Biological Activity

Valproic acid, derived from naturally occurring valeric acid is an FDA approved drug that has long been used in the treatment of epilepsy and other neuropsychiatric disorders, associated with its action on γ amino butyric acid (GABA) levels in the brain and voltage-gated ion channels. ^[1] It is also being explored as an adjuvant agent in various cancer treatments (breast cancer ^[2], pancreatic cancer ^[3], etc.) because of its ability to inhibit histone deacetylase (HDAC).

Successful Applications in CRISPR

(i) In 2017, Takayama and colleagues found that VPA treatment enhanced the efficiency of CRISPR/Cas9-induced biallelic HDR genome editing (only at a transcriptionally active locus) in human ES/iPS (H9) cells by 2-fold. ^[5]
(ii) In the same study, RAD51 overexpression and VPA treatment synergistically increased (more than each treatment on its own) the biallelic HDR efficiency in human ES/iPS cells at both an active and inactive targeted locus. Results were confirmed in 12 loci: AAVS1, c/EBPα, FOXA2, GSC, HHEX, HNF1α, HNF4α, HNF6, IFNαR1, IPS-1, RIG1 and SOX17.  The researchers suggest that VPA loosens nucleosome folding of i

Reference:

1. Chateauvieux, S., Morceau, F., Dicato, M., & Diederich, M. (2010). Molecular and therapeutic potential and toxicity of valproic acid. Journal of biomedicine & biotechnology, 2010, 479364. https://doi.org/10.1155/2010/479364
2. Heers, H., Stanislaw, J., Harrelson, J., & Lee, M. W. (2018). Valproic acid as an adjunctive therapeutic agent for the treatment of breast cancer. European journal of pharmacology, 835, 61–74. https://doi.org/10.1016/j.ejphar.2018.07.057
3. Li, H., Zhang, Z., Gao, C., Wu, S., Duan, Q., Wu, H., Wang, C., Shen, Q., & Yin, T. (2019). Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells. Cell & bioscience, 9, 50. https://doi.org/10.1186/s13578-019-0312-0
4. Gurvich, N., Tsygankova, O. M., Meinkoth, J. L., & Klein, P. S. (2004). Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer research, 64(3), 1079–1086. https://doi.org/10.1158/0008-5472.can-03-0799
5. Takayama, K., Igai, K., Hagihara, Y., Hashimoto, R., Hanawa, M., Sakuma, T., Tachibana, M., Sakurai, F., Yamamoto, T., & Mizuguchi, H. (2017). Highly efficient biallelic genome editing of human ES/iPS cells using a CRISPR/Cas9 or TALEN system. Nucleic acids research, 45(9), 5198–5207. https://doi.org/10.1093/nar/gkx130

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