Bone-targeted treatments in osteogenesis imperfecta

Abstract

Disclosed herein are compounds and methods for treating osteogenesis imperfecta in individuals.In some embodiments, the compounds comprise bone anabolic agents, linkers and bone targeting ligands.In some embodiments, the methods comprise reducing the occurrence or likelihood of bone fracture, increasing bone density or bone strength, and providing compounds to the low density bone sites and weakened bone sites in individuals with osteogenesis imperfecta.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 299,746, filed January 14, 2022, the entirety of which is incorporated herein by reference. [Background technology]

[0002] Osteogenesis imperfecta (OI), also known as brittle bone disease, is a genetic disorder that affects approximately 1 in 15,000 live births. Phenotypes range from occasional fractures due to minor trauma to severe skeletal deformities and extremely fragile bones. Individuals with OI may sustain more than 400 fractures in their lifetime, and repair may be significantly delayed. Treatment of many OI fractures is largely similar to traditional fracture treatments, relying primarily on immobilization. Some attempts to enhance the repair process in individuals with OI with drugs such as teriparatide have only resulted in modest improvement, which may be due to insufficient concentrations at the fracture site. Thus, there is a need for improved fracture-targeted therapies with high affinity to fracture sites and sites of low density and weakened bone to help treat and reduce the occurrence or likelihood of fractures in individuals with OI. Summary of the Invention

[0003] Provided in certain embodiments herein is a method of treating osteogenesis imperfecta (OI) in an individual (e.g., in need of treatment for osteogenesis imperfecta (OI)), comprising administering to the individual (e.g., in need of treatment for osteogenesis imperfecta (OI)) a therapeutically effective amount of a compound having the structure XYZ, where X is a bone anabolic agent, Y is a linker, and Z is a bone-targeting ligand, or a pharma- ceutically acceptable salt thereof.

[0004] In certain embodiments, provided herein is a method of delivering (e.g., targeting) a compound as described herein or a pharma- ceutically acceptable salt thereof to one or more damaged, low-density or weakened bone sites (e.g., areas other than or without fracture sites, such as fractures, skeletal remodeling sites or low-collagen sites) in an individual with, for example, osteogenesis imperfecta (OI). In some embodiments, the one or more damaged, low-density or weakened bone sites are osteotomies, bone grafts, fractures (e.g., microfractures or stress fractures) or skeletal remodeling sites. In some embodiments, the method comprises administering a compound to an individual, the compound having the structure XYZ, where X is a bone anabolic agent, Y is a linker, and Z is a bone targeting ligand. In some embodiments, a therapeutically effective amount of a compound as provided herein is administered and delivered to one or more damaged, low-density or weakened bone sites (e.g., areas other than or without fracture sites, such as fractures, skeletal remodeling sites or low-collagen sites). In some embodiments provided herein, administering the compound delivers (e.g., targets) a therapeutically effective amount of the compound to one or more damaged, low-density, or weakened bone sites (e.g., areas other than or without fracture sites, such as fractures, skeletal remodeling, or low-collagen sites). In some embodiments, such as when the compound provided herein is administered as a diagnostic payload, the compound provided herein is used to identify one or more damaged, low-density, or weakened bone sites (e.g., areas other than or without fracture sites, such as fractures, skeletal remodeling, or low-collagen sites) in an individual. In some embodiments provided herein, the compound includes a diagnostic payload, and administering the compound identifies one or more damaged, low-density, or weakened bone sites (e.g., areas other than or without fracture sites, such as fractures, skeletal remodeling, or low-collagen sites) in an individual.

[0005] In some cases, the individual does not have a fracture.

[0006] In some embodiments provided herein, administering a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof to an individual (e.g., in need of a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof) reduces the occurrence or likelihood of bone fracture in the individual (e.g., in need of a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof). In some embodiments, a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof increases bone density and / or strength (e.g., mechanical strength or structural strength) in an individual (e.g., in need of a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof, such as an individual having OI). In some embodiments provided herein, administering a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof to an individual (e.g., in need of a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof) increases bone density or bone strength (e.g., mechanical strength or structural strength) in the individual. In some embodiments, a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof improves (e.g., promotes) the treatment (e.g., healing or repair) of a bone (e.g., osteotomy, bone graft, or fracture) in an individual (e.g., an individual having OI, in need of a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt). In some embodiments, a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof reduces non-union or delayed union of a bone (e.g., osteotomy, bone graft, or fracture) in an individual (e.g., an individual having OI, in need of a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt). In some embodiments, a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof increases the strength of a bone in an individual (e.g., an individual having OI, in need of a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt). In some embodiments provided herein, administration of a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof to an individual (e.g., in need of a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof) improves (e.g., promotes) the treatment (e.g., healing or repair) of an osteotomy, bone graft, or fracture in the individual.

[0007] In some embodiments, the individual has been diagnosed with OI type 1. In some embodiments, the individual has been diagnosed with OI type 3. In some embodiments, the individual has been diagnosed with OI type 4. In some embodiments, the individual has been diagnosed with OI associated with a genetic mutation (e.g., in the individual), such as a genetic mutation that reduces collagen formation and / or production.

[0008] In some embodiments provided herein, OI is OI type 1. In some embodiments provided herein, OI is OI type 3. In some embodiments provided herein, OI is OI type 4. In some embodiments provided herein, OI is associated with a genetic mutation in an individual's ability to form or process collagen.

[0009] In some embodiments, the individual is an infant, child, adolescent, or young adult.

[0010] In some embodiments, the individual has been diagnosed with childhood OI.

[0011] In some embodiments provided herein, the individual is a pediatric individual with pediatric OI.

[0012] In some embodiments, a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof is delivered to one or more sites of low density bone and / or weakened bone (e.g., a site of low collagen or a site without a fracture site other than a site of skeletal remodeling or a site of a fracture) in an individual (e.g., in need of a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof). In some embodiments provided herein, a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof provides a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof to one or more sites of low density bone or weakened bone (e.g., a site of low collagen or a site without a fracture site other than a site of skeletal remodeling or a site of a fracture) in an individual (e.g., in need of a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof).

[0013] In some embodiments, a compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount sufficient to prevent bone fracture in an individual, such as an individual with OI (e.g., in need of a compound provided herein, or a pharma- ceutically acceptable salt thereof). In some embodiments, a compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount sufficient to reduce the incidence of bone fracture in an individual, such as an individual with OI (e.g., in need of a compound provided herein, or a pharma- ceutically acceptable salt thereof).

[0014] In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof is administered prophylactically to an individual (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof), such as an individual having OI. In some embodiments provided herein, the method includes prophylactically administering a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof to an individual (e.g., in need of prophylactic administration).

[0015] In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof is administered systemically to an individual, such as an individual with OI (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof). In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof is administered distally to an individual, such as an individual with OI (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof). In some embodiments, a compound or a pharma- ceutically acceptable salt thereof administered distally to an individual, such as an individual with OI (e.g., in need of a compound or a pharma- ceutically acceptable salt thereof) accumulates locally (e.g., at the fracture site).

[0016] In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof is administered to an individual, such as an individual with OI (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof), a first and second time. In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof is administered to an individual, such as an individual with OI (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof), one or more times after the second time. In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof is administered (repeatedly) to an individual, such as an individual with OI (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof), for a period of one week or more. In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof is administered (repeatedly) to an individual, such as an individual with OI (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof), for a period of one month or more. In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof is administered (repeatedly) to an individual, such as an individual with OI (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof), for a period of one year or more. In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof is administered (repeatedly) to an individual, such as an individual with OI (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof), for several years. In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof is administered (repeatedly) chronically to an individual, such as an individual with OI (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof).

[0017] In some embodiments, X is a bone anabolic agent (e.g., an agent having bone anabolic activity). In some embodiments, X is a bone anabolic agent that increases collagen production in an individual or improves an individual's ability to form or process collagen. In some embodiments, X is a growth factor, a small molecule, a peptide, a protein, a hormone, or a fragment thereof, e.g., when bound to or released from a compound described herein. In some embodiments, X is a bone anabolic agent selected from the group consisting of an agonist of parathyroid hormone receptor 1, parathyroid hormone (PTH), PTH-related protein (PTHrP), and abaloparatide. In some embodiments, X is Ln2P3.

[0018] In some embodiments provided herein, X is a bone anabolic agent (e.g., having bone anabolic activity) including a growth factor, a small molecule, a peptide, a protein, or a hormone. In some embodiments provided herein, X is a bone anabolic agent selected from the group consisting of an agonist of parathyroid hormone receptor 1, parathyroid hormone (PTH) (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)), PTH-related protein (PTHrP) (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)), and abaloparatide (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)). In some embodiments provided herein, X is abaloparatide (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)). In some embodiments, X is Ln2P3.

