SIRT1
The SIRT1 enzyme is the most well-studied of the seven 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 an advanced its SIRT1 program and has two lead product candidates that target this enzyme:
SRT501: Sirtris’ proprietary formulation of resveratrol which is completing a Phase IIa study in patients with Type 2 Diabetes and is in a Phase IIa study in cancer patients.
SRT2104: Sirtris’ first new chemical entity SIRT1 activator to enter the clinic. SRT2104 is structurally unrelated to and approximately 1000 times more potent than resveratrol. In a Phase I safety study in healthy volunteers, SRT2104 was found to be safe and well tolerated. Sirtris will launch a Phase IIa human trial with SRT2104 in 2009.
Type 2 Diabetes
SIRT1 activation has been shown to stimulate the development of new mitochondria by activating the mitochondria regulator PGC1- α. Mitochondrial activity in metabolically active tissues, such as muscle, will increase metabolic rate, drive glucose metabolism, and thereby improve insulin sensitivity. SIRT1 activation also plays a significant role on other key regulators involved in metabolic stress.
+  SIRT1 Activation Mechanism |
In-vivo evidence
Whole-body overexpression of SIRT1 in 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, SIRT1 activators including resveratrol and Sirtris-developed new chemical entities significantly reduced glucose levels and improve insulin sensitivity.
Mice on a high-fat diet and treated with resveratrol also performed better than untreated mice at a similar weight in an endurance test. The drug treated mice ran almost twice as far in a treadmill exercise test compared to the placebo group. (see marathon mice)
In two Phase IIa human clinical trials of Type 2 Diabetic patients taking SRT501, Sirtris’ proprietary formulation of resveratrol lowered blood glucose levels as determined through an oral glucose tolerance test at the test's two-hour time point, as compared with the placebo groups.
Together these data suggest that activation of SIRT1 with small molecules leads to effects very similar to those observed in animals and humans exposed to calorie restriction.
+ Cardiovascular Disease
Genetic data demonstrate a role for SIRT1 in cardiovascular disease. SIRT1 deficient mice die from cardiac defects. Further, mice over-expressing cardiac SIRT1 (4-8 fold) respond better to oxidative stress and pressure overload than wild-type mice. With aging, these mice show less cardiac hypertrophy, apoptosis/fibrosis, cardiac dysfunction and expression of senescence markers than their wild-type littermates. SIRT1 activation seems to retard aging in the heart and confers stress resistance.
Humans with a single nucleotide polymorphism (SNP) in the SIRT1 gene exhibit a lower incidence of cardiovascular mortality, myocardial infarction, myocardial ischemia, stroke, and arterial surgery. Therefore, SIRT1 activators may have cardiovascular benefits.
+ 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.
+ 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. Calorie restriction also prevents AD-like neuropathology in rodent models through a mechanism that has been shown to involve activation of SIRT1 in the brain. These data support the idea that SIRT1 activators may be broadly applicable in the treatment of neurodegenerative diseases.
+ Cancer
For over 70 years it has been known that calorie restriction extends life span in multiple species including mammals. This effect is attributed to a decrease in cancer rates as well as other diseases that adversely affect the organism. On-going studies in rodents are examining the effects of daily dosing of SIRT1 activators on health, lifespan and incidence of cancer. Data available to date suggest that there has been no tumor growth after 18 months of dosing with resveratrol. Indeed, in transgenic animals in which substantial increases in SIRT1 levels are elicited, spontaneous tumor growth has not been reported. Therefore, it is possible that increased SIRT1 activity with small molecule activators will reduce the disease burden in cancer patients.
Sirtris is collaborating with the National Cancer Institute to test the anti-cancer impact of Sirtris’ SIRT1 activators in numerous models of cancer. The study includes SRT501, a proprietary formulation of resveratrol, and multiple compounds from different chemical classes of Sirtris' new chemical entities, which are up to 1,000 times more potent than resveratrol in in-vitro studies. The National Cancer Institute will test the compounds in well-established cancer cell lines that were previously used in the development of novel and existing chemo-therapeutics. The cell lines to be tested include some of the most common cancer types. The program will also test Sirtris' compounds using in-vivo mouse tumor models to determine if the compounds reduce or limit the growth of the tumor cells.
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