaceutics, vol. 15, no. 12, pp. 5781-5792. https://doi.org/10.1021/acs.molpharmaceut.8b00938

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title = "Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration",

abstract = "Polyglutamine diseases are a set of progressive neurodegenerative disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective therapeutics that can counteract the polyglutamine neurotoxicity. Two peptidylic inhibitors, QBP1 and P3, targeting the protein and RNA toxicities, respectively, have been previously demonstrated by us with combinational therapeutic effects on the Drosophila polyglutamine disease model. However, their therapeutic efficacy has never been investigated in vivo in mammals. The current study aims to (a) develop a brain-targeting delivery system for both QBP1 and L1P3V8 (a lipidated variant of P3 with improved stability) and (b) evaluate their therapeutic effects on the R6/2 transgenic mouse model of polyglutamine disease. Compared with intravenous administration, intranasal administration of QBP1 significantly increased its brain-to-plasma ratio. In addition, employment of a chitosan-containing in situ gel for the intranasal administration of QBP1 notably improved its brain concentration for up to 10-fold. Further study on intranasal cotreatment with the optimized formulation of QBP1 and L1P3V8 in mice found no interference on the brain uptake of each other. Subsequent efficacy evaluation of 4-week daily QBP1 (16 μmol/kg) and L1P3V8 (6 μmol/kg) intranasal cotreatment in the R6/2 mice demonstrated a significant improvement on the motor coordination and explorative behavior of the disease mice, together with a full suppression on the RNA- and protein-toxicity markers in their brains. In summary, the current study developed an efficient intranasal cotreatment of the two peptidylic inhibitors, QBP1 and L1P3V8, for their brain-targeting, and such a novel therapeutic strategy was found to be effective on a transgenic polyglutamine disease mouse model.",

author = "Mengbi Yang and Qian Zhang and Qianwen Wang and S{\o}rensen, {Kasper K.} and Boesen, {Josephine T.} and Ma, {Sum Yi} and Jensen, {Knud J.} and Kwan, {Kin Ming} and Ngo, {Jacky Chi Ki} and Chan, {Ho Yin Edwin} and Zhong Zuo",

year = "2018",

month = dec,

day = "3",

doi = "10.1021/acs.molpharmaceut.8b00938",

language = "English",

volume = "15",

pages = "5781--5792",

journal = "Molecular Pharmaceutics",

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T1 - Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration

AU - Yang, Mengbi

AU - Zhang, Qian

AU - Wang, Qianwen

AU - Sørensen, Kasper K.

AU - Boesen, Josephine T.

AU - Ma, Sum Yi

AU - Jensen, Knud J.

AU - Kwan, Kin Ming

AU - Ngo, Jacky Chi Ki

AU - Chan, Ho Yin Edwin

AU - Zuo, Zhong

PY - 2018/12/3

Y1 - 2018/12/3

N2 - Polyglutamine diseases are a set of progressive neurodegenerative disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective therapeutics that can counteract the polyglutamine neurotoxicity. Two peptidylic inhibitors, QBP1 and P3, targeting the protein and RNA toxicities, respectively, have been previously demonstrated by us with combinational therapeutic effects on the Drosophila polyglutamine disease model. However, their therapeutic efficacy has never been investigated in vivo in mammals. The current study aims to (a) develop a brain-targeting delivery system for both QBP1 and L1P3V8 (a lipidated variant of P3 with improved stability) and (b) evaluate their therapeutic effects on the R6/2 transgenic mouse model of polyglutamine disease. Compared with intravenous administration, intranasal administration of QBP1 significantly increased its brain-to-plasma ratio. In addition, employment of a chitosan-containing in situ gel for the intranasal administration of QBP1 notably improved its brain concentration for up to 10-fold. Further study on intranasal cotreatment with the optimized formulation of QBP1 and L1P3V8 in mice found no interference on the brain uptake of each other. Subsequent efficacy evaluation of 4-week daily QBP1 (16 μmol/kg) and L1P3V8 (6 μmol/kg) intranasal cotreatment in the R6/2 mice demonstrated a significant improvement on the motor coordination and explorative behavior of the disease mice, together with a full suppression on the RNA- and protein-toxicity markers in their brains. In summary, the current study developed an efficient intranasal cotreatment of the two peptidylic inhibitors, QBP1 and L1P3V8, for their brain-targeting, and such a novel therapeutic strategy was found to be effective on a transgenic polyglutamine disease mouse model.

AB - Polyglutamine diseases are a set of progressive neurodegenerative disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective therapeutics that can counteract the polyglutamine neurotoxicity. Two peptidylic inhibitors, QBP1 and P3, targeting the protein and RNA toxicities, respectively, have been previously demonstrated by us with combinational therapeutic effects on the Drosophila polyglutamine disease model. However, their therapeutic efficacy has never been investigated in vivo in mammals. The current study aims to (a) develop a brain-targeting delivery system for both QBP1 and L1P3V8 (a lipidated variant of P3 with improved stability) and (b) evaluate their therapeutic effects on the R6/2 transgenic mouse model of polyglutamine disease. Compared with intravenous administration, intranasal administration of QBP1 significantly increased its brain-to-plasma ratio. In addition, employment of a chitosan-containing in situ gel for the intranasal administration of QBP1 notably improved its brain concentration for up to 10-fold. Further study on intranasal cotreatment with the optimized formulation of QBP1 and L1P3V8 in mice found no interference on the brain uptake of each other. Subsequent efficacy evaluation of 4-week daily QBP1 (16 μmol/kg) and L1P3V8 (6 μmol/kg) intranasal cotreatment in the R6/2 mice demonstrated a significant improvement on the motor coordination and explorative behavior of the disease mice, together with a full suppression on the RNA- and protein-toxicity markers in their brains. In summary, the current study developed an efficient intranasal cotreatment of the two peptidylic inhibitors, QBP1 and L1P3V8, for their brain-targeting, and such a novel therapeutic strategy was found to be effective on a transgenic polyglutamine disease mouse model.

U2 - 10.1021/acs.molpharmaceut.8b00938

DO - 10.1021/acs.molpharmaceut.8b00938

M3 - Journal article

C2 - 30392378

SN - 1543-8384

VL - 15

SP - 5781

EP - 5792

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

IS - 12

ER -

Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration

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