[0019] In some embodiments, X is a parathyroid hormone receptor 1 agonist. In some embodiments, X is PTH. In some embodiments, X is PTHrP. In some embodiments, X is abaloparatide. In some embodiments, X is Ln2P3.

[0020] In some embodiments provided herein, Z is a hydroxyapatite targeting ligand. In some embodiments provided herein, the hydroxyapatite targeting ligand comprises tetracycline, phosphonate (e.g., bisphosphonate (e.g., mono-bisphosphonate, tri-bisphosphonate, or poly-bisphosphonate)), acidic oligopeptide, ranelate, pyrophosphate, or a targeting ligand developed by phage display. In some embodiments, the hydroxyapatite targeting ligand comprises tetracycline, phosphonate (e.g., bisphosphonate (e.g., mono-bisphosphonate, tri-bisphosphonate, or poly-bisphosphonate)), acidic oligopeptide, ranelate, and / or pyrophosphate. In some embodiments, Z comprises a phosphonate or a derivative thereof. In some embodiments, Z comprises a phosphate or a derivative thereof. In some embodiments, Z comprises one or more amino acid residues. In some embodiments provided herein, Z is a linear chain of amino acid residues. In some embodiments provided herein, Z is a branched chain of amino acid residues. In some embodiments provided herein, Z is an acidic oligopeptide. In some embodiments provided herein, Z comprises at least four glutamic acid amino acid residues or at least four aspartic acid amino acid residues. In some embodiments provided herein, Z comprises at least four (e.g., acidic) amino acid residues (e.g., having the same chirality). In some embodiments provided herein, each of the at least four (e.g., acidic) amino acid residues has D chirality. In some embodiments provided herein, Z comprises at least four (e.g., D-) glutamic acid amino acid residues (e.g., 4-20 D-glutamic acid amino acid residues) and / or at least four (e.g., D-) aspartic acid amino acid residues (e.g., 4-20 D-aspartic acid amino acid residues). In some embodiments provided herein, Z comprises a mixture of (e.g., D-) glutamic acid amino acid residues and (e.g., D-) aspartic acid amino acid residues.In some embodiments provided herein, Z comprises at least 10 repeating D-glutamic acid amino acid residues (e.g., DE10 or more, DE15 or more, or DE20 or more). In some embodiments provided herein, Z is 20 repeating D-glutamic acid amino acid residues (DE20). In some embodiments provided herein, Z comprises 4-75 acidic amino acid residues (e.g., D-glutamic acid amino acid residues). In some embodiments provided herein, Z comprises 8-30 acidic amino acid residues (e.g., D-glutamic acid amino acid residues and / or D-aspartic acid amino acid residues). In some embodiments provided herein, Z comprises 8-30 D-glutamic acid amino acid residues. In some embodiments, Z comprises 8-30 D-aspartic acid amino acid residues.

[0021] In some embodiments provided herein, X is abaloparatide (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)) and Z is 20 repeating D-glutamic acid amino acid residues (DE20).

[0022] In some of the embodiments provided herein, Y is a non-releasable linker (eg, comprising at least one carbon-carbon bond and / or at least one amide bond).

[0023] In some of the embodiments provided herein, Y is a releasable linker (e.g., comprising at least one disulfide (SS), at least one ester (e.g., O(C=O)), and / or at least one (e.g., protease-specific) amide bond).

[0024] In some of the embodiments provided herein, X is abaloparatide (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)), Y is a non-releasable oligopeptide linker, and Z is 20 repeating D-glutamic acid amino acid residues (DE20).

[0025] In some of the embodiments provided herein, X is abaloparatide (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)), Y is a releasable oligopeptide linker comprising at least one protease-specific amide bond, and Z is 20 repeating D-glutamic acid amino acid residues (DE20).

[0026] In some of the embodiments provided herein, the compounds have at least 75% or more sequence identity to SEQ ID NO:1 (e.g., at least 80% or more sequence identity, at least 85% or more sequence identity, at least 90% or more sequence identity, or at least 95% or more sequence identity).

[0027] In some embodiments, the compound described herein, such as a compound for treating osteogenesis imperfecta (OI) in an individual (e.g., in need of treatment for osteogenesis imperfecta (OI)), is Compound 1.

[0028] In some embodiments, X is PTHrP, Y is a non-releasable oligopeptide linker, and Z is 20 repeating D-glutamic acid amino acid residues (DE20).

[0029] In some embodiments, the compound has at least 75% or more sequence identity to SEQ ID NO:3 (e.g., at least 80% or more sequence identity, at least 85% or more sequence identity, at least 90% or more sequence identity, or at least 95% or more sequence identity).

[0030] In some embodiments, the compound described herein, such as a compound for treating osteogenesis imperfecta (OI) in an individual (e.g., in need of treatment for osteogenesis imperfecta (OI)), is compound 3.

[0031] In some embodiments, X is Ln2P3, Y is a non-releasable oligopeptide linker, and Z is 10 repeating D-glutamic acid amino acid residues (DE10).

[0032] In some embodiments, the compounds have at least 75% or more sequence identity to SEQ ID NO:4 (e.g., at least 80% or more sequence identity, at least 85% or more sequence identity, at least 90% or more sequence identity, or at least 95% or more sequence identity).

[0033] In some embodiments, the compound described herein, such as a compound for treating osteogenesis imperfecta (OI) in an individual (e.g., in need of treatment for osteogenesis imperfecta (OI)), is compound 4.

[0034] Various aspects of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings, in which: [Brief description of the drawings]

[0035] [Figure 1] FIG. 1 shows the effect of treatment on fracture callus mineralization using compounds disclosed herein. [Diagram 2] FIG. 1 shows the effect of treatment on fracture strength using compounds disclosed herein. [Diagram 3] FIG. 1 shows the effect of treatment on fracture strength using compounds disclosed herein. [Figure 4] FIG. 1 shows the effect of treatment on fracture callus mineralization using compounds disclosed herein. [Diagram 5] FIG. 1 shows the effect of treatment on fracture strength using compounds disclosed herein. [Figure 6]FIG. 6 shows microCT images from the fractured bones of FIGS. 4 and 5. [Figure 7] FIG. 1 shows the effect of treatment on fracture strength using compounds disclosed herein. [Figure 8] FIG. 1 shows the effect of treatment on fracture strength using compounds disclosed herein. [Figure 9] FIG. 1 shows the effect of treatment on fracture strength in males using compounds disclosed herein. [Figure 10] FIG. 1 shows the effect of treatment on bone strength in females using compounds disclosed herein. [Figure 11] FIG. 1 shows the effect of treatment on bone strength using compounds disclosed herein. [Figure 12] FIG. 1 shows the effect of treatment on fracture strength using compounds disclosed herein. [Figure 13] FIG. 1 shows the effect of treatment on fracture stiffness using compounds disclosed herein. [Figure 14] FIG. 1 shows the effect of treatment on fracture stiffness using compounds disclosed herein. [Figure 15A] FIG. 2 shows a SPEC / CT image of a Tc chelator EC20 that chelates m99Tc linked to a compound disclosed herein, taken 21 hours after injection. [Figure 15B] FIG. 15B, which can be superimposed on FIG. 15C, shows a mouse skeleton imaged by SPEC / CT. [Figure 15C] FIG. 15C, which can be superimposed with FIG. 15B, shows the localization of Compound 2 in mice imaged by SPEC / CT. [Figure 16] FIG. 2 shows a SPEC / CT image of a Tc chelator EC20 that chelates m99Tc linked to a compound disclosed herein, taken 21 hours after injection. [Figure 17] FIG. 1 shows the effect of treatment on bone mass using compounds disclosed herein. [Figure 18] FIG. 1 shows the effect of treatment on fracture strength using compounds disclosed herein. [Figure 19] FIG. 1 shows the effect of treatment on fracture strength using compounds disclosed herein. [Figure 20] FIG. 1 shows the effect of treatment on work to fracture using compounds disclosed herein. [Figure 21] FIG. 1 shows the effect of treatment on fracture strength using compounds disclosed herein. [Figure 22] FIG. 1 shows the effect of treatment on work to fracture using compounds disclosed herein. [Figure 23] FIG. 1 shows the effect of treatment on fracture callus mineralization using compounds disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Provided in some embodiments herein are compounds for treating fractured and / or weakened (e.g., low density, brittle) bones in an individual (e.g., in need of bone treatment). In some embodiments, the individual in need of bone treatment has osteogenesis imperfecta (OI). In some embodiments, the individual has been diagnosed with OI type 1, OI type 3, and / or OI type 4. In some embodiments, the individual has been diagnosed with OI associated with a genetic mutation (e.g., in the individual), such as a genetic mutation that reduces collagen formation and / or production. In some embodiments, the individual has been diagnosed with childhood OI.

