To date, there is no treatment for most genetic disorders. We are developing chemicals with drug-like properties that we think will be useful for treating genetic diseases that carry a certain type of mistake in the DNA called a ‘nonsense mutation’. Approximately one-third of inherited diseases are caused by nonsense mutations. Approximately 1800 inherited diseases have been defined to date [http://www.rarediseases.org]. We call these potential drugs ‘small molecule readthrough compounds (SM-RTCs)’. We are especially interested in ‘small molecules’ because we are dedicated to finding a treatment for ataxia-telangiectasia (A-T), a progressive neurodegenerative disease that first appears in early childhood and involves deterioration of the brain. In order for drugs to arrive in the brain, they must cross a complex filter known as the ‘blood-brain barrier’. To do this, they must also be ‘small molecules’. Thus, this Disease Team Award will use A-T as a model but it is also a model for other neurodegenerative diseases, such as Parkinson and Alzheimer disease. In addition to meeting the stringent FDA (Food and Drug Administration) requirements, we will use neural stem cells to test the effectiveness and safety of these SM-RTCs, something that has only recently become feasible through new CIRM-funded technologies and new understanding of how stem cells differentiate into more mature cells. We will then apply for IND (Investigational New Drug) permission to do a clinical trial on our most promising SM-RTC in A-T children. These studies will also provide new insights into the number of different types of mature neuronal cells that exist, those that depend on the A-T protein, and which ones deteriorate in which neurodegenerative diseases. We will use our SM-RTC to rescue some of these neuronal populations. The A-T Disease Team will combine the talents of multi-disciplinary experts in stem cell biology, medicinal chemistry, pharmacology, toxicology, immunology, and drug development. The project will take four years to complete. Once demonstrated safe and effective for A-T, the SM-RTC drug can be tested for treating other genetic diseases with nonsense mutations, such as muscular dystrophy and cystic fibrosis. The principles learned may apply to other neurodegenerative diseases as well. Without CIRM funding, no pharmaceutical company would attempt to develop a drug for a disease as rare as A-T (1 in 40,000); there would simply not be a large enough market for selling the new drug. Thus, CIRM funds provide a unique opportunity for orphan drug development.
This project seeks to develop an oral medication that could be used to treat genetic diseases carrying a nonsense mutation. Nonsense mutations account for roughly one-third of all genetic mutations. To date, approximately 1800 genetic diseases have been identified, encompassing about 500,000 patients in the US. Our drug was discovered by high throughput screening of small molecule chemical libraries, performed entirely at our institute during the past seven years. This class of drugs ‘tricks’ ribosomes into reading through stop codons instead of halting the translation of RNA, hence the name Small Molecule Readthough Compounds (SM-RTCs). We use ataxia-telangiectasia (A-T) as our testing disease model, in part because we have a unique library of >500 cell lines from A-T patients carrying different mutations in the causative ATM gene. A-T is a rare (1 in 40,000) inherited disease characterized by a childhood-onset and progressive neurodegenerative disease, immune deficiency, sensitivity to ionizing radiation, and a high propensity for developing cancer. Patients often die before reaching adulthood. There is no treatment for this fatal disease. Carrier mothers with nonsense mutations (1 in 600) are at a 5-fold increased risk of developing breast cancer. If our drug proves safe and effective for inducing the missing ATM protein, not only would A-T children benefit, but the mothers carrying a nonsense mutation in the ATM gene would also be candidates for prophylactic therapy with our SM-RTC. This same principle should apply to breast cancer patients with nonsense mutations in the BRCA1 gene. Our drug also shows restorative activity in a mouse model of muscular dystrophy and in cells derived from patients with epidermolysis bullosum. Thus, large numbers of genetic patients in the US could benefit from the successful development of this drug. This development will utilize California hospitals and clinics, consultants and other experts. New products will stimulate new biotech investment and tax revenues for California. Human suffering and health care costs will be lowered. Any Intellectual Property generated by this project will be regulated under the guidance of CIRM for the benefit of the state of California.