provide a therapeutic approach to addressing genetic mutations that underly certain rare genetic diseases (eg, epidermolysis bullosa [EB], familial adenomatous polyposis [FAP], class 1 cystic fibrosis [CF], Duchenne muscular dystrophy [DMD]), inflammatory disorders (eg, Crohn’s Disease), and cancers (eg, colon, pancreatic).
Our initial focus is the development of RMAs for rare diseases caused by nonsense mutations. Nonsense mutations, the substitution of a stop codon for a codon specifying an amino acid, result in the production of shortened, nonfunctional proteins.
After a rigorous screening cascade for readthrough activity, several Zikani RMAs have been validated in preclinical functional assays for:
epidermolysis bullosa (RDEB)
APC mutant familial
adenomatous polyposis (FAP)
and colon cancer
Class 1 cystic fibrosis (CF)
Zikani RMAs have shown a 4-fold to 8-fold readthrough activity compared to widely accepted comparators in pre-clinical, clinical, and on-market therapies. This activity points to the potential for higher protein production in multiple diseases.
RDEB is caused by a nonsense mutation in the COL7A1 gene, which codes for the COL7 protein. Without COL7, the epidermis does not anchor to the dermis resulting in very fragile skin, severe blistering, and skin erosion in response to minor injury or friction.1
FAP is caused by a mutation in the adenomatous polyposis coli (APC) gene coding for APC protein, which acts as a tumor suppressor and keeps cells from growing too fast or in an uncontrolled way. It is characterized by polyps developing as early as the teens.2,3
CF is caused by a mutation in the cystic fibrosis transmembrane conductance (CFTR) gene, which codes for the protein that regulates salt and water balance in the lungs and other tissues. It is characterized by the buildup of mucus in the respiratory and digestive track leading to progressive damage to these organs
CFTR mutations are grouped into 5 classes
There are no approved treatments for class 1 CF; management is palliative
References: 1. Genetics home reference: dystrophic epidermolysis bullosa. National Institutes of Health: US National Library of Medicine. Available at: https://ghr.nlm.nih.gov/condition/dystrophic-epidermolysis-bullosa#genes. Accessed January 27, 2020. 2. Genetics home reference: familial adenomatous polyposis. National Institutes of Health: US National Library of Medicine. Available at: https://ghr.nlm.nih.gov/condition/familial-adenomatous-polyposis. Accessed January 27, 2020. 3. Roy HK and Khandekar JD. APC gene testing for familial adenomatosis polyposis. JAMA. 2012;308(5):514-515. 4. Mutyam V, Du M, Xue X, et al. Discovery of clinically approved agents that promote suppression of cystic fibrosis transmembrane conductance regulator nonsense mutations. Am J Respir Crit Care Med. 2016;194(9):1092-1103.