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SIRT1

The SIRT1 enzyme is the most studied of the seven human sirtuin family members. It has emerged as a major therapeutic target for the treatment of Type 2 Diabetes, and may also be important in other disease areas. Sirtris has advanced its SIRT1 program and has three lead clinical stage candidates – SRT2104, SRT2379 and SRT501 – that target this enzyme.

Activating SIRT1: Broad potential for diseases of aging

SIRT1 Activator

Therapeutic indications for SIRT1 activation include the following:

Type 2 Diabetes

SIRT1 activation has been shown to stimulate several key cellular signaling pathways involved in regulating energy utilization including the synthesis of new mitochondria, which are the primary powerhouses of the cell. Mitochondrial activity in metabolically active tissues, such as muscle, will increase metabolic rate, drive glucose metabolism and fatty acid oxidation and thereby improve insulin sensitivity and enhance energy expenditure in multiple tissues. SIRT1 activation also plays a significant role on other key cellular regulators involved in metabolic and oxidative stress.

In-vivo evidence

Whole-body overexpression of SIRT1 in genetically engineered mice produces improved insulin sensitivity and glucose homeostasis.

In three animal models of Type 2 Diabetes (a diet-induced obesity (DIO) mouse model; a leptin-deficient (0b/0b) mouse model; and a leptin recepter deficient (Zucker fa/fa) rat model), Sirtris-developed new chemical entities (NCEs) acting as SIRT1 activators significantly reduced glucose levels and improved insulin sensitivity consistent with increased SIRT1 activity.

Mice on a high-fat diet and treated with these same NCE SIRT1 activators also had reduced weight gain, increased energy expenditure and performed better than untreated mice at a similar weight in an endurance test.

Working from the solid foundation established over the last few years, Sirtris is currently evaluating SRT2104 in a Phase II clinical trial of Type 2 Diabetes.

Cardiovascular Disease

SIRT1 has been shown to be critical in regulating the response to oxidative and hypoxic (low oxygen) stress in endothelial cells. These cells line all the blood vessels in the body (endothelium) and as such are critical gate keepers in maintaining vascular heath. Endothelial cell dysfunction can lead to numerous disorders including atherosclerosis, which can contribute to progressive cardiovascular disease including myocardial infarction, stroke and peripheral arterial disease. Sirtris is currently evaluating one of its NCEs, SRT2104, in a Phase IIa clinical study designed to assess potential cardiovascular benefits by first investigating the impact on endothelial function.

Neurodegenerative Diseases

Development of new drugs for the prevention of neurodegenerative disease has been an area of intense activity with very little progress. Discovery of druggable mechanisms with broad application across different neurodegenerative diseases would represent a significant advance in this therapeutic area. Both SIRT1 activators and overexpression of SIRT1 have been shown to slow in vitro cell death as well as in vivo neurodegeneration. A role for activated SIRT1 in preventing neuronal cell death may be useful for multiple neurodegenerative disorders, such as optic neuritis, ALS and Alzheimer’s disease. These data support the idea that SIRT1 activators may be broadly applicable in the treatment of neurodegenerative diseases.

Inflammation

Inflammation is a complex biological response that is caused by harmful stimuli, such as damaged cells. Abnormal inflammation is associated with a broad variety of diseases, including inflammatory bowel diseases (IBD) and ophthalmic, respiratory and cardiovascular diseases. SIRT1 has been shown to be a negative regulator of several inflammatory pathways. Thus, activation of SIRT1 may be beneficial for many of these inflammatory diseases.

Sirtris’ new chemical entities (NCEs) have shown efficacy in multiple preclinical models of inflammation and other relevant disease models. Sirtris is evaluating one of its NCEs, SIRT2104, in an ongoing Phase I clinical study in inflammation.

Mitochondrial Disorders

Mitochondrial disorders are caused by mutations in mitochondrial DNA (mtDNA) or in nuclear genes important for mitochondrial biogenesis. SIRT1 activation may be beneficial as it has been shown in preclinical models to enhance mitochondrial biogenesis in skeletal muscle and to improve exercise tolerance.

Our discoveries validating SIRT1-dependent activation with small molecules have been well documented in scientific literature, such as:

Scientific Publications Validating Pharmacological SIRT1 Activation

Yoshizaki T, Schenk S, Imamura T, Babendure JL, Sonoda N, Bae EJ, Oh da Y, Lu M, Milne JC, Westphal C, Bandyopadhyay G, Olefsky JM. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab. 2010; 298(3):E419-28.

Funk JA, Odejinmi S, and Schnellmann RG, SRT1720 Induces mitochondrial biogenesis and rescues mitochondrial function after oxidant injury in renal proximal tubule cells. J Pharmacol Exp Ther. 2010; 333:593-601.

He W, Wang Y, Zhang MZ, You L, Davis LS, Fan H, Yang HC, Fogo AB, Zent R, Harris RC, Breyer MD, Hao CM. SIRT1 activation protects the mouse renal medulla from oxidative injury. J Clin Invest. 2010; 120:1056-1068.

Fischer-Posovszky P, Kukulus V, Tews D, Unterkircher T, Debatin KM, Fulda S, Wabitsch M. Resveratrol regulates human adipocyte number and function in a SIRT1-dependent manner. Am J Clin Nutr. 2010 May 12. [Epub ahead of print].

Boily G, He XH, Pearce B, Jardine K, McBurney MW. SIRT1-null mice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene, 2009; 28(32):2882-93.

Yoshizaki T, Milne JC, Imamura T, Schenk S, Sonoda N, Babendure JL, Lu JC, Smith JJ, Jirousek MR, Olefsky JM. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol, 2009; 29:1363-74.

Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab, 2008; 8:347-58.

Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F., Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell, 2006; 127(6):1109-22.

Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L. SIRT1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature, 2004; 429:771-776.

Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 2003; 425(6954):191-6.