ISRIB - Another Potential Anti-Aging Drug in Testing

RapAdmin · November 28, 2021, 2:21am

Last year it was announced that ISRIB was out-licensed from UCSF to Alphabet / Google’s Calico, based on the great pre-clinical data that UCSF had developed, in terms of brain function / memory results.

Normal mice put inside a watery maze took more than a minute to locate the submerged platform that would let them escape. But these mice — which had been injected with a curious new molecule — found it in an average of just 16 seconds. (source)

Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

Source: Drug Reverses Age-Related Mental Decline Within Days

Full Research Paper: Small molecule cognitive enhancer reverses age-related memory decline in mice

I’ve not seen any human clinical trial data, and there are no clinical trials of ISRIB listed on the ClinicalTrials.gov website.

ISRIB seems to be available easily from lab / reagent supply companies, and I’ve seen that some people are starting to do their own personal clinical trials with it. With no human clinical data at all on this compound, that seems a little too aggressive for me personally.

However, in this January, 2021 update it was said:

Human Trials In The Offing

A review co-authored by Walter and published last year in Science (DOI: 10.1126/science.aat5314) provides an overview of diseases of the brain associated with ISR activation. In addition to TBI and age-related cognitive decline, the list included frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, Down syndrome (characterized by a high incidence of Alzheimer’s), Charcot-Marie-Tooth disease (a group of inherited disorders causing nerve damage), vanishing white matter disease (genetic disorder where the body doesn’t make enough myelin), and prion disease (involving abnormally folded proteins).

Recent evidence has shown that the ISR serves as a “universal regulator” of long-term memory formation, they write. Inhibiting the ISR enhances this process, while activation of the IRS prevents it.

The good news, is that in mice at least, it was highly non-toxic.

Since ISRIB has proven to be completely non-toxic in mice when working with a ISRIB derivative for TBI applications, Rosi says she and Walters are “really motivated to… push it to humans as soon as possible. Every day, I get at least five to 10 emails from people suffering asking if they can be in any clinical trials.”

An Educational Overview of ISRIB

Source: Promise of ISR Inhibitors In Treating Age-Related Cognitive Decline

Related Research papers:

ISRIB Related Reading

From: For Researchers | Cognitive Vitality | Alzheimer's Drug Discovery Foundation

ISRIB.pdf (304.4 KB)

RapAdmin · December 13, 2021, 3:50am

A new story related to ISRIB:

AlexKChen · December 22, 2021, 3:27am

It seems like it only fixes a very specific part of aging (doesn’t fix the upstream factors) AND it increases rather than decreases protein synthesis?

RapAdmin · November 27, 2022, 6:36pm

The study, publishing Oct. 10, 2022, in Proceedings of the National Academy of Sciences, found that ISRIB reverses the effects of traumatic brain injury (TBI) on areas of neurons called dendritic spines that are critical to cognition. Mice treated with the drug also showed sustained improvements in working memory.

“Our goal was to see if ISRIB could ameliorate the neural effects of concussion,” said Michael Stryker, PhD, a co-senior author of the study and professor of physiology at UCSF. “We were pleased to find the drug was tremendously successful in normalizing neuronal and cognitive function with lasting effects.”
The authors suggest that TBI triggers a persistent activation of the ISR, which in turn leads to the ongoing proliferation of transient spines that fail to support memory formation. Future experiments will explore whether ISRIB has similar effects on other cell types, brain areas and cognitive tasks.

ISR activation has been implicated in many neurological disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Thus, the researchers believe ISRIB may have therapeutic potential in multiple patient populations.

While there was no evidence of the drug’s toxicity in mice, clinical trials are currently evaluating the safety and effectiveness of ISRIB in humans.

Research Paper:

Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition

https://www.pnas.org/doi/10.1073/pnas.2209427119

RapAdmin · December 27, 2022, 8:08am

More good news on ISRIB. In Talking with calico researchers at the Longevity Summit, it sounds like clinical trials are still moving forward…

And, as mentioned earlier…

Jay · December 27, 2022, 11:03am

Thanks for keeping track of this. Wouldn’t it be great if it turns out to be an effective treatment for Alzheimer’s?

dallascat · December 28, 2022, 9:46pm

Any vendors for ISRIB?

rivasp12 · December 28, 2022, 9:57pm

Quite amazing actually. Could be a real breakthrough. Worth watching.

