EP-4735599-A1 - ANTISENSE OLIGOMER TREATMENT FOR BONE LOSS

Abstract

An isolated or purified antisense oligomer and combinations and cocktails for modifying pre- mRNA splicing or mRNA translation in the SOST gene transcript or part thereof to induce downregulation of the production of functional SOST protein.

Inventors

• ZHENG, MING HAO
• YUAN, JUN
• TAI, CHI PANG

Assignees

• Perron Institute for Neurological and Translational Science Limited

Dates

Publication Date

20260506

Application Date

20240618

Claims (14)

1. 1 . An isolated or purified antisense oligomer and combinations and cocktails for modifying pre- mRNA splicing or mRNA translation in the SOST gene transcript or part thereof to induce downregulation of the production of functional SOST protein.
2. 2. The antisense oligomer of claim 1 for inducing the production of truncated proteins, the production of proteins lacking functional regions or a reduction in the total amount of protein produced.
3. 3. The antisense oligomer of claim 1 that is a phosphorodiamidate morpholino oligomer (PMO) or a 2'-O-methyl phosphorothioate oligomer (2'-OMePS).
4. 4. The antisense oligomer of claim 1 that is selected from the group comprising: i) the sequences set forth in Table 1 ; or ii) SEQ ID NO: 1 -11.
5. 5. A cDNA copy of the antisense oligomer sequences of claim 1 .
6. 6. A vector containing the antisense oligomer sequences of claim 1 or cDNA of claim 5.
7. 7. Cells containing the antisense oligomer sequences of claim 1 , the cDNA of claim 5 or the vector of claim 6.
8. 8. A method for manipulating splicing factor binding in a target protein gene transcript, the method including the step of: a) providing one or more of the antisense oligomers of claim 1 and allowing the oligomer(s) to bind to a target nucleic acid site to induce downregulation of the production of functional SOST protein.
9. 9. A pharmaceutical, prophylactic, or therapeutic composition to treat, prevent or ameliorate the effects of dysregulation of leptin in a subject, the composition comprising: a) one or more antisense oligomers of claim 1 ; and b) one or more pharmaceutically acceptable carriers and/or diluents to induce downregulation of the production of functional SOST protein.
10. 10. The method of claim 8 or composition of claim 9 wherein the bone disease is associated with bone loss in the subject.
11. 11 . The method of claim 8 or composition of claim 9 wherein the bone disease is chosen from: osteoporosis, postmenopausal osteoporosis, osteogenesis imperfecta and bone loss associated with cancer.
12. 12. A method to treat, prevent or ameliorate the effects of bone disease in a subject, comprising the step of: a) administering to the subject an effective amount of one or more antisense oligomers or pharmaceutical composition comprising one or more antisense oligomers of claim 1 to induce downregulation of the production of functional SOST protein.
13. 13. The use of purified and isolated antisense oligomers of claim 1 , for the manufacture of a medicament to treat, prevent or ameliorate the effects of bone disease in a subject.
14. 14. A kit to treat, prevent or ameliorate the effects of bone disease in a subject, which kit comprises at least an antisense oligomer of claim 1 , packaged in a suitable container, together with instructions for its use.

Description

Antisense oligomer treatment for bone loss TECHNICAL FIELD [0001] The present disclosure relates to antisense oligomers for downregulating the expression of functional SOST proteins. The disclosure further provides compositions comprising such antisense oligomers and methods of using the same for the treatment of bone diseases such as osteoporosis. BACKGROUND ART [0002] Osteoporosis, which is characterized by bone loss, is one of the most common disorders affecting ageing population. Given the role of sclerostin in inhibiting bone formation, an antibody against sclerostin named romosozumab (AMG 785, Amgen) has been approved by the U.S. FDA in April 2019 for the treatment of osteoporosis. Although its clinical outcome showed promising efficacy, adverse effects (including increased cardiovascular and cerebrovascular events) have been commonly reported. In addition, the production and purification of antibodies is expensive, which leads to the high cost for monthly injection associated with the use of romosozumab. [0003] Sclerostin, encoded by SOST gene, is a protein mainly produced in bone. As an endogenous inhibitor of canonical Wnt signalling which plays a role in maintaining bone homeostasis, increasing sclerostin contributes to the pathogenesis of various skeletal diseases, such as bone loss. [0004] There is a need for novel methods to modulate and regulate SOST production; or at least the provision of methods to compliment the previously known methods. The present disclosure seeks to provide an improved or alternative method to modulate and regulate functional SOST protein production, through manipulation of the expression of SOST. [0005] The previous discussion of the background art is intended to facilitate an understanding of the present disclosure only. The discussion is not an acknowledgement or admission that any of the material referred to is or was part of the common general knowledge as at the priority date of the application. SUMMARY OF INVENTION [0006] Broadly, according to one aspect of the disclosure, there is provided an isolated or purified antisense oligomer (ASO) for modifying pre-mRNA splicing or mRNA translation in the SOST gene to induce downregulation of the production of functional SOST protein. [0007] Optionally, there is provided an isolated or purified antisense oligomer for inducing the production of proteins with retained introns or partial introns, the production of truncated proteins, the production of proteins lacking functional regions, or a reduction in the total amount of protein produced. [0008] Optionally, the antisense oligomer is a phosphorodiamidate morpholino oligomer (PMO) or a 2'-O-methyl phosphorothioate oligomer (2'-OMePS). [0009] Optionally, the antisense oligomer is selected from the group comprising the sequences set forth in Table 1. Optionally, the antisense oligomer is selected from the list comprising: SEQ ID NO: 1 -11. In one example, the antisense oligomer used in the present disclosure is SEQ ID NO: 3-7. [0010] The disclosure extends, according to a still further aspect thereof, to cDNA or cloned copies of the antisense oligomer sequences of the disclosure, as well as to vectors containing the antisense oligomer sequences of the disclosure. The disclosure extends further also to cells containing such sequences and/or vectors. [001 1] There is also provided a method for manipulating splicing factor binding in a target protein gene transcript, the method including the step of: providing one or more of the antisense oligomers as described herein and allowing the oligomer(s) to bind to a target nucleic acid site to induce downregulation of the production of functional SOST protein. [0012] There is also provided a pharmaceutical, prophylactic, or therapeutic composition to treat, prevent or ameliorate the effects of dysregulation of SOST in a subject, the composition comprising: one or more antisense oligomers as described herein; and one or more pharmaceutically acceptable carriers and/or diluents to induce downregulation of the production of functional SOST protein. [0013] Optionally, the bone disease is associated with bone loss in the subject. Optionally, the bone disease is chosen from: osteoporosis, postmenopausal osteoporosis, osteogenesis imperfecta and bone loss associated with cancer. [0014] The subject with bone disease may be a mammal, including a human. [0015] There is also provided a method to treat, prevent or ameliorate the effects of bone disease in a subject, comprising the step of: administering to the subject an effective amount of one or more antisense oligomers or pharmaceutical composition comprising one or more antisense oligomers as described herein to induce downregulation of the production of functional SOST protein. [0016] There is also provided the use of purified and isolated antisense oligomers as described herein, for the manufacture of a medicament to treat, prevent or ameliorate the effects of bone disease in a subject.