Caveat mTOR, the PTEN Narrative Continues

Posted by Sam Maddox in Research News on July 27, 2016 # Research

Let’s revisit the PTEN-delete story. This has been one of the more hopeful narratives in recent years, formed on the notion that nerve regeneration is possible if faulty nerve cells themselves are repowered.

Quick review: PTEN is a molecular brake of sorts that stops nerve fibers (axons) from regenerating. Remove PTEN and watch axons jam down the spinal cord freeway.

We began covering PTEN in 2010, following a groundbreaking paper from the Zhigang He lab at Harvard with Oswald Steward’s group at UC Irvine’s Reeve-Irvine Research Center. They showed that deleting the gene for PTEN unleashed unprecedented growth of corticospinal axons (CST); these are the long axons in the spinal cord that hook up major voluntary motor functions in the arms, hands and legs. Until PTEN deletion came along, nobody had gotten them to budge. See this, and this, and this for previous coverage.

There are now many teams looking at ways to reset the intrinsic ability of nerve cells to regenerate; we have not arrived at the point of clinical relevance, but the pieces are coming together. One issue is timing of delivery; early experiments knocked out PTEN before injury; last year’s paper from the Kai Liu lab in Hong Kong, “PTEN Deletion Promotes Regrowth of Corticospinal Tract Axons 1 Year after Spinal Cord Injury,” saw strong CST growth after deleting PTEN right after injury, four months later, and even 12 months later.

Another issue is tumor formation. PTEN is a tumor suppressor, and is therefore a factor in uncontrolled grown, e.g. cancer. Is it going to be safe in the long run in treating trauma? Maybe so. In May, the Steward lab at UCI reported that PTEN deletion made for “ healthy, happy neurons.” From a paper by grad student Erin Gutilla, it was reported that day-old mice that had PTEN knocked out were free of any tumors or neuropathies a one and a half years of age. Here’s Steward, explaining the study in a Reeve-Irvine newsletter:

...Mutations in PTEN have been identified in many cancers, and mutating PTEN in early development can cause overgrowth of the brain, called macrocephaly. For these reasons, it was important to determine whether there were negative consequences of deleting PTEN in nerve cells in the way that was needed to induce regeneration.

... Importantly, there was no evidence of any neuropathology or tumors. Instead, the neurons lacking PTEN actually were larger and more healthy-looking than neurons in other parts of the brain, and looked like neurons in young adult mice. It was as if the aging clock had been turned back.

Steward said Gutilla will be looking further at PTEN as a way to reduce nerve blockage and death in neurodegenerative diseases including Parkinson’s, Alzheimer’s, and ALS. He mentioned that PTEN could perhaps be managed to reverse “normal” age related deterioration of neurons. Wow, an anti-aging agent!

And that brings us to another cool paper, “Rapamycin suppresses microglial activation and reduces the development of neuropathic pain after spinal cord injury,” from the Eiji Itoi group in Japan. Before that title makes sense, we need to unravel the PTEN pathways just a bit. Caution: complexity alert.

So, we know that by using genetic tools (new code delivered via inert virus messengers) it is possible to turn off PTEN molecules, well past the onset of spinal cord injury. Here’s what happens: deleting PTEN forces upregulation of another molecule called mTOR; this then provides the axons the mojo to escape their inertia to grow past the injury site. Modulating a nerve’s mTOR activity, therefore, is a potential strategy for axon regeneration after chronic SCI.

Stick with me here: mTOR stands for mammalian target of rapamycin, a most remarkable molecule. It’s target (mTOR) is the link to axon growth. Rapamycin, therefore, is a potential therapy. Indeed, it already exists as a drug (Sirolimus, commonly used to prevent organ transplant rejection).

Immunosuppressant and anti-tumor? There’s a lot going on with rapamycin (discovered in soil samples from the Easter Islands, and named after Rapa Nui, the indigenous peoples’ name for the Islands). The above referenced paper notes that because of its affect on immune response, “rapamycin has significant therapeutic potential to reduce the development of neuropathic pain following SCI.”

Other studies suggest that rapamycin is neuroprotective after SCI. Previously, Itoi reported that “inhibition of mTOR using rapamycin reduces neural tissue damage and locomotor impairment after spinal cord injury (SCI) in mice.”

Which brings us again to anti-aging. There are several examples in the literature of rapamycin-related life-span extension in animal studies. For example, male mice fed a diet with rapamycin lived nine percent longer than those on regular diet, and females lived 14 percent longer than counterparts in the control group.

A fascinating article came out last week in Chemical & Engineering News about rapamycin and its “secrets.” It’s a great read about the history and development of the discovery, and the payoff of basic science research. I’ll leave you with a tantalizing quote about mTOR and the slowing of the aging process.

“There’s this extensive body of literature showing that in every species studied to date—yeast, worms, flies, and mice—if you inhibit mTOR, you extend life span and ameliorate a variety of aging-related diseases,” says Novartis’s Joan Mannick, who led the study. “We thought it wasn’t such a leap of faith to think that inhibiting mTOR in humans might have some beneficial effects on aging-related conditions.” The tricky part, she says, is most aging-related conditions in humans occur over many, many years, making it tough to do clinical studies. Because immune function declines with age and can be tested in a relatively short time frame, it seemed ideal as a marker for studying the effects of mTOR inhibition in people.

Of course there’s still a lot that’s being worked out. Rapamycin has to be balanced as an immune suppressant and as an mTOR inhibitor. From the magazine article:

But don’t rush out for a rapamycin prescription just yet. The scientists who spoke with C&EN say it’s too soon to tell if mTOR inhibitors are safe for long-term use, something that would be required of an antiaging treatment. Given the option, most said they wouldn’t take it.

“I think it’s not the efficacy of rapamycin that’s in question. It’s the toxicity that everybody is concerned about,” says Brian Kennedy, president and chief executive officer of the Buck Institute for Research on Aging. Rapamycin and the approved rapalogs [biosimilar drugs] have side effects, such as mouth sores, but the main concern is their ability to suppress the immune system. The possibility of an extended life span with rapamycin might be cut short by an infection.