Selective HDAC Inhibition
Although many HDAC inhibitors target cancer, the central nervous system (CNS) represents another lucrative therapeutic domain, notes James Rusche, Ph.D., senior vp, R&D, Repligen. “For example, there are a number of CNS genetic diseases caused by a repetition of a DNA triplet sequence. In Friedreich ataxia (FRDA), a repetitive triplet repeat falls within the first intron of the frataxin gene. This causes hypoacetylation and ultimately blocks normal transcription so that the protein produced is fully functional, there is just not enough of it.”
HDAC inhibitors might provide a new therapeutic strategy for treating FRDA, according to Dr. Rusche. “Research at Scripps showed that one class of HDAC inhibitors could increase the mutant frataxin gene expression. While current HDAC inhibitors for oncology may not work due to toxicity and tissue distribution problems, we felt that we could find better molecules more suited to treating Friedreich ataxia.”
Thus, the company needed to find a more selective HDAC inhibitor that could distribute to brain tissue. “Our preclinical candidate is potent, selective, and possesses the pharmacology needed for an orally active, brain-penetrant drug,” Dr. Rusche reports. “This compound, which is selective for HDAC3, increases expression of the frataxin gene in brain tissue when tested in transgenic mouse models of FRDA at concentrations without side effects. We are now gearing up for clinical trials.”
Other CNS applications that modify histone acetylation will likely follow. “We can envision applications such as Huntington disease, spinal muscular atrophy, and memory modulation. This area of modulating memory is just beginning, but animal studies are providing results that encourage further development in this area.”
Although CNS drug development can be challenging, future HDAC therapeutics are on the horizon. “Most compounds do not get into the brain. The second-generation HDAC inhibitors will likely be much more selective with lowered toxicity and improved delivery to the target tissue. Diseases of the CNS are one important example of how next-generation HDAC inhibitors will provide a much broader opportunity for therapeutics development.
Epigenetic agents like HDAC inhibitors have a low therapeutic window. One way to overcome such issues is to utilize a cell-targeting approach for delivery, notes Alan Drummond, Ph.D., CSO and founder at Chroma Therapeutics. “Since HDACs work intracellularly, the main challenge is to limit the number of cells that are exposed to the drug. We have developed a method for intracellular delivery specifically to monocytes and macrophages, which are key protagonists in inflammatory conditions.”
The company’s esterase sensitive motif (ESM) technology involves the attachment of a chemical group onto an HDAC inhibitor. Once inside the monocyte or macrophage, it is cleaved by a specific carboxylesterase to give rise to an active charged species that cannot readily migrate out of the cell. The intracellular accumulation of the pharmacologically active acid leads to enhanced potency and duration of effect, but only in cells expressing this specific enzyme.
“Tolerability is always the potential Achilles heel with epigenetic agents,” according to Dr. Drummond. “We found a direct cell-targeting approach that appears to direct the epigenetic effect to a subset of cells that were important in pathology leading to reduce systemic toxicity. The physiochemical properties of the acid product determine longevity of effect and tolerability, not organs such as the liver. We have now shown up to 1,000-fold selective delivery to human monocytes in blood.
“This technology is an example of how to specifically target drugs such as HDACs and non-HDAC intracellular targets to macrophages/monocytes,” Dr. Drummond reports. “Additionally, such targeting also has applications for treating monocytic tumors, for example in acute myelogenous leukemia subtypes. Finally, new research has revealed that macrophages can play a major role in tumor progression and metastasis. We are currently studying the potential of this technology to target such cells in order to reverse this effect.”