Anti-aging drug and AMPK activator Rapamycin currently in clinical trials to treat Progeria

"Hutchinson-Gilford Progeria Syndrome" by The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. Scaffidi P, Gordon L, Misteli T; https://commons.wikimedia.org/wiki/File:HIV-budding-Color.jpg#/media/File:HIV-budding-Color.jpg. "HIV-budding-Color" by Photo Credit: C. Goldsmith. Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus.

And yet more and more evidence (see the LinkedIn post below) that a common thread connects many diseases we think have nothing to do with each other. Following on from my post yesterday about the anti-aging drug and AMPK activator rapamycin currently in clinical trials to reduce the latent HIV-1 reservoir (headed by researchers at the University of California, San Francisco (UCSF), Boston Children's Hospital/Harvard Medical School recently initiated a clinical trial in December of 2015 to investigate if rapamycin is also able to reverse accelerated aging defects in children diagnosed with Hutchinson-Gilford progeria syndrome.  Similar to the beneficial effects of methylene blue, sulforaphane, and retinoic acid on progeria cells, rapamycin has also shown beneficial effects on progeria cells in the lab and all 3 compounds enhance the immune response.  What the Harvard and UCSF researchers don't realize is that the immune enhancing properties and the correction of cellular aging defects by these compounds are the result of the indirect activation of AMPK, an ancient gene/protein which is present in nearly every cell in the body. Activation of AMPK (e.g. via exercise, numerous plant-based compounds) enhances the lifespan (how long you live) and healthspan (life without disease) of almost every organism that it’s present in.  That a single pathway can connect a genetic disease to viral infections and possibly many other disease states (cancer, neurological disorders, autoimmune diseases, etc) is almost unthinkable. Almost:-) If this gene/protein is that powerful, could it be responsible for the beginning of human life itself????  Stay tuned:-)

Clinical Trial Official Title: Phase I/II Trial of Everolimus in Combination With Lonafarnib in Progeria 

As a follow-on to yesterday’s post describing the recent filing and subsequent commencement of a clinical trial to determine if the anti-aging drug and AMPK activator rapamycin is capable of reducing the latent HIV-1 reservoir in patients currently on suppressive anti-retroviral therapy, a clinical trial registration, first received by ClinicalTrilas.gov on October 13, 2015 and sponsored by Boston Children's Hospital (a teaching affiliate of Harvard Medical School), seeks to determine if everolimus (a derivative of rapamycin that acts via the same mechanism of mTOR inhibition) can be administered safely to Hutchinson-Gilford progeria patients (along with the farnesyltransferase inhibitor lonafarnib) and is capable of ameliorating or reversing phenotypical manifestations of the accumulation of the toxic protein progerin.

This is a Phase I/II study (determining both safety and efficacy) with an estimated enrollment of 80 patients, a start date of December 2015, and an estimated primary completion date of December 2018 (final data collection date for primary outcome measure).  Patient recruitment and study location will occur at Boston Children's Hospital.  A portion of the details of the clinical trial are reproduced below with a link provided as well.

As noted below, primary outcome measures include an increase in weight gain and change in pulse wave velocity, a measure of arterial stiffness that is associated with the accumulation of the toxic protein progerin in cells that comprise the vascular system (particularly vascular smooth muscle cells).

Interestingly, in light of studies showing that the splicing factor SRSF1 inhibits the reactivation of latent HIV-1 and the recently initiated clinical trial to determine if rapamycin is able to reduce the latent HIV-1 reservoir, UV radiation has been shown in separate studies to increase the levels SRSF1 as well increase the levels of the toxic protein progerin, indicating that alteration of gene splicing is a dynamic process that can be beneficially or deleteriously influenced by environmental factors as well as select compounds [1-3].

Indeed, normal humans produce the same toxic protein progerin via use of the same cryptic splice site in the LMNA gene as progeria patients, just at much lower levels that increase with age [4].  Additionally, SRSF1 activity promotes the faulty splicing of genes involved in the maintenance of the vascular system in normal humans (e.g. VEGF, tissue factor, endoglin), leading to accelerated endothelial cell senescence [5].  The endogenous SRSF1 inhibitor p32 has also been shown to be upregulated during HIV-1 reactivation, promote efficient mitochondrial functionality and oxidative phosphorylation (i.e. ATP production), and act as a chaperone that is necessary for ULK-1-mediated autophagy [1,6,7].

Such evidence places the activation of AMPK by rapamycin at a focal point connecting the pathophysiology of both HIV-1 latency and progeria.  Indeed, rapamycin was recently found to potently activate AMPK in vivo as well as induce autophagy and mitochondrial biogenesis [8]. The induction of ULK1-dependent autophagy by rapamycin was also shown be significantly decreased when the splicing factor p32 was inhibited, indicating that p32 activity is critical for rapamycin-induced autophagy [7].  Interestingly, rapamycin’s mechanism of action is ascribed to its inhibition of mTORC1, a protein complex that is implicated in a number of disease states.  mTORC1 has been found to activate SRSF1 and rapamycin has been shown to inhibit  various pathological mechanisms downstream of SRSF1 by inhibiting mTOR [9].

