Disease Indications
Cardiovascular Disease
“Cardiovascular disease is the greatest scourge affecting the industrialized nations. As with previous scourges, bubonic plague, yellow fever and small pox, cardiovascular disease not only strikes down a significant fraction of the population without warning, but also causes prolonged suffering and disability in even larger number. In the United States alone, despite recent encouraging declines, cardiovascular disease is still responsible for almost 1 million fatalities each year and more than half of all deaths.”
Eugene Braunwald M.D. 1980
The statement above was made in 1980. Unfortunately, it is still true today, and forms the preface to the 8th Edition of Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, published in October, 2007.
Genomics can change this and Genescient will play a significant role
Genescient’s longevity genes were used to “query” publicly available case-control cohort lists of genome-wide sets of SNPs such as those produced by the Wellcome Trust Case Control Consortium (WTCCC). The WTCCC dataset consisted of ~3000 common controls and 2000 cases for each of several diseases, including Coronary Artery Disease, and Hypertension.
Based on the WTCCC dataset, we identified 34 SNPs, corresponding to more than a dozen genes. Several of these genes are newly implicated in the development of cardiovascular disease. Genescient is already testing several substances that act on these gene targets.
Diabetes Mellitus
There are 23.6 million people in the United States (8% of the population) who have diabetes. The total prevalence of diabetes (some 90% of which is late-onset) increased 13.5% from 2005 to 2007. Diabetes is associated with an increased risk for a number of serious and sometimes life-threatening complications, such as renal failure, blindness and most of all, cardiovascular disease. The risk of incurring a myocardial infarction (heart attack) for a diabetic person is the same as the risk of a person who has already head a heart attack.
If we could predict and treat at-risk individuals at an early stage in the disease, we could prevent many of the complications associated with diabetes, and possibly the development of the disease itself. Based on analysis if Genome Wide Association Studies such as the WTCCC dataset (See “Cardiovascular Disease” above), Genescient identified 35 SNPs, associated with type 1 diabetes and 43 SNPs associated with type 2 diabetes. These genetic hits corresponded to a few dozen genes, several of which are newly implicated in the development of diabetes. Genescient is already testing one substance that acts on some of these targets.
Immunosenescence
Immunosenescence appears gradually with age and results in a decline in a host’s capacity to respond to infections and cancers. Therefore, infectious diseases often become more lethal in the elderly and most forms of cancer become much more prevalent with age. Somewhat surprisingly, immunosenescence can also lead to T-cell dysregulation or autoimmunity, wherein the immune system loses specificity and can no longer distinguish native cells and proteins from invading pathogens. The later effect may be the main reason for the increase in pro-inflammatory cytokines with age and chronic inflammation. A successful treatment of immunosenescence and/or chronic inflammation could be used by millions of people and provide billions in revenue.
There are currently no really good treatments for immunosenescence. Stimulation of the immune system using mushroom or bacterial polysaccharide supplements has provided benefits to some patients. The steroid hormone DHEA has been reported to overcome the age-related defect in immunity of old mice against influenza in at least one study. Vigorous exercise has also been shown to increase lymphocyte count. However, none of these treatments are patented drugs, and really effective immunosenescence treatments have not yet appeared. Genescient’s longevity gene data set and its model animal system provides Genescient with a unique doorway into the discovery of Immunosenescence treatments. The Drosophila model used by Genescient has many orthologous human-like genes involved in the immunity and inflammation pathways.
Neurodegenerative Diseases
Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common form of dementia, which is currently incurable and terminal. In the early stages, the first recognized symptoms are short-term memory loss, but bodily functions are gradually lost leading to death with a mean life expectancy of about 7 years following diagnosis. The causes of Alzheimer’s disease are not well understood, but extracellular beta-amyloid plaques and intracellular tangles are thought by many to play a role in the disease. More recently, some researchers have pointed to the presence of plaques and tangles in many elderly without detectable AD symptoms and have come to believe that AD is caused more by inflammation and/or the aging of neuronal cells than by the near-universal presence of plaques and tangles in the brains of the elderly. Whatever the cause, AD is one of the most economically costly diseases to society (worldwide cost may approach 100 billion dollars annually) due to the AD patient’s accumulating needs for care and attention for even the most simple functions of life. Any successful treatment in this area would clearly be a blockbuster.
