초록 ▼

폐 전달 및 표적 유전자 억제 효율이 향상된 BMT101의 최적화된 구조를 개발함.

폐섬유화 동물모델을 이용하여 기도 내 투여된 BMT101의 표적 유전자 억제 효율 및 치료 효과를 확인하여 효력 용량범위를 확보함.

BMT101의 생체시료 내 정량 분석법을 개발 및 검증하고, PK study를 통하여 생체 내 분포를 확인함.

Nebulizer 타입에 따른 BMT101 aerosol 발생 가능성 확인 및 TSI system을 이용한 BMT101 aerosol의 폐 전달 효율 분석을 통하여 흡입을

폐 전달 및 표적 유전자 억제 효율이 향상된 BMT101의 최적화된 구조를 개발함.

폐섬유화 동물모델을 이용하여 기도 내 투여된 BMT101의 표적 유전자 억제 효율 및 치료 효과를 확인하여 효력 용량범위를 확보함.

BMT101의 생체시료 내 정량 분석법을 개발 및 검증하고, PK study를 통하여 생체 내 분포를 확인함.

Nebulizer 타입에 따른 BMT101 aerosol 발생 가능성 확인 및 TSI system을 이용한 BMT101 aerosol의 폐 전달 효율 분석을 통하여 흡입을 통한 BMT101의 폐 전달 방법을 확립함.

흡입투여 효력시험 장비를 확립하고 BMT101의 기도 내 투여 결과를 바탕으로 흡입투여 용량을 설정함. 폐섬유화 동물모델에 BMT101을 aerosol 상태로 흡입투여하고 다양한 분석 등을 통하여 BMT101의 효력 용량범위를 확보함.

IND 승인을 위한 비임상 독성시험 안전성 자료를 확보하고, 1상 임상시험을 설계함.

(출처 : 요약서 3p)

Abstract ▼

Purpose&Contents
1. Purpose
- Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive fibrosis in the lung tissue and the 3-year mortality of diagnosed patients is more than 50%. Therefore, development of new therapeutics which can effectively stop or resolve f

Purpose&Contents
1. Purpose
- Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive fibrosis in the lung tissue and the 3-year mortality of diagnosed patients is more than 50%. Therefore, development of new therapeutics which can effectively stop or resolve fibrosis is necessary.

- In this study, using a lung fibrosis animal model, we evaluate the therapeutic efficacy of BMT101, a CTGF-targeting siRNA which has been confirmed to have an antifibrotic activity. Based on the results, we aim to expand the application of BMT101 to IPF treatment.

- Finally, we plan to achieve Partnering/License-Out with global pharmaceutical companies to develop BMT101 as a therapeutic for idiopathic pulmonary fibrosis.

2. Contents
- Optimization of BMT101 for enhanced stability, efficiency and reduced toxicity
- Analysis of cytokine levels in response to BMT101 treatment
- Dose-finding study of BMT101 which shows therapeutic effect for lung fibrosis (intratracheal route)
- Development and validation of bio-analytical method for BMT101 PK / PD study
- Optimization of BMT101 structure
- Development of formulation/delivery method for pulmonary delivery of BMT101
- Dose-finding study of BMT101 which shows therapeutic effect for lung fibrosis (inhalation route)
- Synergistic effect of BMT101 while co-administered with standard drugs for IPF
- Pre-clinical toxicity study Establishment of clinical trial protocol

Results
1. Optimization of BMT101 structure
- Stability and target knockdown efficacy of BMT101 were enhanced by chemical and structural modifications.
- Analysis of immune-related cytokine expression confirmed that BMT101 does not induce a nonspecific immune response.

2. Therapeutic effect of BMT101 in IPF mouse model
- Intratracheally administered BMT101 inhibited target gene expression and had a therapeutic efficacy in IPF mouse model. Efficacy dose range of BMT101 was determined.
- On-target therapeutic effect of BMT101 was confirmed using scrambled cp-asiRNA in IPF mouse model.
- The quantification method of BMT101 in biological samples including the lung tissue and blood was developed and validated.
- PK study confirmed that most of the BMT101 administered intratracheally is delivered to the lung and its systemic exposure is insignificant.
- PD study revealed the duration in which BMT101 maintains its target gene inhibitory effect after single administration. This is a reference for setting the administration interval of BMT101.

3. Development of BMT101 inhalation formulation and evaluation of its therapeutic effect in IPF mouse model
- During aerosol generation using a nebulizer, the structural and functional stability of BMT101 was maintained and BMT101 aerosol particle size was suitable for delivery to the lung peripheral regions in which the lesions of idiopathic pulmonary fibrosis reside.
- Inhalation efficacy test system for IPF mouse model was established.
- Inhaled BMT101 inhibited target gene expression and had a therapeutic efficacy in IPF mouse model. Efficacy dose range of BMT101 was determined.
- Comparison of therapeutic efficacy between BMT101 and a standard IPF drug, Nintedanib revealed that BMT101 has a comparable efficacy in IPF mouse model.

4. Safety profiling for IND application
- BMT101 safety data were obtained from preclinical toxicity studies.
- Outline and design of phase 1 clinical trial was established.

Expected Contribution
1. Structural optimization of siRNA therapeutics with enhanced efficacy and stability
- We addressed the effect of siRNA structural changes on its intracellular delivery and target gene knockdown efficiency, by introduction of phosphorothioate (PS) and lipid moiety, or antisense strand length optimization.

- Based on this know-how in optimizing siRNA structure, we can develop siRNA therapeutics with enhanced efficacy and stability in the future.

