SYN 01

SYN-01, SYN-510

Synthena AG

Preclinical

Synthena , presumed to be under license from  University of Bern , is investigating (presumably SYN-01 ), a lead from the tricyclo(tc)-DNA based antisense oligonucleotides (AON) developed using its proprietary tricyclo-DNA technology platform, for the treatment of Duchenne muscular dystrophy. In January 2017, the drug was listed as being in preclinical development.

Patent

WO-2019142135

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019142135&tab=PCTDESCRIPTION&_cid=P22-JYQVON-19722-1

Process for preparing tricyclo-deoxyribonucleic acid (tc-DNA) which may be used as building blocks for tc-DNA containing antisense oligonucleotide-based therapies.

Antisense technology is an effective means for reducing the expression of specific gene products and can therefore be useful in therapeutic, diagnostic, and research applications.

Generally, the principle behind antisense technology is that an antisense oligomeric compound (a sequence of nucleotides or analogues thereof) hybridizes to a target nucleic acid and modulates gene expression activities or function, such as transcription and/or translation.

[003] Antisense oligomeric compounds may be prepared from chemically-modified antisense oligonucleotides, which may include a variety of different structural variations depending upon the therapeutic strategy. For example, tricyclo-deoxyribonucleic acids (tc-DNA) are conformationally constrained DNA analogs.

[004] There is a need in the field for processes that allow for the bulk preparation of tc-DNA nucleoside precursors that may be used as building blocks for tc-DNA containing antisense oligonucleotide-based therapies.

Example 4 – Cvclopropanation of Compound 17 with Carbenoid Prepared from CH2I2 and Et₂Zn in the Absence of Additives

[00127] According to the following scheme, compound 17 was converted to tc-DNA Nucleoside Precursor 18 using the cyclopropanation conditions set forth in Examples 4 to 7 :

[00128] 1.07 g purified a-anomer (3.736 mmol) 17 was dissolved in 37 ml of dry CH₂C1₂ and cooled to 0 °C (ice). Subsequently, 22.3 ml (22.3 mmol, 6 eq.) Et₂Zn 1.0 M in hexane (Aldrich) were added dropwise and stirred under Ar for 30 min at 0 °C. Then, 3.02 ml (37.2 mmol, 10 eq.) of CH₂I₂ were added dropwise over 15 min at the same temperature and stirred for further 2 h at 0 °C. Afterwards the cooling bath was removed and the mixture was stirred for additional 21 h at ambient temperature. TLC showed substantial amount of unreacted a- 17. It was diluted by addition of EtOAc and quenched with 50 mL of sat. aqueous NH₄Cl. Extractive work-up provided 1.79 g of crude which was purified by chromatography on silica-gel giving 0.43 g (39%) of 18 and 0.49 g of mixture of compound 17 and 18 (approximately 20:80).

PATENT

WO2018193428

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018193428

claiming a composition comprising an oligomeric compound having tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and a lipid moiety.

EXAMPLE 1

Inventive compositions for the treatment of Duchenne muscular dystrophy

Evaluation of efficacy

[00464] Adult mdx mice were treated weekly over 4 weeks with intravenous injections of different 13-mer AONs targeting the donor splice site of exon 23 of the dystrophin pre-mRNA (M23D: +2-11), namely with either SY-0308, SY-0210 and the inventive SY-0299, SY-0343, SY-0442 and SY-0455. SY-0308 (also named “tcDNA-PO M23D” interchangeably herein) corresponds to p-CCTCGGCTTACCT-OH of SEQ ID NO: l, with all nucleotides being tc-DNAs and all internucleosidic linkage groups being phosphorodiester linkage groups, and p being a phosphate moiety at the 5′ end. SY-0210 (also named “tcDNA-PS M23D” interchangeably herein) corresponds to p-CCTCGGCTTACCT-OH of SEQ ID NO: 1, with all nucleotides being tc-DNAs and all internucleosidic linkage groups being phosphorothioate linkage groups, and p being a phosphate moiety at the 5′ end. The inventive composition SY-0343 is herein interchangeably referred to as “Palm-2PS-tcDNA-PO M23D” which is depicted in the following:

[00465] The inventive composition SY-0442 is herein interchangeably referred to as “Palm-lPS-tcDNA-PO M23D” which is depicted in the following:

[00466] The inventive composition SY-0299 is herein interchangeably referred to as “Palm-2PO-tcDNA-PO M23D” which is depicted in the following:

//////////////////SYN-01, SYN 01, SYN01, preclinical , Duchenne muscular dystrophy, University of Bern,