更新于：2024-11-01

BGA-002

更新于：2024-11-01

概要

研发状态

概要

基本信息

药物类型

反义肽核酸

别名

16 base single stranded peptide nucleic acid oligonucleotide ¿ 7 aminoacids peptide、16-base single-stranded peptide nucleic acid oligonucleotide linked to 7-amino acid peptide

+ [1]

靶点

N-Myc

作用机制

N-Myc抑制剂(MYCN proto-oncogene, bHLH transcription factor inhibitors)、基因转录抑制剂

治疗领域

肿瘤呼吸系统疾病其他疾病

在研适应症

神经母细胞瘤软组织肉瘤小细胞肺癌

非在研适应症-

原研机构

Biogenera SpA

在研机构

Biogenera SpA

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (欧盟)

关联

100 项与 BGA-002 相关的临床结果

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100 项与 BGA-002 相关的转化医学

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100 项与 BGA-002 相关的专利（医药）

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项与 BGA-002 相关的文献（医药）

2024-08-01·Nucleic Acid Therapeutics

Preclinical Pharmacokinetics in Tumors and Normal Tissues of the Antigene PNA Oligonucleotide MYCN-Inhibitor BGA002

Article

作者: Tonelli, Roberto ; Nieddu, Giammario ; Della Pasqua, Oscar ; Bortolotti, Sonia ; Cerisoli, Lucia ; Angelucci, Silvia ; Bartolucci, Damiano ; Montemurro, Luca ; Amadesi, Camilla ; Scardovi, Anna Lisa ; Hrelia, Patrizia ; Oosterholt, Sean

Although MYCN has been considered an undruggable target, MYCN alterations confer poor prognosis in many pediatric and adult cancers. The novel MYCN-speciﬁc inhibitor BGA002 is an antigene peptide nucleic acid oligonucleotide covalently bound to a nuclear localization signal peptide. In the present study, we characterized the pharmacokinetics (PK) of BGA002 after single and repeated administration to mice using a novel specific enzyme-linked immunosorbent assay. BGA002 concentrations in plasma showed linear PK, with dose proportional increase across the tested dose levels and similar exposure between male and female and between intravenous and subcutaneous route of administration. Repeated dosing resulted in no accumulation in plasma. Biodistribution up to 7 days after single subcutaneous administration of [¹⁴C]-radiolabeled BGA002 showed broad tissues and organ distribution (suggesting a potential capability to reach primary tumor and metastasis in several body sites), with high concentrations in kidney, liver, spleen, lymph nodes, adrenals, and bone marrow. Remarkably, we demonstrated that BGA002 concentrates in tumors after repeated systemic administrations in three mouse models with MYCN amplification (neuroblastoma, rhabdomyosarcoma, and small-cell lung cancer), leading to a significant reduction in tumor weight. Taking into account the available safety profile of BGA002, these data support further evaluation of BGA002 in patients with MYCN-positive tumors.

2022-12-01·Journal of Experimental & Clinical Cancer Research

The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma

Article

作者: Bartolucci, Damiano ; Fischer, Matthias ; Pession, Andrea ; Scardovi, Anna Lisa ; Bortolotti, Sonia ; Cerisoli, Lucia ; Amadesi, Camilla ; Hrelia, Patrizia ; Martelli, Alberto Maria ; Raieli, Salvatore ; Valente, Sabrina ; Nieddu, Giammario ; Paganelli, Francesca ; Lampis, Silvia ; Angelucci, Silvia ; Montemurro, Luca ; Pasquinelli, Gianandrea ; Tonelli, Roberto