RapAdmin · December 28, 2022, 10:01pm

ISRIB seems to be a chemical that is widely available from laboratory supply companies, but you need to work in a lab (or know someone who does) to be able to order it:

It certainly looks promising…

Paul_2.0 · May 11, 2023, 12:13am

I did a little digging on ISRIB as I was curious to know where things are with it. It looks as Calico has very recently launched in four clinical trials. One of them is in healthy volunteers. I was wondering if there are any pharmacology people here who might be able to make a connection between the combination of drugs in this trial?

They’ve also recently dosed the first patient in clinical stage 1b trial for vanishing white matter disease and is also conducting a trail in ALS patients

Brief Summary:

This study follows an open-label, single arm design with two periods with rosuvastatin, digoxin and ABBV-CLS-7262

Detailed Description:

Period 1: One single dose of rosuvastatin and one single dose of digoxin on Day 1.

Period 2: Multiple doses of ABBV-CLS-7262 once daily from Day 1 to Day 8. On Day 5, one single dose of rosuvastatin and one single dose of digoxin with the dose of ABBV-CLS-7262 on that day.

RapAdmin · May 11, 2023, 12:20am

Good find! Interesting clinical study… I wonder why they are dosing with these other two drugs.

and another clinical study

Some interesting information:

In Alzheimer’s models, ISRIB generated mixed results. It prevented Aβ-induced cell death (Hosoi et al., 2016) but did not improve cognition in either the APPswe or hAPP-J20 models of AD, and daily dosing led to significant mortality in the former (Briggs et al., 2017; Johnson and Kang, 2016). Other researchers reported that ISRIB prevented synaptic loss and memory deficits in an Aβ toxicity model, and restored synaptic function and memory in older APP/PS1 mice (Oliveira et al., 2021).

More - see link below:
https://www.alzforum.org/therapeutics/abbv-cls-7262

RapAdmin · May 11, 2023, 12:27am

Just found this paper and recent webinar presentation related to ISRIB:

regimenf_calicosabbv-cls-7262drugsciencewebinar_2023sm.pdf (5.0 MB)

RapAdmin · May 11, 2023, 3:59am

I see that their ISRIB drug ABBV-CLS-7262 is in phase 1 clinical trials:

AbbVie Pipeline Update 2.9.23.pdf (229.9 KB)

But its moving into Phase 2/3 now. More details on the new ALS Clinical Trial for ALS being done at MassGeneral:

regimen.f.brochure.23.pdf (533.8 KB)

Paul_2.0 · May 11, 2023, 4:45am

It’s interesting to see it being applied to multiple conditions. And great that it seems to be finally moving into clinical trials, so hopefully we’ll have some answers soon. I’m really curious to know the reasoning behind the drug combination trial. I wonder which pathways they’re trying to target.

RapAdmin · May 11, 2023, 5:15am

It would be helpful if we could find out the dosing range they are using. They will target the highest value applications first, and other applications could take many years.

It would be reasonable I think, since its now passed Phase 1 safety trials, for biohackers to get their hands on the compound and start testing it for other indications using their dosing information.

Paul_2.0 · May 11, 2023, 5:34am

. You’re exactly right, if there’s a way to find out the dosage, then it’s probably worth trying. I did a search on reddit and it seems as though some people have tried it, although the results seem mixed. I assume it was also without any idea of an efficacious dose. Is there any way to find out what the ALS treatment protocol is?

RapAdmin · May 11, 2023, 6:20am

I just used my phone to scan the codes in the above flyer to get the web page addresses. If someone could go through the process and attend the webinars they could probably get the dosing information (mg of ISRIB/ Regimen F- ABBV-CLS-7262)

They have weekly webinars on the study - perhaps someone could participate and ask about dosing they are using in the trial

Clinical Trial information here - interesting that they are trying Trehalose as well as ISRIB (and other drugs). They seem to be keeping the dosing information private … unlike all the other drugs.

