Neurodegenerative diseases, which usually manifest later in life, come in many forms and attack the brain or central nervous system or both, depriving their victims of various motor or intellectual abilities. Most neurodegenerative diseases have no effective treatment. The Company will leverage new proprietary technologies with a focus on developing effective therapies for amyotrophic lateral sclerosis (ALS) and other diseases caused by repeat expansion mutations.
People diagnosed with C9orf72 ALS survive an average of three to five years following diagnosis, although the disease is variable, and some survive longer. Most ALS cases are “sporadic”, which means they occur without any family history of the disease. Scientists suspect that a combination of genetic and environmental factors cause sporadic ALS, but the specific factors are not known. Approximately 10% of ALS cases, however, have a family history and scientists have identified a large number of genetic mutations that cause these familial cases.
The most common familial form of ALS is caused by a repeat expansion in a gene known as C9orf72. Mutations in this gene account for between 25% and 40% of all familial ALS cases (depending on the population), and also approximately 7% of sporadic ALS cases. Mutations in this gene also cause about 25% of the cases of another neurodegenerative disease, frontotemporal dementia, or FTD. Some people with the C9orf72 expansion mutation develop ALS, some FTD and some have both disorders.
Mutations in the C9orf72 gene act in a dominant manner, meaning you need only one copy of the gene to get the disease. If you carry the mutated gene, your children have a 50% chance of inheriting the disease. For families with the disease, whether or not to have genetic testing is often a difficult decision. Those who learn that they have the gene have to live with the knowledge that they are likely to develop a devastating disease for which there is no cure.
The team at RanTran is working aggressively to change that, pursuing therapies based on successful studies in mice aimed at targeting and reducing toxic repeat associated non-ATG (RAN) proteins, which kill neurons.
RAN translation is the abnormal translation of RNA into toxic proteins that occurs in diseases caused by repeat expansion mutations, or mutations in which small segments of the genetic code are repeated too many times. For example, the mutation in C9orf72 that causes ALS is a repeat expansion mutation in which the repeated sequence is six letters of the genetic code, GGGGCC (or G4C2). Most people have fewer than 25 G4C2 repeats while repeats in people at risk of developing disease exceed ~60. The number of repeats in some patients may be much higher, as many as 4,000 or more.
Dr. Ranum, a co-founder of the Company, discovered RAN translation in 2011 and and her lab at the University of Florida have developed BAC transgenic mice with the expanded C9orf72 gene, and these mice develop phenotypes strikingly similar to both ALS and FTD making them an ideal and unique tool to test potential therapeutic strategies. In experiments using this mouse model, the Ranum lab has shown that strategies that reduce RAN protein levels in these mice improve survival and behavior of the mice and prevent motor neurons from dying, improving a key feature of the disease required for muscle strength. This foundational work by the Ranum lab demonstrates that RAN proteins drive disease and identifies promising therapeutic opportunities for C9orf72 ALS and other repeat expansion diseases that produce RAN proteins.
The Company is licensing key intellectual property created by Dr. Ranum and her lab at the University of Florida, including rights to use novel therapeutic and diagnostic technologies for C9orf72 ALS/FTD and other repeat expansion diseases. Additionally, the Company will use and license a BAC transgenic mouse model developed in the Ranum lab.
|TYPE||GENE||Number of Cases in U.S.*|
|Myotonic Dystrophy Types 1&2||DMPK and ZNF9||150,000|
|Spinocerebellar Ataxia Types 8 &31||ATXN8, ATXN8-OS, TK2 and BEAN||150,000 for all hereditary and sporadic ataxias (specific info for SCA8 and 31 not known)|
|Fragile X Tremor Ataxia Syndrome||FMR1||32,000—43,000|
|Fuch’s Endothelial Corneal Dystrophy||TCF4||Over 6 million people (specific info for TCF4 is not known, but it is common)|