[0037] Provided in certain embodiments herein are compounds and methods for treating fractured and / or weakened (e.g., low density, brittle) bones in individuals (e.g., in need of bone treatment) with one or more bone diseases. Provided in certain embodiments herein are compounds and methods for treating osteogenesis imperfecta (OI) in individuals (e.g., in need of OI treatment). In some embodiments, the compounds described herein are administered to individuals (e.g., in need of the compounds described herein) to treat OI. In some embodiments, administering the compounds to individuals (e.g., in need of the compounds) results in significant improvement in the bone condition associated with OI. In some embodiments, the compounds described herein are targeted compounds. In some embodiments, the targeted compounds have targeting specificity for fractured bone sites, low density bone sites and / or weakened bone sites.

[0038] In some embodiments, the individual does not have a fracture.

[0039] In some embodiments, administration of the compounds described herein improves and promotes fracture repair in individuals with OI disease states.

[0040] In some embodiments, the compounds described herein promote fracture repair in individuals without ectopic bone formation (eg, OI disease states).

[0041] In some cases, individuals with OI have multiple sites of skeletal remodeling (e.g., bone turnover), such as a result of poor skeletal phenotype that disrupts normal bone homeostasis.In some cases, the increase in skeletal remodeling (e.g., bone turnover) in individuals with OI leads to multiple weakened bone sites and low density bone sites throughout the individual to various degrees.Therefore, it is surprising that the increase in skeletal remodeling (e.g., bone turnover (e.g., by administering the compound described herein)) improves bone healing (e.g., fracture healing) in individuals with OI.

[0042] In some cases, individuals with OI have genetic mutations that reduce collagen formation and / or production, such as resulting in collagen synthesis defects. In some cases, collagen synthesis defects are associated with low amounts of hydroxyapatite in bone. Therefore, it would be surprising if a compound that targets hydroxyapatite (e.g., bone anabolic compound) could significantly increase the bone healing rate and / or improve bone strength (e.g., mechanical bone strength and structural bone strength) in individuals diagnosed with OI. Furthermore, some embodiments provided herein are compounds as described herein or pharma- ceutically acceptable salts thereof that improve (e.g., promote) the treatment (e.g., healing or repair) of bone (e.g., osteotomy, bone graft or fracture) in individuals with OI. In some embodiments, administering a compound as described herein improves callus mineralization in individuals with OI.

[0043] In some embodiments, a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof reduces non-union or delayed union of a bone (e.g., osteotomy, bone graft, or fracture) in an individual (e.g., an individual having OI, in need of a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof).

[0044] In some embodiments, a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof increases bone strength in an individual (e.g., an individual having OI, in need of a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof).

[0045] In some cases, the ability of anabolic agents linked to hydroxyapatite ligands to promote fracture repair in type 3 OI disease conditions was analyzed. Type 3 is the most severe non-lethal form of OI, and the human population experiences the most fractures. In some cases, type 3 was modeled in Col1a2oim(- / -) mice (e.g., a well-established model of type 3 OI) as described elsewhere herein (e.g., see Examples). In some cases, the compound is administered distally and accumulates locally at the fracture site.

[0046] In some cases, a significant increase (e.g., greater than 85%) in percent bone mass was observed in mice administered a compound provided herein (e.g., Ab46-D-Glu20) over saline groups. In some cases, mechanical testing resulted in between a 220% to 300% increase in force to fracture in mice administered a compound provided herein (e.g., Ab46-D-Glu20) over saline control groups.

[0047] In some cases, significant improvement in radiographic healing was observed with administration of a compound provided herein (e.g., Ab46-D-Glu20) over a control. In some cases, the Col1a2oim mouse model (e.g., like most cases of OI) causes defects in collagen formation, such as resulting in poor bone quality. Radiographic healing cannot fully reveal the overall mechanical quality of the bone may still be compromised, but mechanical testing does reveal bone quality. In some cases, dramatically more force was required to re-fracture the bone after administration of a compound provided herein (e.g., Ab46-D-Glu20). In some cases, improved mechanical stability (e.g., in the context of OI) means that once the fracture has healed radiographically (and the individual is removed from the stabilizing cast or splint), the individual has enough bone strength to return to normal activity without fear of re-fracture. In some cases, the targeted bone anabolic agents provided herein (e.g., Ab46-D-Glu20) improve structural and mechanical healing of fractures in both adult and pediatric type 1 and type 3 OI. In some cases, the targeted bone anabolic agents provided herein (e.g., Ab46-D-Glu20) result in beneficial improvements in BMD, thereby strengthening the remainder of the skeleton (e.g., reducing future fractures). In some cases, the bone targeted therapeutic agents provided herein (e.g., Ab46-D-Glu20) improve and promote fracture healing and prevent future fractures, such as improving the overall quality of life of OI patients. OI is an underserved population that would greatly benefit from a treatment that, in conjunction with conventional treatments, not only improves fracture repair, but is safe enough to be used multiple times throughout a lifetime. By targeting the bone anabolic agent to the fracture site, a sufficient concentration of the anabolic agent can be delivered to the fracture site to safely promote healing. In some cases, for example, if the physician observes healing via radiographs, the individual will likely be allowed to move (and continue normal activities) without a cast splint. In some cases, for example, the process of measuring bone mass percentage has limited measurement of the amount of callus bridging, such as by focusing on measurements at healing via radiographs.

[0048] Figure 1 shows the Col1a2 expression in type 3 (- / -) OI. oim FIG. 1 shows the effect of treatment with Compound 1 (SEQ ID NO: 1, AVSEHQLLHDKGKSIQDLRRRELLEKLLxKLHTAEIRATSEVSPNSeeeeeeeeeeeeeeeeee, where x=Aib and "e" represents D-glutamic acid) on fracture callus mineralization in a mouse model. After reaching skeletal maturity, 12-week-old female mice were modeled with midshaft femoral fractures stabilized by osteotomy. Type 3 OI mice were treated twice a week for 6 weeks after fracture. Fracture callus mineralization was assessed by quantification of high-resolution MicroCT (scanco) images of the fracture callus. Compound 1 significantly improved fracture callus mineralization in Type 3 OI mice. As shown in FIG. 1, Compound 1 results in approximately 100% improvement in fracture callus mineralization compared to saline controls. In some cases, improved callus mineralization results in structurally improved bone in individuals with OI.

[0049] In some examples, the compounds described herein result in mechanically improved bone in individuals with OI. oim FIG. 2 shows the effect of treatment with Compound 1 on fracture strength in a mouse model. After reaching skeletal maturity, 12-week-old female mice were subjected to a midshaft femoral fracture model stabilized by osteotomy. Type 3 OI mice were treated twice a week for 6 weeks after fracture. Break strength was assessed by 4-point bending to failure of the fractured femur. Maximum load assesses the maximum load the femur withstood before fracture in a biomechanical evaluation. A contralateral untreated femur is presented here to show recovery to previous unfractured strength during treatment. As shown in FIG. 2, Compound 1 increases the maximum load (in Newtons) required for the bone to fracture by approximately 300% (compared to saline bones). FIG. 2 also shows that bones treated with Compound 1 have an approximately 40% higher maximum load required to fracture compared to unfractured bones.

[0050] Figure 3 shows the effect of treatment with Compound 1 on fracture strength in the Col1a2oim mouse model of type 3 (- / -) OI. After reaching skeletal maturity, 12-week-old female mice were subjected to a mid-shaft femoral fracture model stabilized by osteotomy. Type 3 OI mice were treated twice a week for 6 weeks after fracture. Fracture strength was assessed by 4-point bending to failure of the fractured femur. Work to fracture evaluates the total amount of energy absorbed by the femur before fracture in a biomechanical evaluation. The contralateral untreated femur is presented here to show recovery to previous unfractured strength during treatment. As shown in Figure 3, for bones treated with Compound 1, work to fracture, or the total amount of energy absorbed by the bone before fracture, is increased by approximately 150% compared to bones repaired with saline and approximately 70% compared to unfractured bones.

[0051] Provided herein in certain embodiments is a method for treating osteogenesis imperfecta (OI) in an individual (e.g., in need of treatment for osteogenesis imperfecta (OI)), comprising administering to the individual (e.g., in need of treatment for osteogenesis imperfecta (OI)) a therapeutically effective amount of a compound having the structure XYZ, where X is a bone anabolic agent, Y is a linker, and Z is a bone-targeting ligand, or a pharma- ceutically acceptable salt thereof.

