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In vivo somatic cell gene transfer of an engineered Noggin mutein prevents BMP4-induced heterotopic ossification.
J Bone Joint Surg Am. 2003 Dec; 85(12):2332-42.JB

Abstract

BACKGROUND

The formation of the skeleton requires inductive signals that are balanced with their antagonists in a highly regulated negative feedback system. Inappropriate or excessive expression of BMPs (bone morphogenetic proteins) or their antagonists results in genetic disorders affecting the skeleton, such as fibrodysplasia ossificans progressiva. BMP signaling mediated through binding to its receptors is a critical step in the induction of abnormal ossification. Therefore, we hypothesized that engineering more effective inhibitors of this BMP-signaling process may lead to the development of therapies for such conditions.

METHODS

BMP4-induced heterotopic ossification was used as a model for testing the ability of the BMP antagonist Noggin to block de novo bone formation, either by local or systemic delivery. Since Noggin naturally acts locally, a Noggin mutein, hNOGDeltaB2, was engineered and was shown to circulate systemically, and its ability to block heterotopic ossification was tested in a mouse model with use of adenovirus-mediated somatic cell gene transfer.

RESULTS

A mouse model of BMP4-induced heterotopic ossification was developed. Local delivery of wild-type NOG inhibited heterotopic ossification, but systemic administration was ineffective. In contrast, systemic delivery of the adenovirus encoding hNOGDeltaB2 resulted in systemic levels that persisted for more than two weeks and were sufficient to block BMP4-induced heterotopic ossification.

CONCLUSIONS

BMP4-induced heterotopic ossification can be prevented in vivo either by local delivery of wild-type Noggin or after somatic cell gene transfer of a Noggin mutein, hNOGDeltaB2. Furthermore, the data in the present study provide proof of concept that a naturally occurring factor can be engineered for systemic delivery toward a desirable pharmacological outcome.

CLINICAL RELEVANCE

Blocking bone formation is clinically relevant to disorders of heterotopic ossification in humans, such as fibrodysplasia ossificans progressiva. Furthermore, development of BMP antagonists as therapeutic agents may provide modalities for the treatment of other pathologic conditions that arise from aberrant expression of BMPs and/or from a lack of their antagonists.

Authors+Show Affiliations

Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. david.glaser@uphs.upenn.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14668502

Citation

Glaser, David L., et al. "In Vivo Somatic Cell Gene Transfer of an Engineered Noggin Mutein Prevents BMP4-induced Heterotopic Ossification." The Journal of Bone and Joint Surgery. American Volume, vol. 85, no. 12, 2003, pp. 2332-42.
Glaser DL, Economides AN, Wang L, et al. In vivo somatic cell gene transfer of an engineered Noggin mutein prevents BMP4-induced heterotopic ossification. J Bone Joint Surg Am. 2003;85(12):2332-42.
Glaser, D. L., Economides, A. N., Wang, L., Liu, X., Kimble, R. D., Fandl, J. P., Wilson, J. M., Stahl, N., Kaplan, F. S., & Shore, E. M. (2003). In vivo somatic cell gene transfer of an engineered Noggin mutein prevents BMP4-induced heterotopic ossification. The Journal of Bone and Joint Surgery. American Volume, 85(12), 2332-42.
Glaser DL, et al. In Vivo Somatic Cell Gene Transfer of an Engineered Noggin Mutein Prevents BMP4-induced Heterotopic Ossification. J Bone Joint Surg Am. 2003;85(12):2332-42. PubMed PMID: 14668502.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo somatic cell gene transfer of an engineered Noggin mutein prevents BMP4-induced heterotopic ossification. AU - Glaser,David L, AU - Economides,Aris N, AU - Wang,Lili, AU - Liu,Xia, AU - Kimble,Robert D, AU - Fandl,James P, AU - Wilson,James M, AU - Stahl,Neil, AU - Kaplan,Frederick S, AU - Shore,Eileen M, PY - 2003/12/12/pubmed PY - 2004/1/14/medline PY - 2003/12/12/entrez SP - 2332 EP - 42 JF - The Journal of bone and joint surgery. American volume JO - J Bone Joint Surg Am VL - 85 IS - 12 N2 - BACKGROUND: The formation of the skeleton requires inductive signals that are balanced with their antagonists in a highly regulated negative feedback system. Inappropriate or excessive expression of BMPs (bone morphogenetic proteins) or their antagonists results in genetic disorders affecting the skeleton, such as fibrodysplasia ossificans progressiva. BMP signaling mediated through binding to its receptors is a critical step in the induction of abnormal ossification. Therefore, we hypothesized that engineering more effective inhibitors of this BMP-signaling process may lead to the development of therapies for such conditions. METHODS: BMP4-induced heterotopic ossification was used as a model for testing the ability of the BMP antagonist Noggin to block de novo bone formation, either by local or systemic delivery. Since Noggin naturally acts locally, a Noggin mutein, hNOGDeltaB2, was engineered and was shown to circulate systemically, and its ability to block heterotopic ossification was tested in a mouse model with use of adenovirus-mediated somatic cell gene transfer. RESULTS: A mouse model of BMP4-induced heterotopic ossification was developed. Local delivery of wild-type NOG inhibited heterotopic ossification, but systemic administration was ineffective. In contrast, systemic delivery of the adenovirus encoding hNOGDeltaB2 resulted in systemic levels that persisted for more than two weeks and were sufficient to block BMP4-induced heterotopic ossification. CONCLUSIONS: BMP4-induced heterotopic ossification can be prevented in vivo either by local delivery of wild-type Noggin or after somatic cell gene transfer of a Noggin mutein, hNOGDeltaB2. Furthermore, the data in the present study provide proof of concept that a naturally occurring factor can be engineered for systemic delivery toward a desirable pharmacological outcome. CLINICAL RELEVANCE: Blocking bone formation is clinically relevant to disorders of heterotopic ossification in humans, such as fibrodysplasia ossificans progressiva. Furthermore, development of BMP antagonists as therapeutic agents may provide modalities for the treatment of other pathologic conditions that arise from aberrant expression of BMPs and/or from a lack of their antagonists. SN - 0021-9355 UR - https://www.unboundmedicine.com/medline/citation/14668502/In_vivo_somatic_cell_gene_transfer_of_an_engineered_Noggin_mutein_prevents_BMP4_induced_heterotopic_ossification_ L2 - http://dx.doi.org/10.2106/00004623-200312000-00010 DB - PRIME DP - Unbound Medicine ER -