Clinical Bioinformatics

From Dr. Saphic-Mihajlovic, Department of Psychiatry, University of Illinois, Chicago, IL – from the poster, “Pharmacogenomic-Validated Treatment for Treatment Resistant OCD and MDD: A Case Study.” Using AssureRx Health’s test for CYP2D6, CYP2D19 and other biomarkers.

Two studies, published in the latest edition of Nature Genetics, have identified 5 new common variants of genes encoding proteins that appear to be involved in conveying susceptibility to late onset Alzheimer’s disease (LOAD). Until recently, only four genes associated with late-onset Alzheimer’s have been confirmed. The gene for apolipoprotein E-e4, APOE-e4, identified over 15 years ago, has the largest effect on risk. Over the past two years, three additional genes have been identified, including CR1, CLU, and BIN1. The present study adds another four — MS4A, CD2AP, CD33, and EPHA1 — and contributes to identifying and confirming two other genes, BIN1 and ABCA7, thereby doubling the number of genes known to play a role in Alzheimer’s disease

Most cases of early-onset Alzheimer disease are also caused by gene mutations that are also inherited. Researchers have found that this form of the disorder can result from mutations in one of three genes: APP, PSEN1, or PSEN2. When any of these genes is altered, large amounts of a toxic protein fragment called amyloid beta peptide are produced in the brain. This peptide can build up in the brain to form clumps called amyloid plaques, which are characteristic of Alzheimer disease. A buildup of toxic amyloid beta peptide and amyloid plaques may lead to the death of nerve cells and the progressive signs and symptoms of this disorder.

The recent study, conducted by the Alzheimer’s Disease Genetics Consortium, reports genetic analysis of more than 11,000 people with Alzheimer’s disease and a nearly equal number of elderly people who have no symptoms of dementia. Three other consortia contributed confirming data from additional people, bringing the total number of people analyzed to over 54,000. The consortium also contributed to the identification of a fifth gene reported by other groups of investigators from the United States, the United Kingdom, France, and other European countries. The study is the result of a large collaborative effort with investigators from 44 universities and research institutions in the United States, led by Gerard Schellenberg at University of Pennsylvania.

“If we eradicate the affect of these 10 genes we could eradicate 60 per cent of Alzheimer’s disease,” said Professor Julie Williams from Cardiff University. Genetics is thought to account for between 60 and 79 per cent of the risk of developing Alzheimer’s disease.

From the publication of Hollingworth et al (2011) –

“Five of the recently identified Alzheimer’s disease susceptibility loci in CLU, CR1, ABCA7, CD33 and EPHA1 have putative functions in the immune system; PICALM, BIN1, CD33 and CD2AP are involved in processes at the cell membrane, including endocytosis, and APOE, CLU and ABCA7 are involved in lipid processing. It is conceivable that these processes would play strong roles in neurodegeneration and Amyloid beta peptide clearance from the brain. These findings therefore provide new impetus for focused studies aimed at understanding the pathogenesis of Alzheimer’s disease.”

References:

Hollingworth, P. et al (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nature Genetics (2011) doi:10.1038/ng.803. Received 09 September 2010 Accepted 10 March 2011 Published online 03 April 2011.

Naj, A.C. et al (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nature Genetics (2011) doi:10.1038/ng.801. Received 27 September 2010 Accepted 10 March 2011 Published online 03 April 2011

The bulleted text is taken largely from a presentation by Dr. Felix W. Frueh, formerly Associate Director for Genomics Office of Clinical Pharmacology and Biopharmaceutics, CDER/FDA, and now Director of Research & Development, Medco Health Solutions.

For example, biomarkers are used widely in the development of oncology drugs. Cancer is recognized as a major cause of mortality the world over; accounting for 7.4 million (or 13%) of all deaths in 2004. The World Health Organization (WHO) estimates incidence of cancer to continue rising to reach an estimated 9.2 million deaths in 2015. The rising prevalence of the disease forms one of the major factors driving the growth of the use of cancer biomarkers in drug development and discovery. Biomarkers are chemical, physical, or biological parameters that can be used to indicate disease states. Cancer biomarkers facilitate high-speed, non-invasive cancer diagnosis; and enhance early cancer detection and screening. The demand for cancer biomarkers is also increasing because of their ability to trace the exact type of cancer and to target patient-specific molecular structure.

Exploratory Biomarkers:
• Lay groundwork for probable or known valid biomarkers
-Hypothesis generation
• Fill in gaps of uncertainty about disease targets, variability in drug response, animal – human bridges and new molecule selection
-Learn and improve success in future drug development programs
• Can be “de novo” or “sidebar” study embedded in (pivotal) clinical efficacy trials
-Biomarkers associated with clinical outcome

Target Product Profile:
• What’s the Benefit?
• Ideally: Statement of what to go to the market with (desired outcome)
• Can include, e.g. optimal labeling
• Provides grounds for discussion during pre pre-IND or IND phase, (or later)
• Important to revisit the profile characteristics over the period of development
• Genomic biomarkers provide good opportunity to create TPP-

Use Genomic Biomarker for:
• Stratification to separate responders from non non-responders
• Stratification to exclude patients at risk for AE
• Enrichment of responder population

Get:
• Increased chance of winning,
• In a shorter period of time,
• At less cost (decreased size of trial).

Figure #1 shows examples of the application of biomarkers to the drug discovery and development pipeline:

The legendary hydra was a monster that when you cut off one of its heads, 2 more grew back.

The “re-alignment” of programs at the National Center for Research Resources (NCRR) at the National Institutes of Health, which funded some programs in medical informatics such as the Biomedical Informatics Research Network (BIRN), has led to a proposed re-mapping of funded programs to at least 2 possible new Centers or Institutes: NCATS (National Center for Advancing Translational Science), which may harbor the CTSA programs, and an “Interim Infrastructure Unit” that will harbor the “Biomedical Informatics Research Network” (BIRN).

Since NCRR funded several medical informatics projects, it is now believed that one or another of these new entities will become the equivalent of a National Center for Biomedical Informatics Research and Computational Biology (“BearCub”). Of some interest, the National Library of Medicine, which houses some of the many NIH medical informatics projects, is not an intended recipient of any of NCRR’s translational science or biomedical informatics programs.