RECTAS

RECTAS is a pre-mRNA splicing modulator.^1,2,3,4 It corrects aberrant splicing in a splicing reporter assay for disease genes with dual color (SPREADD) using HeLa cells expressing IKBKAP, the gene encoding elongator complex protein 1 (ELP1), with a point mutation in intron 20 (IVS20 + 6T>C), which is associated with the neurodegenerative disease familial dysautonomia (FD).¹ RECTAS (2 µM) restores the modification of cytoplasmic tRNAs with uridine in the wobble position in primary human fibroblasts from patients with FD to the same level as in primary human fibroblasts from carriers of the FD mutation. It increases the mRNA levels of correctly spliced PARK7, a gene whose mutations are associated with early-onset Parkinson's disease, in neural precursor cells differentiated from fibroblasts of patients with the homozygous PARK7 c.192G>C exonic splicing mutation when used in combination with the chemical chaperone phenylbutyric acid (Item No. 11323).³ Intratumoral administration of RECTAS decreases tumor volume and increases survival and the number of tumor-infiltrating CD8⁺ T cells in an MC-38 murine colon carcinoma model.⁴

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1. Yoshida, M., Kataoka, N., Miyauchi, K., et al. Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia. Proc. Natl. Acad. Sci. USA. 112(9), 2764-2769 (2015).

2. Ajiro, M., Awaya, T., Kim, Y.J., et al. Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia. Nat. Commun. 12(10, 4507 (2021).

3. Boussaad, I., Obermaier, C.D., Hanss, Z., et al. A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease. Sci. Transl. Med. 12(560), eaau3960 (2020).

4. Matsushima, S., Ajiro, M., Iida, K., et al. Chemical induction of splice-neoantigens attenuates tumor growth in a preclinical model of colorectal cancer. Sci. Transl. Med. 14(673), eabn6056 (2022).