AbstractBackgroundNeuroblastoma is a deadly childhood cancer, and MYCN-amplified neuroblastoma (MNA-NB) patients have the worst prognoses and are therapy-resistant. While retinoic acid (RA) is beneficial for some neuroblastoma patients, the cause of RA resistance is unknown. Thus, there remains a need for new therapies to treat neuroblastoma. Here we explored the possibility of combining a MYCN-specific antigene oligonucleotide BGA002 and RA as therapeutic approach to restore sensitivity to RA in NB.MethodsBy molecular and cellular biology techniques, we assessed the combined effect of the two compounds in NB cell lines and in a xenograft mouse model MNA-NB.ResultsWe found that MYCN-specific inhibition by BGA002 in combination with RA (BGA002-RA) act synergistically and overcame resistance in NB cell lines. BGA002-RA also reactivated neuron differentiation (or led to apoptosis) and inhibited invasiveness capacity in MNA-NB. Moreover, we found that neuroblastoma had the highest level of mRNA expression of mTOR pathway genes, and that BGA002 led to mTOR pathway inhibition followed by autophagy reactivation in MNA-NB cells, which was strengthened by BGA002-RA. BGA002-RA in vivo treatment also eliminated tumor vascularization in a MNA-NB mouse model and significantly increased survival.ConclusionTaken together, MYCN modulation mediates the therapeutic efficacy of RA and the development of RA resistance in MNA-NB. Furthermore, by targeting MYCN, a cancer-specific mTOR pathway inhibition occurs only in MNA-NB, thus avoiding the side effects of targeting mTOR in normal cells. These findings warrant clinical testing of BGA002-RA as a strategy for overcoming RA resistance in MNA-NB.

2019-12-15·Cancer Research1区 · 医学

A Novel MYCN-Specific Antigene Oligonucleotide Deregulates Mitochondria and Inhibits Tumor Growth in MYCN-Amplified Neuroblastoma

1区 · 医学

Article

作者: Angelucci, Silvia ; Tonelli, Roberto ; Amadesi, Camilla ; Bartolucci, Damiano ; Venturelli, Leonardo ; Teti, Gabriella ; Montemurro, Luca ; Hrelia, Patrizia ; Raieli, Salvatore ; Cerisoli, Lucia ; Falconi, Mirella ; Scardovi, Anna Lisa ; Fischer, Matthias ; Lampis, Silvia ; Nieddu, Giammario ; Pession, Andrea

AbstractApproximately half of high-risk neuroblastoma is characterized by MYCN amplification. N-Myc promotes tumor progression by inducing cell growth and inhibiting differentiation. MYCN has also been shown to play an active role in mitochondrial metabolism, but this relationship is not well understood. Although N-Myc is a known driver of the disease, it remains a target for which no therapeutic drug exists. Here, we evaluated a novel MYCN-specific antigene PNA oligonucleotide (BGA002) in MYCN-amplified (MNA) or MYCN-expressing neuroblastoma and investigated the mechanism of its antitumor activity. MYCN mRNA and cell viability were reduced in a broad set of neuroblastoma cell lines following BGA002 treatment. Furthermore, BGA002 decreased N-Myc protein levels and apoptosis in MNA neuroblastoma. Analysis of gene expression data from patients with neuroblastoma revealed that MYCN was associated with increased reactive oxygen species (ROS), downregulated mitophagy, and poor prognosis. Inhibition of MYCN caused profound mitochondrial damage in MNA neuroblastoma cells through downregulation of the mitochondrial molecular chaperone TRAP1, which subsequently increased ROS. Correspondingly, inhibition of MYCN reactivated mitophagy. Systemic administration of BGA002 downregulated N-Myc and TRAP1, with a concomitant decrease in MNA neuroblastoma xenograft tumor weight. In conclusion, this study highlights the role of N-Myc in blocking mitophagy in neuroblastoma and in conferring protection to ROS in mitochondria through upregulation of TRAP1. BGA002 is a potently improved MYCN-specific antigene oligonucleotide that reverts N-Myc–dysregulated mitochondrial pathways, leading to loss of the protective effect of N-Myc against mitochondrial ROS.Significance:A second generation antigene peptide oligonucleotide targeting MYCN induces mitochondrial damage and inhibits growth of MYCN-amplified neuroblastoma cells.

100 项与 BGA-002 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
神经母细胞瘤	临床前	意大利	Biogenera SpA	2022-04-30
软组织肉瘤	临床前	意大利	Biogenera SpA	2022-04-30
小细胞肺癌	临床前	意大利	Biogenera SpA	-