[0052] In some embodiments, a compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount sufficient to prevent bone fracture in an individual, such as an individual with OI (e.g., in need of a compound provided herein, or a pharma- ceutically acceptable salt thereof). In some embodiments, a compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered in an amount sufficient to reduce the incidence of bone fracture in an individual, such as an individual with OI (e.g., in need of a compound provided herein, or a pharma- ceutically acceptable salt thereof).

[0053] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is prophylactically administered to an individual (eg, in need of the compound or a pharma- ceutically acceptable salt thereof) in a therapeutically effective amount.

[0054] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered systemically to an individual (eg, in need of the compound or a pharma- ceutically acceptable salt thereof) in a therapeutically effective amount.

[0055] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered distally to an individual (e.g., in need of the compound or a pharma- ceutically acceptable salt thereof) in a therapeutically effective amount. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof administered distally to an individual (e.g., in need of the compound or a pharma- ceutically acceptable salt thereof) accumulates locally at the fracture site.

[0056] In some embodiments, the compounds provided herein or pharma- ceutically acceptable salts thereof reduce the occurrence or likelihood of bone fracture in an individual (e.g., in need of a compound provided herein or a pharma- ceutically acceptable salt thereof), such as an individual diagnosed with OI. In some embodiments, the compounds provided herein or pharma- ceutically acceptable salts thereof increase bone density or bone strength (e.g., mechanical bone strength or structural bone strength) in an individual. In some embodiments, a therapeutically effective amount of a compound provided herein is an amount effective to reduce the severity or occurrence, such as the mean, of bone fractures.

[0057] In some embodiments, administering a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof to an individual (e.g., in need of a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt) reduces the incidence or likelihood of fracture in the individual (e.g., in need of a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt). In some embodiments, administering a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof to an individual (e.g., in need of a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt) increases bone density or bone strength (e.g., mechanical strength or structural strength) in the individual. In some embodiments, reducing the incidence or likelihood of fracture in an individual (e.g., in need of a reduced incidence or likelihood of fracture) is achieved by prophylactically administering a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof to an individual (e.g., in need of a reduced incidence or likelihood of fracture). In some embodiments, reducing the incidence or likelihood of fracture in an individual (e.g., in need of a reduced incidence or likelihood of fracture) is achieved by systemically administering a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt thereof to an individual (e.g., in need of a reduced incidence or likelihood of fracture).

[0058] Figures 11 and 12 show Col1a2 in type 1 (+ / -) OI. oimFigure 1 shows the effect of treatment with Compound 1 on bone strength in a mouse model. 12-week-old female mice were modeled after osteotomy for midshaft femoral fractures. Type 1 OI mice were treated twice a week for 5 weeks after fracture. Bone strength was assessed by 4-point bending to fracture of the unfractured contralateral femur. Maximum load (Figure 11) assesses the maximum load the femur withstood before fracture in a biomechanical assessment. Work to fracture (Figure 12) assesses the total amount of energy absorbed by the femur before fracture in a biomechanical assessment. Bone-targeted anabolic agent treatment dramatically improves bone strength of the contralateral femur. As shown in Figure 11, the unfractured bones of mice treated with Compound 1 have a maximum load required to fracture that is approximately 30% higher than the unfractured bones of control mice. As shown in Figure 12, the work to fracture, or the total amount of energy that the unfractured bone can absorb before fracture, is approximately 40% higher in the unfractured bones of mice treated with Compound 1 than in control mice.

[0059] Figures 13 and 14 show the Col1a2 expression in osteogenesis imperfecta type 3 (- / -) and type 1 (- / +). oim1 shows the effect of treatment with compound 1 on fracture stiffness in a mouse model. After reaching skeletal maturity, 12-week-old female mice were subjected to osteotomy-stabilized midshaft femoral fracture model, and type 1 and type 3 OI mice were treated twice a week for 5 and 6 weeks after fracture, respectively. Fracture strength was assessed by 4-point bending until fracture of the fractured femur. Modulus evaluates the stiffness of the femur during biomechanical evaluation. Lower stiffness is indicative of brittleness leading to future fracture. The improvement in stiffness that occurs at the fracture callus is indicative of a healthier bone that is less brittle and less likely to fracture in the future. In some cases, lower bone stiffness is indicative of bone brittleness, such as associated with a higher risk of fracture. In some cases, higher bone stiffness is indicative of a healthier bone, such as a bone that is less brittle and less likely to fracture. In some cases, the majority of the compound is localized to the fracture callus (e.g., due to the large amount of hydroxyapatite exposed at the fracture site and DE20 can bind to hydroxyapatite via chelation of calcium components). In some cases, there was also some moderate accumulation at sites of elevated resorption throughout the skeleton of type 3 OI (e.g., this was responsible for the improvement of the unfractured skeleton observed in Figures 13 and 14). In some cases, for example, in unfractured type 3 mice, accumulation at sites of high bone turnover throughout the skeleton was still observed, thus demonstrating that this targeting technique can be used to prophylactically deliver therapeutic agents to sites of bone injury and high turnover in individuals with OI without fractures to strengthen bone and prevent fractures. As shown in Figure 13, the fractured bones of mice with type 3 OI treated with Compound 1 are about 100% stiffer than the fractured bones of control mice and about 50% stiffer than the unfractured bones of control mice. As shown in Figure 14, the fractured bones of mice with type 1 OI treated with Compound 1 are about 60% stiffer than the fractured bones of control mice and about 10% stiffer than the unfractured bones of control mice.

[0060] OI is often considered a complex disease characterized by many subtypes that are related to genetic mutations in the ability to form or process collagen properly. In some embodiments, the compounds provided herein are effective in improving bone health in individuals with different types of OI. In some embodiments, OI is type 1 OI. Type 1 OI is the most common form of OI, affecting more than half of all individuals with OI. In some embodiments, OI is type 3 OI. Type 3 OI is the most severe non-fatal form of OI and experiences the most fractures in the human population. In some embodiments, OI is type 4 OI. In some embodiments, OI is related to genetic mutations in individuals with the ability to form or process collagen.

[0061] Figure 4 shows Col1a2 in type 1 (+ / -) and type 3 (- / -) OI. oim Figure 4 shows the effect of treatment with Compound 1 on fracture callus mineralization in a mouse model. After reaching skeletal maturity, 12-week-old female mice were subjected to a midshaft femoral fracture model stabilized by osteotomy. Type 1 and type 3 OI mice were treated twice a week for 5 and 6 weeks after fracture, respectively. Fracture callus mineralization was evaluated by quantification of high-resolution MicroCT (scanco) images of the fracture callus. Compound 1 significantly improved fracture callus mineralization for both type 1 and type 3 OI mice. As shown in Figure 4, Compound 1 results in approximately 100% improvement in fracture callus mineralization compared to saline controls in mice with type 3 OI, and approximately 50% improvement in fracture callus mineralization compared to saline controls in mice with type 1 OI. In some cases, improved callus mineralization results in structurally improved bones in individuals with OI.

[0062] Figure 5 shows Col1a2 in type 1 (+ / -) and type 3 (- / -) OI. oimFigure 5 shows the effect of treatment with Compound 1 on fracture strength in a mouse model. After reaching skeletal maturity, 12-week-old female mice were subjected to a midshaft femoral fracture model stabilized by osteotomy. Type 1 and Type 3 OI mice were treated twice a week for 5 and 6 weeks after fracture, respectively. Break strength was assessed by 4-point bending until fracture of the fractured femur. The contralateral untreated femur is presented here to show recovery to previous unfractured strength during treatment. As shown in Figure 5, Compound 1 increases the maximum load (in Newtons) required for the bone to fracture in mice with Type 3 OI by approximately 300% (compared to saline bones) and by approximately 40% compared to Type 3 unfractured bones. Additionally, Compound 1 increases the maximum load (in Newtons) required for the bone to fracture in mice with Type 1 OI by approximately 70% (compared to saline bones).

[0063] Figure 6 shows the median microCT image from the fractured bones of Figures 4 and 5. Each image is a composite of 20 microCT slices. Lighter shading indicates higher bone density than darker shading. The white areas continue to be the original cortical bone, while the darker shading corresponds to new cancellous and woven bone. As shown in Figure 6, Compound 1 promotes healthier, denser bone (e.g., lighter shading) than the saline control.