2. Development of an effective therapeutic for IPF treatment
- This study revealed the excellent therapeutic effect of BMT101 in IPF animal model. Based on these results, we intend to develop BMT101 as a new IPF therapeutics.

- Major unmet medical needs for the current IPF therapies are insufficient efficacy to reduce fibrosis and a high frequency of gastrointestinal adverse effects. Recent clinical trials on IPF reported that some patients showed reduced lung fibrosis and improved lung functions from baseline in response to new drug candidates. One of the drug candidates is Pamrevlumab, a monoclonal antibody drug targeting CTGF which is a critical regulator of fibrosis.

- As BMT101 and Pamrevlumab share the same target protein CTGF, we expect that BMT101 will have a therapeutic efficacy in human. Unlike Pamrevlumab that acts on already synthesized proteins, BMT101 inhibits CTGF expression at mRNA level and thus can have a more fundamental therapeutic effect. Therefore, BMT101 can be an effective therapeutic for IPF treatment.

- We demonstrated an antifibrotic effect of BMT101 in the previous and current studies in two different indications, BMT101 will be successfully applied to additional fibrotic disorders, such as liver, kidney and retinal fibrosis.

3. Expansion of target organ and administration route for RNAi therapeutics
- Lung diseases including IPF have not been major target indications for development of RNAi therapeutics, mainly due to drug delivery problems.
In this study, we demonstrated that the lung is an available target organ for application of RNAi therapeutics through an inhalation administration.

- We evaluated the possibility of aerosol generation of siRNA for inhalation administration and established the inhalation efficacy test system in IPF animal model. Using this system, we can easily try to develop RNAi therapeutics for various lung diseases in addition to IPF.

- Recently, it was reported that MRG-201, a micro RNA (miRNA) therapeutic which has structurally very similar to siRNA, is being developed for IPF treatment. The therapeutic efficacy of MRG-201 has been demonstrated using inhalation administration in IPF animal models, further supporting that oligonucleotide therapeutics can be developed for treatment of lung diseases with a strategy of inhalation administration.

(출처 : SUMMARY 8p)

목차 Contents

• 표지 ... 1
• 제출문 ... 2
• 보고서 요약서 ... 3
• 국문 요약문 ... 5
• SUMMARY ... 8
• Contents ... 12
• 목차 ... 13
• 제 1 장. 연구개발과제의 개요 ... 14
• 1.1절. 연구개발 목적 ... 14
• 1.2절. 연구개발의 필요성 ... 14
• 1.3절. 연구개발 범위 ... 15
• 제 2 장. 국내외 기술개발 현황 ... 16
• 2.1절. RNAi (RNA interference, RNA 간섭) 치료제의 작용 원리 ... 16
• 2.2절. RNAi 치료제 개발 현황 및 관련 기술 ... 16
• 2.3절. 특발성 폐섬유화증 (Idiopathic pulmonary fibrosis, IPF) 의 치료제 현황 및 개발 방향 ... 17
• 2.4절. 개발 중인 주요 IPF 치료제 ... 17
• 2.5절. 개발중인 IPF 치료제 대비 BMT101의 경쟁력 ... 18
• 제 3 장. 연구수행 내용 및 결과 ... 20
• 3.1절. 연구개발 추진전략 및 방법 ... 20
• 3.2절. 연구개발 추친체계 ... 21
• 3.3절. 연구개발 추진일정 ... 22
• 3.4절. 연구수행 내용 ... 23
• 3.5절. 연구개발 성과 ... 61
• 3.6절. 사업화 계획 및 매출 실적 ... 63
• 제 4 장. 목표달성도 및 관련분야 기여도 ... 66
• 4.1절. 연구개발 목표달성도 ... 66
• 4.2절. 목표달성 과정에서의 문제점 ... 67
• 4.3절. 관련분야 기여도 ... 70
• 제 5 장. 연구결과의 활용계획 ... 72
• 5.1절. 추가연구의 필요성 ... 72
• 5.2절. 타 연구에의 응용 ... 72
• 5.3절. 향후 개발 계획 ... 73
• 제 6 장. 연구과정에서 수집한 해외과학기술정보 ... 77
• 6.1절. 글로벌 제약사의 특발성 폐섬유화증 치료제 개발 현황 ... 77
• 6.2절. BMT101과 동일 타겟에 대한 IPF 치료제 개발 ... 77
• 6.3절. BMT101과 유사한 구조적 특징을 가진 IPF 치료제 개발 상황 ... 78
• 제 7 장. 연구개발성과의 보안등급 ... 80
• 제 8 장. 국가과학기술종합정보시스템에 등록한 연구시설·장비 현황 ... 81
• 제 9 장. 연구개발과제 수행에 따른 연구실 등의 안전조치 이행실적 ... 82
• 9.1절. 연구활동종사자 환경안전교육 실시 ... 82
• 9.2절. 실험실 안전점검 실시 ... 83
• 9.3절. 실험실 환경개선사업 실시 ... 84
• 9.4절. 실험폐기물관리 강화 ... 84
• 9.5절. 연구활동종사자 특수건강검진 실시 ... 85
• 9.6절. 화학물질별 사고 예방 및 대응 방안 구축 ... 85
• 9.7절. 연구활동종사자 보험가입 ... 85
• 제 10 장. 연구개발과제의 대표적 연구실적 ... 86
• 제 11 장. 기타사항 ... 87
• 제 12 장. 참고문헌 ... 88
• 별첨: 실적 증빙자료 ... 89
• 별첨: FINAL PROGRESS REPORT 국문 요약서 ... 97
• 끝페이지 ... 104