Experimental: Regimen E - SLS-005 Trehalose

Participants are randomized to receive either active SLS-005 Trehalose or matching placebo. Drug: SLS-005 Trehalose
Drug: SLS-005 Trehalose
Administration: Infusion
Dose: 0.75 g/kg weekly

Experimental: Regimen F- ABBV-CLS-7262

Participants are randomized to receive either active ABBV-CLS-7262 or matching placebo.
Drug: ABBV-CLS-7262
Drug: ABBV-CLS-7162

Administration: Oral

Dose: Dose 1 or Dose 2

More information from this page on the drug:

Now Enrolling

Regimen F: ABBV-CLS-7262, by Calico and AbbVie- Now Recruiting

ABBV-CLS-7262 is an investigational drug developed by Calico Life Sciences LLC in collaboration with AbbVie Inc. ABBV-CLS-7262 aims to restore function in cells affected by ALS by normalizing protein synthesis and preventing further sequestration and aggregation of TDP-43, thereby protecting neurons, and possibly slowing ALS progression.

The integrated stress response (ISR) is a fundamental transient process that regulates cell function during various stressful conditions. Tissue studies suggest that the ISR is chronically induced in people with ALS. It is proposed that TDP-43 aggregates, a hallmark feature in the motor neurons of people with ALS, could be formed by a chronically induced ISR. ABBV-CLS-7262 activates the protein complex eIF2B, which is a key regulator of the ISR. Binding of ABBV-CLS-7262 desensitizes eIF2B to stress and decreases the ISR. Reduction of the ISR restores normal protein synthesis, reduces TDP-43 sequestration in stress granules, and may decrease TDP-43 aggregation.

A prior first-in-human study of ABBV-CLS-7262 showed that this drug was well-tolerated by participants, demonstrated target engagement by increasing eIF2B enzymatic activity, and suppressed the ISR in blood cells. ABBV-CLS-7262 crossed the blood brain barrier at concentrations predicted to be efficacious in ALS. ABBV-CLS-7262 is currently being investigated in a Phase 1b study in people with ALS (NCT04948645), and will be studied further as part of the HEALEY ALS Platform Trial.

Watch a webinar about the science behind ABBV-CLS-7262

Watch this video for more information on the mechanism of action behind ABBV-CLS-7262.

Download General Platform Trial Brochure
Download Regimen F Brochure
Download Lumbar Puncture Brochure

RapAdmin · July 3, 2023, 7:46pm

A new paper on ISRIB (this one is out of China):

ISRIB alleviates aging-associated brown fat UCP1 translational repression and thermogenic deficiency

Upon cold exposure, aged people with lower metabolic rate cannot rapidly increase the higher levels of heat production, and are seriously threatened by the hypothermia, extensive cold stress responses and risk of mortality. Here, we show that brown fat thermogenic activity is obviously deficient in aged mice, associating with reduction of UCP1 expression and inhibition of its mRNA translation. As we considered, aging aggravates brown fat oxidative stress and activates the integrated stress response (ISR), inducing the phosphorylation of eIF2α to block the global mRNA translation. Therefore, small-molecule ISR inhibitor (ISRIB) treatment attenuates the higher level of eIF2α phosphorylation, restores the repression of Ucp1 mRNA translation and improves UCP1-mediated thermogenic function to defend cold stress in aged mice. Furthermore, ISRIB treatment increases the relative lower metabolic rates, and alleviates glucose intolerance and insulin resistance in aged mice. Thus, we have uncovered a promising drug that reverses the aged-related the deficiency of UCP1-mediated thermogenesis to combat cold stress and associated metabolic diseases.

jnorm · December 28, 2023, 5:18pm

The ITP is currently testing 2BAct, which has oral bioavailability and reaches the brain, and like ISRIB is an eIF2B activator, although it potentially has concerning effects on the heart.

The molecule was well-tolerated in the animal studies described here, and did not elicit any relevant effects in a rat cardiovascular (CV) safety study; however, significant anomalies were observed in a dog CV model. This CV safety liability makes this particular molecule unsuitable for human dosing. [ref]

Essentially what both 2BAct and ISRIB do is tone down the integrated stress response (ISR). The ISR responds to various cellular stressors to promote cell survival, but its excessive or prolonged activation promotes cell death.

For evidence that the ISR is over activated in aging, see Does aging affect the ISR?.

What’s interesting is that various anti-aging strategies (rapamycin, acarbose, calorie restriction, methionine restriction) appear at first glance to increase ISR activation, due to their increasing ATF4 protein levels. However, these anti-aging strategies even more so increase CHOP protein levels, and as CHOP may function to fine-tune the ISR (see Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR), these strategies may actually be preventing excessive ISR activation. The trend towards larger Δ[CHOP]/Δ[ATF4] for the strategies providing the largest lifespan increase further supports fine-tuning/preventing over-activation of the ISR as a potential longevity strategy.