[0064] In some cases, OI begins in childhood at birth, with many of the fractures in an individual's life occurring during adolescence. In some embodiments, the individual has childhood OI. Figures 7 and 8 show the Col1a2 oimFIG. 1 shows the effect of treatment with Compound 1 on fracture strength in a mouse model. Six-week-old pediatric mice were modeled with midshaft femoral fractures stabilized by osteotomy. Type 1 OI mice were treated twice a week for four weeks after fracture. Fracture strength was assessed by four-point bending to failure of the fractured femur. Maximum load (FIG. 7) assesses the maximum load the femur withstood before fracture in a biomechanical assessment. Work to fracture (FIG. 8) assesses the total amount of energy absorbed by the femur before fracture in a biomechanical assessment. As shown in FIG. 7, the maximum load required for bones to fracture in pediatric mice is approximately 160% higher with Compound 1 than in bones treated with a saline control. As shown in FIG. 8, the work to fracture, or the total amount of energy that pediatric mice bones can absorb before fracture, is approximately 80% higher in bones treated with Compound 1 than in bones treated with a saline control.

[0065] In some embodiments, the individual is male. In some embodiments, the individual is female. In some embodiments, the effect of gender on the response of bone-targeted anabolic agents in stimulated fracture healing in OI and stabilized midshaft femoral fracture repair in type 1 OI Col1a2oim(+ / -) mice, such as using the methods described herein, was evaluated. In some examples, the compound is administered distally and accumulates locally at the fracture site. Figures 9 and 10 show the effect of gender on the response of bone-targeted anabolic agents in stimulated fracture healing in OI and stabilized midshaft femoral fracture repair in type 1 OI Col1a2oim(+ / -) mice, such as using the methods described herein ... oimThe effect of treatment with Compound 1 on fracture strength in a mouse model is shown. Male (Figure 9) and female (Figure 10) mice aged 12 weeks were subjected to a midshaft femoral fracture model stabilized by osteotomy. Type 1 OI mice were treated twice a week for 5 weeks after fracture. Break strength was assessed by 4-point bending to fracture of the fractured femur. Maximum load assesses the maximum load the femur withstood before fracture in a biomechanical evaluation. The contralateral untreated femur is presented here to show recovery to previous unfractured strength during treatment. No response difference between the sexes was observed. As shown in Figure 9, the fractured bones of male mice treated with Compound 1 have a maximum load required to fracture approximately 70% higher than those of control mice. As shown in Figure 10, the fractured bones of female mice treated with Compound 1 have a maximum load required to fracture 80% higher than those of control mice.

[0066] In some embodiments, a therapeutically effective amount of a compound provided herein is delivered to one or more sites of low density or weakened bone (e.g., a site of skeletal remodeling, or a site of low collagen other than a fracture site, or a site without a fracture site) in an individual, such as an individual having OI (e.g., in need of a therapeutically effective amount of a compound provided herein). In some embodiments, a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof provides a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof to one or more sites of low density or weakened bone (e.g., a site of skeletal remodeling, or a site of low collagen other than a fracture site, or a site without a fracture site) in an individual (e.g., in need of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof).

[0067] Provided herein in certain embodiments is a method for delivering (e.g., targeting) a compound or a pharma- ceutically acceptable salt thereof to one or more damaged, low-density or weakened bone sites (e.g., areas other than or without fracture sites, such as fractures, skeletal remodeling sites or low-collagen sites) in an individual with osteogenesis imperfecta (OI). In some embodiments, the method comprises administering a compound to the individual, the compound having a structure XYZ, where X is a bone anabolic agent, Y is a linker, and Z is a bone-targeting ligand. In some embodiments, administering the compound delivers (e.g., targets) a therapeutically effective amount of the compound to one or more damaged, low-density or weakened bone sites (e.g., areas other than or without fracture sites, such as fractures, skeletal remodeling sites or low-collagen sites). In some embodiments, the one or more damaged, low-density or weakened bone sites are osteotomies, bone grafts, fractures (e.g., microfractures or stress fractures), or skeletal remodeling areas. In some embodiments, the compound comprises a diagnostic payload, and administration of the compound identifies one or more damaged, low density, or weakened bone sites in an individual (e.g., areas other than a fracture site, such as a fracture, a site of skeletal remodeling, or a site of low collagen, or areas without a fracture site).

[0068] In some embodiments, the low density bone sites or weakened bone sites are associated with skeletal remodeling or low collagen sites. In some embodiments, the low density bone sites or weakened bone sites result from skeletal remodeling or low collagen sites. In some embodiments, the skeletal remodeling sites and / or low collagen sites are found throughout the individual's entire body. In some embodiments, the skeletal remodeling sites are found in sites without fractures. In some embodiments, the skeletal remodeling sites and / or low collagen sites are found in sites found other than fracture sites. In some embodiments, the skeletal remodeling sites are found in sites found other than fracture sites. In some embodiments, the skeletal remodeling sites are found in sites found other than fracture sites. In some embodiments, the individual with OI has multiple sites of increased skeletal remodeling that further contribute to the poor skeletal phenotype associated with OI, such as due to a disruption of normal bone homeostasis. In some embodiments, such effects result in an additional osteopenic state that results in even weaker bones than, for example, bones produced as a result of genetic disruption of collagen. In some embodiments, the increased skeletal remodeling is mosaic, such as occurring at multiple sites throughout the individual's bones, such as to varying degrees. In some embodiments, such remodeling sites are weak or low density bone sites, or sites of potential future fractures. In some embodiments, increased skeletal resorption provides sites of exposed hydroxyapatite for bone-targeting anabolic agents to accumulate at sites other than only the fracture site, such as sites requiring improved bone deposition, resulting in favorable accumulation throughout the remainder of the skeleton at sites of weakening or low density (e.g., areas other than fracture sites, such as fractures, skeletal remodeling sites, or low collagen sites, or areas without fracture sites). In some embodiments, when evaluating the remainder of the skeleton in OI mice treated with bone-targeting anabolic agents, dramatic improvements in skeletal strength were identified, such as due to accumulation of targeted agents in these unfractured skeletons (e.g., leading to increased bone mineral density). In some cases, this demonstrates that targeted anabolic agents can not only improve and promote fracture healing, but they can also be used to prevent future fractures by improving the strength of weakened areas of the skeleton.In some embodiments, a targeted diagnostic payload is delivered to the exposed hydroxyapatite. In some embodiments, delivery of a targeted diagnostic payload to the exposed hydroxyapatite is useful for identifying one or more sites of weakened or low density bone in an individual (e.g., a region other than a fracture site, such as a fracture, a skeletal remodeling site, or a site of low collagen, or a region without a fracture site).

[0069] FIG. 15A-C shows, for example, a 12-week-old female Col1a2 mouse with a midshaft femur fracture 2 weeks after fracture. oim Figure 15 shows imaging of type 3 (- / -) mice using SPECT / CT (MiLabs U-SPECT-II / CT) at 21 hours with Compound 1 labeled with m99Tc-EC20 (SEQ ID NO: 2, eeeeeeeeeeeeeeeeeeee(AEEA)βDapDC((m99Tc), where AEEA means 2,2-aminoethoxyethoxyacetic acid, βDap means beta diaminopropionic acid, ((m99Tc) means chelated m99Tc, D means aspartic acid, C means cysteine, and "e" stands for D-glutamic acid). As shown in Figure 15A-C, Compound 2 accumulated at the sites of fractures, as well as at sites of low density and weakened bone throughout the body. Figure 15B and Figure 15C are images of the mouse skeleton and localization of Compound 2, which can be overlaid to provide Figure 15A.

[0070] FIG. 16 shows Compound 2 in a 12-week-old female Col1a2 rat without a midshaft femur fracture 2 weeks after fracture. oim Type 3 (- / -) mice were imaged at 21 hours using SPECT / CT (MiLabs U-SPECT-II / CT).As shown in Figure 16, in the absence of fracture, Compound 2 accumulated in areas of low density and weakened bone throughout the body.

[0071] In some examples, the compounds provided herein increase the bone mass fraction of a fractured bone in an individual in need of the compounds provided herein (e.g., an individual with a fracture and OI). In some examples, the compounds provided herein significantly increase the bone mass fraction of a fractured bone in an individual in need of the compounds provided herein (e.g., an individual with a fracture and OI). In some examples, the compounds provided herein increase the bone mass fraction of one or more fractured bones by at least about 40% (e.g., about 50-55%) in an individual in need of the compounds provided herein (e.g., an individual with a fracture and OI) compared to a saline control (e.g., FIG. 1).

