- Induction of stress response pathways by modulation of heat shock protein (Hsp) activity is a promising strategy for neuroprotection and other forms of cytoprotection.
- Reata is developing a novel class of compounds designed to potently inhibit Hsp90. Inhibition of Hsp90 leads to the activation of Hsp70. Hsp70 plays a critical role in protein folding and mitochondrial protein import.
- RTA 901, our lead compound, has profound activity in animal models of insensate diabetic neuropathy (IDN), a serious condition that currently has no effective treatment. RTA 901 also has positive effects on mitochondrial bioenergetics. RTA 901 is under development for indications that could include amyotrophic lateral sclerosis, diabetic neuropathy, spinocerebellar ataxia, and spinal bulbar muscular atrophy.
Neuroprotective Heat Shock Protein Modulators
Heat shock proteins (Hsps), organized into several families based on molecular weight (Hsp90, Hsp70, Hsp60, etc.) and function, play important roles in multiple aspects of the cellular stress response. The expression of Hsps can be induced by a variety of stimuli, including thermal, oxidative, mechanical, chemical, and pathophysiological stresses. One important function of Hsps, under both normal and stressful conditions, is to act as molecular chaperones, promoting proper folding of client proteins that would otherwise misfold and lose function1. Hsps also appear to play significant roles in antigen processing and inflammatory signaling2, and Hsp70 has been shown to have a critical function in promoting mitochondrial importation of proteins that are essential for efficient energy production3. Activation of the transcription factor HSF-1 to induce expression of Hsp70 is recognized as a promising strategy for treating neurodegenerative diseases, chronic inflammatory diseases, and other pathologies, and the development of selective Hsp modulators has been an area of significant interest. Reata has licensed multiple classes of novel Hsp modulators that overcome mechanistic limitations of previous compounds in this category. The lead compound, RTA 901, has shown profound activity in animal models of the insensate form of diabetic neuropathy, a condition that affects millions of Americans and has no effective therapy.
Mitochondrial Protein Import
Reata’s Hsp modulators were designed to induce expression of Hsp70, a molecular chaperone established to play a critical role in protein folding/quality control and mitochondrial protein import. Mitochondria rely on Hsp70-dependent protein import mechanisms for almost all of their activity, including that of the electron transport chain to produce ATP3. Recent insights have indicated a potentially profound role of Hsp70 activation in neuroprotection and neuronal regeneration, since nerve cells are particularly high consumers of ATP and rely heavily on Hsp70-dependent protein import for proper mitochondrial function4. The role of Hsp70 in quality control of protein expression is also significant in the context of many neurodegenerative diseases, which involve toxic aggregation of misfolded proteins.
Reata’s lead molecules from this program have demonstrated remarkable nonclinical activity in a range of models of neurodegeneration and neuroprotection, including diabetic neuropathy and neural inflammation. These agents have shown significant rescue of nerve function, restoration of thermal and mechanical sensitivity, improvement in nerve conductance velocity, and increases in mitochondrial function of relevant neuronal tissues in rodent disease models5. The profound effects with RTA 901, our primary lead molecule, are achieved with once-daily oral dosing in these preclinical models6. RTA 901 also has demonstrated acceptable tolerability in early GLP toxicology studies. Reata’s Hsp90 inhibitors also have shown significant neuroprotective activity in models of Alzheimer’s disease7 and demyelinating motor nerve diseases8.
RTA 901 has completed non-GLP toxicology studies, and has been manufactured at scale to support GLP toxicology studies and early clinical development. GLP toxicology studies are ongoing. Potential future clinical indications include amyotrophic lateral sclerosis, diabetic neuropathy, spinocerebellar ataxia, and spinal bulbar muscular atrophy. This technology is not subject to any existing commercial partnerships or collaborations.
- Santoro et al. Heat shock factors and control of the stress response. Biochem Pharmacol. 2000; 59(1):55-63.
- Turturici et al. Hsp70 and its molecular role in nervous system diseases. Biochem Res Int. 2011; 2011: 618127.
- Fan et al. Function of cytosolic chaperones in Tom70-mediated mitochondrial import. Protein Pept Lett; 18(2) 122-31.
- Brown. Heat shock proteins and protection of the nervous system. Ann N Y Acad Sci. 2007; 1113:147-58.
- Ma et al. Heat shock protein 70 is necessary to improve mitochondrial bioenergetics and reverse diabetic sensory neuropathy following KU-32 therapy. J Pharmacol Exp Ther. 2014; 348(2):281-92.
- Reata Pharmaceuticals, Inc., internal data.
- Menchen et al. Neuronal protection by a novel C-terminal Hsp90 modulator. KU ScholarWorks Dissertation. 2012.
- Li et al. Induction of heat shock protein 70 (Hsp70) prevents neuregulin-induced demyelination by enhancing the proteasomal clearance of c-Jun. ASN Neuro. 2012; 4(7): e00102.