Gene therapeutics for treating bone disorders

A transgenic and viral technology, applied in gene therapy, bone diseases, genetic engineering, etc., can solve problems such as increasing the risk of stroke and increasing bone tissue destruction

Pending Publication Date: 2021-02-12
UNIV OF MASSACHUSETTS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in the context of inflammatory arthritis, anti-sclerostin antibodies have been observed to

Method used

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  • Gene therapeutics for treating bone disorders
  • Gene therapeutics for treating bone disorders
  • Gene therapeutics for treating bone disorders

Examples

Experimental program
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Effect test

Embodiment 1

[0180] Several key regulators of bone formation have been identified as therapeutic targets for osteoporosis. For example, inhibition of the naturally occurring bone formation inhibitor sclerostin (SOST) or the adapter protein schnurri-3 (SHN3, also known as HIVEP3) leads to a progressive increase in bone mass due to increased OB activity. Unlike SHN3 and SOST, which mainly function in OB, cathepsin K (CTSK) is highly expressed in OC, and its inhibition increases bone mass by blocking OC activity. Finally, treatment with bone anabolic factors including PTH, PTH-related protein (PTHrP) or DJ-1 promoted bone formation. In this example, gene therapy agents that can manipulate the expression of these candidate genes through the use of bone-targeting adeno-associated virus (AAV)-mediated gene silencing or addition are described. In some embodiments, therapeutic agents (e.g., compositions described in this disclosure) have only limited activity on bone remodeling and regeneration b...

Embodiment 2

[0223] Example 2: Development of Novel Gene Therapeutics for Osteoporosis Using AAV-Mediated Gene Addition

[0224] In some embodiments, intermittent treatment with subcutaneously injected recombinant PTH peptide (1-34aa) or recombinant PTHrP peptide (1-36aa) increases OB activity and promotes bone formation. These peptides (teriparatide, abaloparatide) are FDA approved and are currently used in human patients with osteoporosis. In some embodiments, the secreted factor DJ-1 acts as a mediator of cross-sensing between OB and endothelial cells. In some embodiments, treatment of DJ-1 promotes OB differentiation in human MSCs and angiogenesis in human endothelial cells, while it inhibits OC differentiation.

[0225]This example describes the delivery of scAAV9 serotypes encoding secreted osteogenic factors to animals via intramuscular (IM) injection, whereby the injected muscle acts as a biological pump, providing a steady high level of these factors in the blood circulation. ...

Embodiment 3

[0228] Example 3: Inducible deletion of Shn3 in osteoblasts promotes bone formation in adult mice

[0229] To examine the effect of short-term inhibition of SHN3 on bone formation, the Shn3 fl / fl mice and mature osteoblasts (Shn3 Ocn-Ert ) to generate inducible, osteoblast-specific Shn3-knockout mice. These mice were further combined with the Cre reporter gene Rosa mT / mG Mouse crosses to visualize Cre-expressing cells (Shn3 Ocn-Ert ;Rosa mT / mG ). Treatment of Shn3 with tamoxifen Ocn-Ert ;Rosa mT / mG Mice resulted in GFP expression in mature osteoblasts located on the trabecular and cortical bone surfaces, indicating an osteoblast-specific deletion of Shn3 (Fig. 23). Thus, these mice showed a significant increase in trabecular bone mass compared to tamoxifen-treated control mice (Figure 23). These results demonstrate that inducible deletion of Shn3 in mature osteoblasts is sufficient to increase bone mass in adult mice.

[0230] Cre-encoding scAAV9 vector (scAAV9-Cre,...

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Abstract

In some aspects, the disclosure relates to compositions and methods for modulating ( e.g., increasing and/or decreasing) bone mass in a subject. In some aspects, the disclosure provides isolated nucleic acids, and vectors such as rAAV vectors, configured to express transgenes that promote (e.g., increase) or inhibit (e.g., decrease) activity, differentiation, or function of certain types of bone cells, for example osteoblasts, osteoclasts, osteocytes, etc. In some embodiments, the isolated nucleic acids and vectors described by the disclosure are useful for treating disorders and conditions associated with increased bone mass (e.g., osteopetrosis) or decreased bone mass (e.g., osteoporosis).

Description

[0001] related application [0002] Pursuant to 35 U.S.C. §119(e), this application claims U.S. Provisional Application No. 62 / 647,595, entitled "Gene Therapy Agents for the Treatment of Bone Disorders," filed March 23, 2018, and February 1, 2019 Priority to U.S. Provisional Application No. 62 / 799,843, entitled "Gene Therapeutic Agents for the Treatment of Bone Disorders," was filed. Background technique [0003] Defects in bone metabolism give rise to a variety of different bone diseases, including those associated with pathological loss or bone mass as well as those associated with pathological increase in bone mass. Effects on bone mass may be systemic or localized. For example, osteoporosis is a disease characterized by decreased bone mass and is a major source of fragility and suffering associated with aging. An estimated 10 million Americans over the age of 50 have osteoporosis, and approximately 1.5 million individuals suffer osteoporosis-related fractures each year, ...

Claims

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Application Information

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IPC IPC(8): A61P19/08A61P19/10C12N15/861C12N15/63C12N15/113
CPCC12N15/113A61P19/10A61P19/08C12N15/63C12N2310/531C12N2320/32C12N2330/51C12N2310/141C12N2310/14C12N15/111C12N15/1137C12N15/86C12N2750/14143C12N2750/14145A01K2217/075A01K2227/105A01K2267/035A61K48/005A61P19/00C07K14/005C07K14/635C12N2750/14122C12N2750/14171
Inventor 沈载赫高光平谢军金瀞慜王丹梁软淑
Owner UNIV OF MASSACHUSETTS
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