[0072] In some examples, the compounds provided herein increase the fracture strength of a fractured bone in an individual in need of the compounds provided herein (e.g., an individual with a fracture and OI). In some examples, the compounds provided herein significantly increase the fracture strength of a fractured bone in an individual in need of the compounds provided herein (e.g., an individual with a fracture and OI). In some examples, the compounds provided herein increase the fracture strength of one or more fractured bones in an individual in need of the compounds provided herein (e.g., an individual with a fracture and OI) by at least about 100% (e.g., 150% or more, 200% or more (e.g., about 150-300%) compared to a saline control (e.g., FIG. 2).

[0073] In some examples, the compounds provided herein increase the work to fracture of a fractured bone in an individual in need of the compounds provided herein (e.g., an individual with a fracture and OI). In some examples, the compounds provided herein significantly increase the work to fracture of a fractured bone in an individual in need of the compounds provided herein (e.g., an individual with a fracture and OI). In some examples, the compounds provided herein increase the work to fracture of one or more fractured bones in an individual in need of the compounds provided herein (e.g., an individual with a fracture and OI) by at least about 40% (e.g., about 60%) compared to saline control (e.g., FIG. 3).

[0074] In some embodiments, compounds provided herein, such as compound 3 (SEQ ID NO:3, AVSEHQLLHDKGKSIQDLIUGTFFLHHLIAEIHTAEnLATSEVSPNSeeeeeeeeeeeeeeeeee, where "e" represents D-glutamic acid), localize PTHrP to bone via a targeting ligand.

[0075] Laminin is a protein component of the extracellular matrix (ECM). In some instances, laminin mediates cell adhesion to surfaces via either syndecans or integrins. In some instances, human laminin-a2 LG1 domain mediates cell adhesion via syndecan-1, such as by inducing phosphorylation and membrane localization of protein 326 kinase Cd.254 Ln2_P3 or DLTIDDSYWYRI, which is one of the bioactive cores of human laminin a2 chain.254. In some instances, laminin promotes osteointegration of dental implants, improves overall cell adhesion, and activates osteoblasts.

[0076] In some embodiments, compounds provided herein, such as compound 4 (SEQ ID NO: 4, eeeeeeeeee(AEEA)4DLTIDDSYWYRI, where AEEA is 2,2-aminoethoxyethoxyacetic acid and "e" represents D-glutamic acid), localize the Ln2_P3 motif to bone via a 4-miniPEG spacer and targeting ligand attached to the N-terminus.

[0077] Figure 17 shows Col1a2 in type 1 (+ / -) OI. oim Figure 17 shows the effect of treatment with Compound 3 and Compound 4 on fracture callus mineralization in a mouse model. After reaching skeletal maturity, 12-week-old mice were subjected to a midshaft femoral fracture model stabilized by osteotomy. Type 1 OI mice were treated subcutaneously daily for 5 weeks after fracture. Fracture callus mineralization was evaluated by quantification of high-resolution MicroCT (scanco) images of the fracture callus. In some cases, mice were administered 38 nmol / kg / d of Compound 4, Compound 3, or PBS vehicle control (daily). In some cases, Compound 4 significantly improved fracture callus mineralization in Type 1 OI mice. In some cases, Compound 3 significantly improved fracture callus mineralization in Type 1 OI mice. As shown in Figure 17, Compound 4 resulted in approximately 200% improved fracture callus mineralization, and Compound 3 resulted in approximately 300% improved fracture callus mineralization, compared to saline control. In some instances, improved callus mineralization results in structurally improved bone in individuals with OI.

[0078] In some examples, the compounds described herein provide mechanically improved bone in individuals with OI. oimThe effect of treatment with Compound 3 and Compound 4 on fracture strength in a mouse model is shown. After reaching skeletal maturity, 12-week-old female mice were subjected to a midshaft femoral fracture model stabilized by osteotomy. Type 1 OI mice were treated subcutaneously daily for 5 weeks after fracture. Break strength was assessed by 4-point bending until fracture of the fractured femur. In some cases, mice were administered 38 nmol / kg / d Compound 4, Compound 3, or PBS vehicle control (daily). Maximum load assesses the maximum load the femur withstood before fracture in a biomechanical evaluation. The contralateral untreated femur is presented here to show recovery to previous unfractured strength during treatment. As shown in Figure 18, Compound 4 increases the maximum load (in Newtons) required for the bone to fracture by approximately 200% (compared to control). As shown in Figure 18, Compound 3 increases the maximum load (in Newtons) required for the bone to fracture by approximately 100% (compared to control).

[0079] Figures 19 and 20 show Col1a2 in type 1 (+ / -) OI. oim Figure 1 shows the effect of treatment with Compound 3 on bone strength in a mouse model. 12-week-old female mice were modeled after osteotomy-stabilized midshaft femoral fracture. Type 1 OI mice were treated subcutaneously daily for 5 weeks after fracture. Bone strength was assessed by 4-point bending to fracture of the unfractured contralateral femur. Maximum load (Figure 19) assesses the maximum load the femur endured before fracture in a biomechanical assessment. Work to fracture (Figure 20) assesses the total amount of energy absorbed by the femur before fracture in a biomechanical assessment. Bone-targeted anabolic agent treatment dramatically improves bone strength in the contralateral femur. As shown in Figure 19, re-fractured bones in mice treated with Compound 3 have a maximum load required to fracture that is approximately 10% higher than re-fractured bones in control mice. As shown in FIG. 20, the work to fracture, or the total amount of energy that an unfractured bone can absorb before fracture, is approximately 40% higher in the unfractured bones of mice treated with Compound 3 than in control mice.

[0080] In some embodiments, Figures 17-20 demonstrate that targeting ligands (De10, De20, etc.) can be used to deliver therapeutic peptides other than abaloparatide (e.g., PTHrP, Ln2P3, etc.) to bone. In some examples, compound 4 demonstrates that de20 is not the only bone targeting ligand that can be used to localize therapeutic peptides to bone fractures (e.g., in mice with OI). For example, other bone targeting molecules with affinity for hydroxyapatite (e.g., other acidic peptides, phosphonates, phosphates, tetracyclines, ranelates, alendronates, etc.) can be used to localize anabolic payloads to bone fractures in individuals with osteogenesis imperfecta.

[0081] In some embodiments, targeted QK effectively and significantly improves bone healing in normal healthy conditions. In some cases, QK improves normal fracture healing by acting on endothelial cells to re-establish vascularization to bone.

[0082] However, in OI disease state, the main factor that delays fracture healing is the impairment of collagen produced by osteoblasts. Moreover, OI is a genetic disease that is mainly caused by frameshift or premature stop mutations in COL1A1 or COL1A2 genes. In some cases, the loss of (normal) collagen affects bone quality and quantity (e.g., the amount of bone that forms).

[0083] Figure 21 shows Col1a2 in type 1 (+ / -) OI. oimFigure 1 shows the effect of treatment with targeted compound QK-De10 on fracture strength in mouse model. After reaching skeletal maturity, 12-week-old mice were subjected to midshaft femoral fracture model stabilized by osteotomy. Type 1 OI mice were treated subcutaneously daily for 5 weeks after fracture. Fracture strength was assessed by 4-point bending until fracture of the fractured femur. Maximum load evaluates the maximum load that the femur withstood before fracture in biomechanical evaluation. In some cases, mice were administered QK-De10 or PBS vehicle control (daily). In some cases, QK-De10 cannot improve fracture callus strength in type 1 OI mice.

[0084] Figure 22 shows Col1a2 in type 1 (+ / -) OI. oim The effect of treatment with the targeted compound QK-De10 on fracture strength in a mouse model is shown. After reaching skeletal maturity, 12-week-old mice were subjected to midshaft femoral fracture model stabilized by osteotomy. Type 1 OI mice were treated daily subcutaneously for 5 weeks after fracture. Fracture strength was assessed by 4-point bending to fracture of the fractured femur. Work to fracture evaluates the total amount of energy absorbed by the femur before fracture in a biomechanical evaluation. In some cases, QK-De10 cannot improve fracture callus strength in type 1 OI mice.

[0085] Figure 23 shows Col1a2 in type 1 (+ / -) OI. oim The effect of treatment with the targeted compound QK-De10 on fracture callus mineralization in a mouse model is shown. After reaching skeletal maturity, 12-week-old mice were subjected to a midshaft femoral fracture model stabilized by osteotomy. Type 1 OI mice were treated daily subcutaneously for 5 weeks after fracture. Fracture callus mineralization was evaluated by quantification of high-resolution MicroCT (scanco) images of the fracture callus. In some cases, QK-De10 cannot improve fracture callus mineralization in type 1 OI mice.

