Anyone heard about what’s going on with ISRIB, are they going to do human trials or what? The studies they have released are incredible. Maybe they’re trying to keep it all under the radar and keep this potential miracle drug away from the public? That’s what my conspiracy brain says, keep all the goodies for themselves, those billionaire elites. Why is there such a delay, it’s really weird isn’t it?
Can someone write a few sentences explaining what it is, what evidence there is for its use and for what, and what clinical trials were planned?
Is it time to conduct an N-1??
Not sure what the dose should be but 10mg is only $135.
@Anuser: Peter Walter, biochemist: ‘The ISRIB molecule could become a wonder drug’ (El Pais)
See this thread: ISRIB - Another Potential Anti-Aging Drug in Testing
Google’s “Calico” division is doing ongoing clinical trials. No announcements yet. But they are not using ISRIB directly, they are using another molecule that controls ISRIB levels for some reason… its more complex I suspect than just taking ISRIB, but I’m not sure why. Perhaps someone can do a deep dive into the research to figure out why Calico is using Fosigotifator in their trials instead of just ISRIB:
Pursuant to their 2014 collaboration, Calico and AbbVie are investigating fosigotifator (ABBV- CLS-7262) as a potential regulator of the ISR. Fosigotifator directly targets eIF2B and increases the activity of elF2B complexes carrying VWM variations. In preclinical studies, fosigotifator has demonstrated the ability to decrease the ISR in the brain and spinal cord in disease models that carry VWM variations and has been shown to improve coordination and movement problems. It is hypothesized that if proper function of the elF2B protein complex can be restored, brain white matter damage and loss may be prevented in people with VWM.
https://www.calicolabs.com/clinical-trial-vanishing-white-matter/
Related:
References
Yao Liang Wong, et al. The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes. eLife 7:e32733 (2018). https://doi.org/10.7554/eLife.32733
Yao Liang Wong, et al. eIF2B activator prevents neurological defects caused by a chronic integrated stress response. eLife 8:e42940 (2019). https://doi.org/10.7554/eLife.42940
James J. Lee, et al. eIF2B Activator Rescues Neonatal Lethality of an eIF2Bα Sugar Phosphate Binding Mutation Associated with Vanishing White Matter Disease. bioRxiv 2023.05.06.539602 (2023). https://doi.org/10.1101/2023.05.06.539602
Related reading:
ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B
https://bohrium.dp.tech/paper/arxiv/812808606431838209
Inhibition of the Integrated Stress Response Restores Cognition After Brain Injury
A. Chou,† N. Day,‡ T. Jopson,‡ F. Cho,† C. Sidrauski,ÅòŘ
P. Walter,Ř# and S. Rosi†‡Åò*
Brain and Spinal Injury Center, University of California,
San Francisco, CA, USA
Neuroscience Graduate Program, University of California,*
San Francisco, CA, USA
Department of Physical Therapy Rehabilitation Science,
University of California, San Francisco, CA, USA
Department of Neurological Surgery, University of California,*
San Francisco, CA, USA
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA*
Howard Hughes Medical Institute, University of California,
San Francisco, CA, USA
The integrated stress response (ISR) controls mRNA translation by phosphorylation of the eukaryotic translation initiation factor eIF2.
ISRIB is a drug-like small-molecule ISR inhibitor (in-cell EC* 50 = 5 nM) that enhances memory consolidation in normal animals. Loss of cognitive functions and sustained ISR are associated with numerous neurological conditions, including traumatic brain injury (TBI). We investigated the efficacy of ISRIB on the cognitive deficits induced by TBI using two different animal models tested in two different cognitive tasks. First, focal contusion injury was induced by controlled cortical impact (CCI) in C57B6 mice. Spatial learning and memory retention were measured in the radial arm water maze starting 28 days after injury. Either ISRIB (2.5 mg/kg) or vehicle was administered intraperitoneally the day prior to and at the end of each training day for a total of three injections. In agreement with previous reports, TBI animals receiving vehicle only failed to learn the location of the escape platform. In striking contrast, ISRIB-treated TBI animals learned as well as the noninjured animals. Memory consolidation was measured 24 h and 7 days after training in the absence of any additional treatment. At both times, ISRIB-treated TBI animals remembered the location of the hidden platform indistinguishable from noninjured controls. Thus, ISRIB completely restored the ability of the injured animals to learn and remember a new task. Most importantly, this memory was fully consolidated, as it could be recalled without further treatment. Second, diffuse TBI was modeled by closed-head injury (CHI) in C57B6 mice and the delayed matching-to-place paradigm was used in a dry maze (modified Barnes maze) to assess working/ episodic-like learning and memory. Fourteen days after injury either ISRIB (2.5 mg/kg) or vehicle was administered intraperitoneally prior to and then again at the end of each training day for a total of four injections. As for the CCI experiments, ISRIB-treated animals performed indistinguishable from uninjured controls, indicating that ISRIB treatment completely reversed the deficits induced by CHI. We conclude that in these models targeting the ISR at time points late after injury can completely reverse chronic loss of cognitive functions induced by head trauma.*
Digging into old twitter posts on ISRIB:
Source: x.com
Open Source Paper:
The integrated stress response (ISR) is activated by phosphorylation of the translation initiation factor eIF2 in response to various stress conditions. Phosphorylated eIF2 (eIF2-P) inhibits eIF2’s nucleotide exchange factor eIF2B, a twofold symmetric heterodecamer assembled from subcomplexes. Here, we monitor and manipulate eIF2B assembly in vitro and in vivo. In the absence of eIF2B’s α-subunit, the ISR is induced because unassembled eIF2B tetramer subcomplexes accumulate in cells. Upon addition of the small-molecule ISR inhibitor ISRIB, eIF2B tetramers assemble into active octamers. Surprisingly, ISRIB inhibits the ISR even in the context of fully assembled eIF2B decamers, revealing allosteric communication between the physically distant eIF2, eIF2-P, and ISRIB binding sites. Cryo-electron microscopy structures suggest a rocking motion in eIF2B that couples these binding sites. eIF2-P binding converts eIF2B decamers into ‘conjoined tetramers’ with diminished substrate binding and enzymatic activity. Canonical eIF2-P-driven ISR activation thus arises due to this change in eIF2B’s conformational state.