As the activation of AMPK is critical for T cell activation (and thus latent HIV-1 reactivation) and because AMPK activation significantly increases mitochondrial biogenesis as well as activates ULK1 to induce autophagy, the indirect activation of AMPK by rapamycin and/or its derivatives via mTOR inhibition likely explains its beneficial effects in HIV-1 and progeria [10,11].  Indeed, preclinical studies using rapamycin in progeria cells indicated that rapamycin corrected cellular aging defects by inducing the degradation of progerin by activating autophagy [12]. Because p32 is critical for rapamycin-induced autophagy by ULK1 and because rapamycin, similar to metformin, activates AMPK and AMPK induces autophagy by phosphorylating and activating ULK1, the beneficial effects of rapamycin in progeria likely involves AMPK-mediated alteration of gene splicing as well as AMPK-mediated induction of autophagy.

Indeed, autophagy has also been shown to be essential for and upregulated on T cell activation and metformin has recently been shown to beneficially alter gene splicing in cells taken from patients with the genetic disorder myotonic dystrophy type I (DMI) in an AMPK-dependent manner.  Metformin also altered gene splicing in diabetic patients who were taking metformin but who did not have DM1 [13,14].

The figure below depicts this novel and unprecedented connection, a connection that was first elucidated in a paper I authored and published in 2015.

https://www.linkedin.com/pulse/anti-aging-drug-ampk-activator-rapamycin-currently-clinical-finley-6127552216376107008?published=u

Excerpt from: Phase I/II Trial of Everolimus in Combination With Lonafarnib in Progeria

Official Title: Phase I/II Trial of Everolimus in Combination With Lonafarnib in Progeria

Sponsor: Children's Hospital Boston
Information provided by (Responsible Party): Monica E. Kleinman, Children's Hospital Boston
ClinicalTrials.gov Identifier: NCT02579044

First received: October 13, 2015
Last updated: December 23, 2015
Last verified: December 2015

Estimated Enrollment: 80
Study Start Date: December 2015
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)

Further study details as provided by Children's Hospital Boston: 

Primary Outcome Measures:

• Maximum-tolerated dose (MTD) of everolimus when administered orally in combination with lonafarnib in subjects with progeria [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]For Phase I portion of protocol
• Number and type of dose-limiting toxicities when everolimus and lonafarnib are administered in combination to children with progeria [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]For Phase I portion of protocol
• Annual increase in weight gain [ Time Frame: 24 Months ] [ Designated as safety issue: No ]For Phase II portion of protocol
• Change in pulse wave velocity (PWV) [ Time Frame: 24 months ] [ Designated as safety issue: No ]For Phase II portion of protocol 

Secondary Outcome Measures:

• Markers of progeria-specific activity [ Time Frame: 24 Months ] [ Designated as safety issue: No ]For Phase II portion of protocol
• Trough levels of everolimus in combination with lonafarnib in progeria [ Time Frame: 12 months ] [ Designated as safety issue: No ]For Phase I portion of protocol

References:

1. Berro R, Kehn K, de la Fuente C, et al. Acetylated Tat regulates human immunodeficiency virus type 1 splicing through its interaction with the splicing regulator p32. J Virol. 2006 Apr;80(7):3189-204.
2. Comiskey DF Jr, Jacob AG, Singh RK, Tapia-Santos AS, Chandler DS. Splicing factor SRSF1 negatively regulates alternative splicing of MDM2 under damage. Nucleic Acids Res. 2015 Apr 30;43(8):4202-18.
3. Takeuchi H, Rünger TM. Longwave UV light induces the aging-associated progerin. J Invest Dermatol. 2013 Jul;133(7):1857-62.
4. McClintock D, Ratner D, Lokuge M, et al. The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin. PLoS One. 2007 Dec 5;2(12):e1269.
5. Blanco FJ, Bernabéu C. The Splicing Factor SRSF1 as a Marker for Endothelial Senescence. Front Physiol. 2012 Mar 28;3:54.
6. Hu M, Crawford SA, Henstridge DC, et al. p32 protein levels are integral to mitochondrial and endoplasmic reticulum morphology, cell metabolism and survival. Biochem J. 2013 Aug 1;453(3):381-91.
7. Jiao H, Su GQ2, Dong W, et al. Chaperone-like protein p32 regulates ULK1 stability and autophagy. Cell Death Differ. 2015 Apr 29.
8. Chiao YA, Kolwicz SC, Basisty N, et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY). 2016 Feb;8(2):314-27.
9. Karni R, Hippo Y, Lowe SW, Krainer AR. The splicing-factor oncoprotein SF2/ASF activates mTORC1. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15323-7.
10. Tamás P, Hawley SA, Clarke RG, et al. Regulation of the energy sensor AMP activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med 2006;203(7):1665–70.
11. Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 2011 Sep 15;25(18):1895-908.
12. Cao K, Graziotto JJ, Blair CD, et al. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci Transl Med. 2011 Jun 29;3(89):89ra58.
13. Hubbard VM, Valdor R, Patel B, Singh R, Cuervo AM, Macian F. Macroautophagy regulates energy metabolism during effector T cell activation. J Immunol. 2010 Dec 15;185(12):7349-57.
14. Laustriat D, Gide J, Barrault L, et al. In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin. Mol Ther Nucleic Acids. 2015 Nov 3;4:e262.