[0086] In some examples, Figures 21-23 show that compound 5 fails to significantly improve bone strength and bone mass in mice with type 1 OI. In some examples, Figures 21-23 show that compounds lacking direct osteoblast stimulating activity fail to improve bone strength and bone mass in mice with type 1 OI. As suggested by the data provided herein, the amount of bone formed correlates with the ability of the compound to activate osteoblast activity on bone, highlighting that bone anabolic agents that increase osteoblast differentiation or activity (and / or block apoptosis), such as abaloparatide, PTHrP, Ln2P3, may be more likely to provide an effective treatment for fracture healing in OI than anabolic agents that do not, such as QK. Similarly, anabolic agents that directly affect collagen production and quality may be more likely to provide an effective treatment for fracture healing in OI than anabolic agents that do not.

[0087] Provided herein in certain embodiments is a compound having the structure XYZ, where X is a bone anabolic agent, Y is a linker, and Z is a bone-targeting ligand, or a pharma- ceutically acceptable salt thereof.

[0088] In some embodiments, X is a bone anabolic agent (eg, an agent having bone anabolic activity).

[0089] In some embodiments, X is a bone anabolic agent that stimulates or activates osteoblasts (directly). In some embodiments, X is an agent that increases osteoblast differentiation. In some embodiments, X is an agent that increases osteoblast activity. In some embodiments, X is an agent that blocks osteoblast apoptosis.

[0090] In some embodiments, X is a bone anabolic agent that (directly) affects collagen production. In some embodiments, X is an agent that increases collagen production.

[0091] In some embodiments, X is a bone anabolic agent that increases the production of collagen in an individual or improves the individual's ability to form or process collagen.

[0092] In some embodiments, X is a bone anabolic agent that targets sites of low collagen, such as fracture sites, non-fracture sites, or sites without a fracture site.

[0093] In some embodiments, e.g., when attached to or released from a compound described herein, X is a growth factor, a small molecule, a peptide, a protein, a hormone, or a fragment thereof.

[0094] In some embodiments, X is an antibody.

[0095] In some embodiments, X is a bone anabolic agent selected from the group consisting of an agonist of parathyroid hormone receptor 1, parathyroid hormone (PTH), PTH-related protein (PTHrP), and abaloparatide.

[0096] In some embodiments, X is a bone anabolic agent (e.g., having bone anabolic activity) including a growth factor, a small molecule, a peptide, a protein, or a hormone. In some embodiments, X is a bone anabolic agent selected from the group consisting of an agonist of parathyroid hormone receptor 1, parathyroid hormone (PTH) (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)), PTH-related protein (PTHrP) (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)), and abaloparatide (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)). In some embodiments, X is abaloparatide (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)).

[0097] In some embodiments, X is a parathyroid hormone receptor 1 agonist.

[0098] In some embodiments, X is PTH.

[0099] In some embodiments, X is PTHrP.

[0100] In some embodiments, X is abaloparatide.

[0101] In some embodiments, X is Ln2P3.

[0102] In some embodiments, X is QK.

[0103] In some embodiments, Z is a hydroxyapatite targeting ligand.

[0104] In some embodiments, the hydroxyapatite targeting ligand comprises a tetracycline, a phosphonate (e.g., a bisphosphonate (e.g., a mono-bisphosphonate, a tri-bisphosphonate, or a poly-bisphosphonate)), an acidic oligopeptide, ranelate, pyrophosphate, or a targeting ligand developed by phage display.

[0105] In some embodiments, the hydroxyapatite targeting ligand comprises a tetracycline, a phosphonate (e.g., a bisphosphonate (e.g., a mono-bisphosphonate, tri-bisphosphonate, or poly-bisphosphonate)), an acidic oligopeptide, ranelate, and / or pyrophosphate.

[0106] In some embodiments, the hydroxyapatite targeting ligand comprises a phosphate, a phosphonate, or a derivative thereof.

[0107] In some embodiments, Z comprises one or more amino acid residues. In some embodiments, Z is a linear chain of amino acid residues. In some embodiments, Z is a branched chain of amino acid residues.

[0108] In some embodiments, Z is an acidic oligopeptide. In some embodiments, Z comprises at least four glutamic acid amino acid residues or four aspartic acid amino acid residues. In some embodiments, Z comprises at least four amino acid residues. In some embodiments, Z comprises at least four acidic amino acid residues. In some embodiments, Z comprises at least four amino acid residues having the same chirality. In some embodiments, Z comprises at least four amino acid residues, one or more of the amino acid residues having D-chirality. In some embodiments, Z comprises at least four amino acid residues, one or more of the amino acid residues having D-chirality and one or more others of the amino acid residues having L-chirality. In some embodiments, Z comprises at least four acidic amino acid residues having the same chirality. In some embodiments, each of the at least four amino acid residues has D-chirality. In some embodiments, each of the at least four acidic amino acid residues has D-chirality. In some embodiments, one or more amino acid residues have L-chirality.

[0109] In some embodiments, Z comprises at least four glutamic acid amino acid residues. In some embodiments, Z comprises at least four D-glutamic acid amino acid residues. In some embodiments, Z comprises 4-20 D-glutamic acid amino acid residues. In some embodiments, Z comprises at least four aspartic acid amino acid residues. In some embodiments, Z comprises at least four D-aspartic acid amino acid residues. In some embodiments, Z comprises 4-20 D-aspartic acid amino acid residues. In some embodiments, Z comprises at least four (e.g., D-) glutamic acid amino acid residues (e.g., 4-20 D-glutamic acid amino acid residues) and / or at least four (e.g., D-) aspartic acid amino acid residues (e.g., 4-20 D-aspartic acid amino acid residues). In some embodiments, Z comprises a mixture of (e.g., D-) glutamic acid amino acid residues and (e.g., D-) aspartic acid amino acid residues.

[0110] In some embodiments, Z comprises at least 10 repeated D-glutamic acid amino acid residues (e.g., DE10 or more, DE15 or more, or DE20 or more). In some embodiments, Z comprises at least 15 repeated D-glutamic acid amino acid residues (e.g., DE15 or more, or DE20 or more). In some embodiments, Z comprises at least 20 repeated D-glutamic acid amino acid residues (e.g., DE20 or more). In some embodiments, Z is 20 repeated D-glutamic acid amino acid residues (DE20).

[0111] In some embodiments, Z comprises 4 to 75 acidic amino acid residues (e.g., D-glutamic acid and / or D-aspartic acid amino acid residues). In some embodiments, Z comprises 8 to 30 acidic amino acid residues (e.g., D-glutamic acid amino acid residues).

[0112] In some embodiments, Z comprises between 8 and 30 D-glutamic acid amino acid residues.

[0113] In some embodiments, Z comprises between 8 and 30 D-aspartic acid amino acid residues.

[0114] In some embodiments, Z is DE10.

[0115] In some embodiments, Z is DE20.

[0116] In some embodiments, X is abaloparatide (eg, or a derivative or fragment thereof (eg, having bone anabolic activity)) and Z is 20 repeating D-glutamic acid amino acid residues (DE20).

[0117] In some embodiments, Y is a non-releasable linker. In some embodiments, Y is a non-releasable linker that comprises at least one carbon-carbon bond. In some embodiments, Y is a non-releasable linker that comprises at least one amide bond. In some embodiments, Y is a non-releasable linker (e.g., comprises at least one carbon-carbon bond and / or at least one amide bond).

[0118] In some embodiments, Y is a releasable linker. In some embodiments, Y is a releasable linker comprising at least one disulfide (SS). In some embodiments, Y is a releasable linker comprising at least one ester (e.g., O(C=O)). In some embodiments, Y is a releasable linker comprising at least one amide bond. In some embodiments, Y is a releasable linker comprising at least one protease-specific amide bond. In some embodiments, Y is a releasable linker (e.g., comprising at least one disulfide (SS), at least one ester (e.g., O(C=O)), and / or at least one (e.g., protease-specific) amide bond).

[0119] In some embodiments, X is abaloparatide (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)), Y is a non-releasable oligopeptide linker, and Z is 20 repeating D-glutamic acid amino acid residues (DE20).

[0120] In some embodiments, X is abaloparatide (e.g., or a derivative or fragment thereof (e.g., having bone anabolic activity)), Y is a releasable oligopeptide linker comprising at least one protease-specific amide bond, and Z is 20 repeating D-glutamic acid amino acid residues (DE20).

[0121] In some embodiments, the XYZ elements may be those disclosed in U.S. Patent No. 10,960,054, and U.S. Patent Application Publication Nos. 17 / 058,884, 17 / 058,887, and 17 / 058,891, which are incorporated by reference in their entireties. In some embodiments, the XYZ elements may be those disclosed in application numbers PCT / US2017 / 064081, PCT / US2019 / 034759, PCT / US2019 / 034764, and PCT / US2019 / 034767, which are incorporated by reference in their entireties.