Currently available treatments for AD provide small symptomatic benefits and have failed to delay or to stop the progression of the disease. In 2008, more than 500 clinical trials were testing various possible treatments for Alzheimer’s, but none of these treatments have proven effective as of mid 2009.
Genescient’s longevity genes were used to “query” a publicly available case-control Canadian Alzheimer’s cohort dataset for a genome-wide sets of SNPs (Arch.Neurol.2008;65(1):doi:10.1001/archneurol.2007.34) and a second cohort consisting of 750 autopsy-proven Alzheimer’s disease cases and a similar number of controls. A number of Genescient’s longevity genes were implicated in Alzheimer’s disease and some of these genes were found to be novel. Compounds that act on a subset of these genes have tested positive in our Drosophila longevity assays.
Parkinson’s Disease
Genescient has identified, within its library of longevity genes, several genes previously reported as associated with Parkinson’s disease. An example is Parkin, a ubiquitin-protein
ligase. Genescient human/Drosophila database has 14 genes associated with the
ubiquitin-ligase system.
In 2004, Japanese researchers reported the following:
We identified a novel gene and confirmed that mutations of this novel gene were found only in the patients with autosomal recessive Parkinson’s disease. The novel gene was named parkin. We conducted mutational analysis on more than 700 families with Parkinson’s disease. We also established a method to detect compound heterozygotes of parkin mutations. Mutations of the parkin gene were found in approximately 50% of autosomal recessive families. Many kinds of exonic deletions and point mutations were found. This type of familial Parkinson’s disease had been considered to be unique among Japanese, but since we started mutational analysis of the parkin gene, we confirmed the world wide distribution of parkin gene mutations. Then we analyzed functions of parkin protein with the collaboration with Dr. Keiji Tanaka of Tokyo Metropolitan Institute of Medical Sciences. We found that parkin protein was a ubiquitin-protein ligase of the ubiquitin system.
The Genescient human/drosophila data set also includes a number of genes involved in essential Mitochondrial functions and Autophagy. Dysfunction in macroautophagy has been related to neurodegenerative disorders such as Parkinson’s disease.
As more Genome Wide Association Studies (GWAS) become available, Genescient will be able to confirm more and more genomic targets for future Parkinson’s therapeutics.
Genescient is already testing several substances acting on these targets.
Sepsis or Systemic Inflammatory Response Syndrome (SIRS)
Sepsis is a life-threatening condition caused by an overwhelming infection of toxic bacteria in the blood stream and resulting in systemic inflammation (harmful levels of the cytokines IL-1, IL-6, IL-8, TNFα, and white blood cells). Places where an infection might start include the lungs (bacterial pneumonia), the bowel (peritonitis), kidneys, or the skin (surgical wounds, bedsores or ulcers). Severe sepsis can lead to organ dysfunction or failure, low blood pressure (< 90 mm Hg), rapid heartbeat, fever, delirium, and acute inflammation. If untreated, sepsis can readily lead to septic shock, multiple organ dysfunction, and death in more than 50% of cases. Sepsis is the 2nd leading cause of death in non-coronary patients and the 10th most common cause of death overall. It is most common in the elderly, young children, and critically ill patients.
Common treatments for sepsis include: raising blood pressure (e.g. norepinephrine, epinephrine, dobutamine), broad spectrum antibiotics, identification of the source of infection, and support for organ dysfunction. In severe clinical cases, hydrocortisone and recombinant activated protein C has been used with some success. Overall, there is a pressing need for better treatments for all forms of sepsis, given the high mortality rate. The greatest potential for a Genescient drug development would target organ dysfunction and lowering inflammatory cytokines IL-1, IL-6, IL-8, TNFα.
Inflammatory genes are readily found in our longevity genomic data base. Organ dysfunction is addressed by genes involved in mitochondria metabolism, protein degradation mechanisms (the ubiquitin-proteasome system) and autophagy (lysosomes and peroxisomes), which are the cell’s garbage disposal systems. These disposal systems become overwhelmed during sepsis and require stabilization. Autophagy failure is now thought to be one of the main reasons for the accumulation of cell damage during aging. Autophagy failure is also very likely a major cause of cell and organ damage during sepsis. Genescient has a significant advantage in this area of drug development because of the many genes we have discovered in the area of autophagy and because of the Drosophila experiments now being carried out by Genescient. Moreover, therapeutic substances that Genescient identifies may generally act to promote broad-based resistance to toxic stress.