[0122] In some embodiments, the compound has at least 75% or more sequence identity to SEQ ID NO:1 (e.g., at least 80% or more sequence identity, at least 85% or more sequence identity, at least 90% or more sequence identity, or at least 95% or more sequence identity).

[0123] In some embodiments, X is PTHrP, Y is a non-releasable oligopeptide linker, and Z is 20 repeating D-glutamic acid amino acid residues (DE20).

[0124] In some embodiments, the compound has at least 75% or more sequence identity to SEQ ID NO:3 (e.g., at least 80% or more sequence identity, at least 85% or more sequence identity, at least 90% or more sequence identity, or at least 95% or more sequence identity).

[0125] In some embodiments, X is Ln2P3, Y is a non-releasable oligopeptide linker, and Z is 10 repeating D-glutamic acid amino acid residues (DE10).

[0126] In some embodiments, the compound has at least 75% or more sequence identity to SEQ ID NO:4 (e.g., at least 80% or more sequence identity, at least 85% or more sequence identity, at least 90% or more sequence identity, or at least 95% or more sequence identity).

[0127] In some embodiments, X is QK, Y is a non-releasable oligopeptide linker, and Z is 10 repeating D-glutamic acid amino acid residues (DE10).

[0128] In some embodiments, the compound has at least 75% or more sequence identity or greater to compound 5 (e.g., at least 80% or more sequence identity, at least 85% or more sequence identity, at least 90% or more sequence identity, or at least 95% or more sequence identity).

[0129] In some embodiments, the compound described herein, such as a compound for treating osteogenesis imperfecta (OI) in an individual (e.g., in need of treatment for osteogenesis imperfecta (OI)), is Compound 1.

[0130] In some embodiments, the compound described herein, such as a compound for treating osteogenesis imperfecta (OI) in an individual (e.g., in need of treatment for osteogenesis imperfecta (OI)), is compound 3.

[0131] In some embodiments, the compound described herein, such as a compound for treating osteogenesis imperfecta (OI) in an individual (e.g., in need of treatment for osteogenesis imperfecta (OI)), is compound 4.

[0132] In some embodiments, X is PTH, Y is a non-releasable oligopeptide linker, and Z is 20 repeating D-glutamic acid amino acid residues (DE20). EXAMPLES

[0133] These examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0134] [Example 1] In vivo study of osteogenesis imperfecta mice In vivo experiments were performed using heterozygous and homozygous Col1a2 oim (OI type 1 (+ / -) and OI type 3 (- / -)) mice. After reaching skeletal maturity, 12-week-old female and / or male mice were subjected to osteotomy-stabilized midshaft femoral fracture model. OI mice were treated subcutaneously (with saline control or a compound provided herein, such as Ab46-D-Glu20) twice a week for 5 or 6 weeks after fracture. After 5 weeks of study in heterozygous mice and 6 weeks of study in homozygous mice, fracture callus mineralization / density was measured using quantification of high-resolution MicroCT (scanco) images of the fracture callus.

[0135] [Example 2] Biodistribution To evaluate the ability of bone-targeting therapeutics to deliver therapeutic agents to the fracture surface, fractured and non-fractured Col1a2 oim Type 3 mice (- / -) were injected with a compound provided herein (e.g., SEQ ID NO: 2). The compound was injected into mice to evaluate biodistribution. 21 hours after injection, the biodistribution of the compound was evaluated by SPEC-CT.

[0136] Specifically, SEQ ID NO:2 was administered to Col1a2 mice from 12-week-old female mice that had fractured the midshaft femur 2 weeks after the fracture. oimType 3 mice (- / -) were injected with 100 mg / kg of 1000 mg ...

[0137] While preferred embodiments have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will now occur to those skilled in the art without departing from the present disclosure. It is to be understood that various alternatives to the embodiments described herein may be employed in practicing the present disclosure.

Claims

1. The use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating osteogenesis imperfecta (OI) in an individual, wherein the compound has the structure X-Y-Z, where X is an anabolic agent, Y is a linker, and Z is a bone-targeting ligand.

2. The use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a pharmacopoeia for targeting one or more damaged bone sites, low-density bone sites or weakened bone sites in an individual having osteogenesis imperfecta (OI), wherein the compound has the structure X-Y-Z, where X is an anabolic agent, Y is a linker, and Z is a bone-targeting ligand.

3. The compound comprises a diagnostic payload, and the diagnostic payload, when administered to the individual, is compared to an individual that has not been administered the compound. To reduce the occurrence or likelihood of fractures in the aforementioned individual, To increase bone density or bone strength in the said individual, and / or To promote the healing or repair of osteotomies, bone grafts, or fractures in the aforementioned individual, The use described in claim 1 or 2.

4. The use according to claim 1 or 2, wherein the OI is type 1 OI, type 3 OI, or type 4 OI.

5. The use according to claim 1 or 2, wherein the OI is related to a gene mutation in the individual that has the ability to form or process collagen.

6. The use according to claim 1 or 2, wherein the OI is pediatric OI.

7. The use according to claim 1 or 2, wherein X increases the production of collagen in the organism or improves the organism's ability to form or process collagen.

8. The use according to claim 1 or 2, wherein X comprises a growth factor, a small molecule, a peptide, a protein, or a hormone.

9. The use according to claim 1 or 2, wherein X is selected from the group consisting of parathyroid hormone receptor 1 agonists, parathyroid hormone (PTH), PTH-related protein (PTHrP), and abaloparatide.

10. The use according to claim 1 or 2, wherein Z is a hydroxyapatite-targeting ligand.

11. The use according to claim 1 or 2, wherein Z is a hydroxyapatite-targeting ligand comprising tetracycline, phosphate or derivative thereof, phosphonate or derivative thereof, acidic oligopeptide, ranerate, pyrophosphate, or a hydroxyapatite-targeting ligand developed by phage display.

12. The use according to claim 1 or 2, wherein Z is a linear amino acid chain, a branched amino acid chain, and / or an acidic oligopeptide.

13. The use according to claim 1 or 2, wherein Z comprises at least four glutamic acid amino acid residues or four aspartic acid amino acid residues, wherein optionally at least four of the amino acid residues have the same chirality.

14. The use according to claim 13, wherein each of the at least four amino acid residues has D-chirality.

15. The use according to claim 1 or 2, wherein Z comprises at least four glutamic acid amino acid residues and / or at least four aspartic acid amino acid residues.

16. The use according to claim 1 or 2, wherein Z comprises a mixture of glutamic acid amino acid residues and aspartic acid amino acid residues.

17. Z comprises at least 10 repeating D-glutamic acid amino acid residues, and / or Z is a set of 20 repeating D-glutamic acid amino acid residues (DE20). The use described in claim 1 or 2.

18. Z is, 4 to 75 acidic amino acid residues, 8 to 30 acidic amino acid residues, and / or 8 to 30 D-glutamic acid amino acid residues The use according to claim 1 or 2, including the use described in claim 1 or 2.

19. The use according to claim 1 or 2, wherein X is abaloparatide, or a derivative or fragment thereof having anabolic activity, and Z is 20 repeating D-glutamic acid amino acid residues (DE20).

20. The use according to claim 1 or 2, wherein Y is a non-release linker comprising at least one carbon-carbon bond and / or at least one amide bond, or Y is a releaseable linker comprising at least one disulfide, at least one ester and / or at least one amide bond.

21. X is abaloparatide, Y is a non-release oligopeptide linker, and Z is 20 repeating D-glutamic acid amino acid residues (DE20), or X is abaloparatide, Y is a releaseable oligopeptide linker containing at least one protease-specific amide bond, and Z is 20 repeating D-glutamic acid amino acid residues (DE20). The use described in claim 1 or 2.

22. The use according to claim 1 or 2, wherein the compound has at least 75% or more sequence identity with SEQ ID NO: 1, SEQ ID NO: 3, or SEQ ID NO:

4.

23. The use according to claim 1 or 2, wherein the compound is compound 1, compound 3, or compound 4.

24. X is PTHrP, or X is PTHrP, Y is a non-releaseable oligopeptide linker, and Z is 20 repeating D-glutamic acid amino acid residues (DE20). The use described in claim 1 or 2.

25. X is Ln2P3, or However, Ln2P3 is present, Y is a non-releaseable oligopeptide linker, and Z is a set of 10 repeating D-glutamic acid amino acid residues (DE10). The use described in claim 1 or 2.

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