HomeENGLISH MAGAZINEBrain aneurysms: genetics unveils the mistake, drug repurposing helps it

Brain aneurysms: genetics unveils the mistake, drug repurposing helps it

Brain aneurysms are a bulge in a blood vessel caused by a weakness in the blood vessel wall. As blood passes through the weakened blood vessel, blood pressure causes a small area to bulge outwards. They can develop anywhere in the body but are most common in the abdominal aorta (the artery that carries blood away from the heart) and the brain. It’s difficult to estimate exactly how many people are affected by brain aneurysms as they usually cause no symptoms until they rupture, but experts believe it could be anywhere from 1 in 100 to as many as 1 in 20 people. Treatment is difficult, involving complex surgery which is currently only attempted in select cases. In a notable example, Game of Thrones actress Emilia Clarke suffered from two aneurysms while filming the series, undergoing surgery as a result. Working in collaboration with colleagues at University of Washington School of Medicine in Seattle, USA, scientists at the University of Sussex may now have found a safer and more efficient possible treatment involving “tyrosine kinase inhibitors”, a new class of drugs currently used to treat cancers.

Using sophisticated ‘next generation’ DNA sequencing technologies, teams in Washington lead by Manuel Ferreira, Associated Professor of Neurological Surgery, identified a new genetic basis of a form of brain aneurysm (PDGFRB mutations). This was unexpected, as mutations in this gene have been previously identified in completely different human developmental disorders. Dr. Mark O’Driscoll, Professor of Human Molecular Genetics at the Genome Damage and Stability Centre at the University of Sussex, then found that multiple disease-associated mutations in PDGFRB caused a specific abnormality in its encoded protein. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant that cause an aminoacid (Tyr562Cys) switch within the juxtamembrane-coding region of platelet-derived growth factor receptor β gene (PDGFR-B). This abnormality causes its activity to remain locked in a hyper-active form, referred to as ‘gain-of-function variants’ – in effect, causing the protein to always remain ‘turned-on’.

PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-activation (phosphorylation) of the receptor with downstream activation of signaling pathways (c-Src, ERK and PI3K-Akt). Publishing their findings in this months’ edition of the American Journal of Human Genetics, the Sussex team also demonstrated that this abnormal form of the protein can, in some cases, be countered by a drug which is currently used in cancer treatments. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. This is an extremely exciting discovery which shows how basic lab-derived observations on a genetic level can move into a clinical setting and start making big changes to public healthcare and treatments. Our research focused primarily on understanding the genetic and cellular mechanisms underlying a particular type of aneurysm. By finding a new genetic basis in some patients, we were also able to demonstrate that a known cancer drug could counter this genetic basis in most instances.

Understanding the genetics behind diseases like this is crucial in identifying possible treatments; and next steps of the team are now working to test this drug further. Drug repurposing is not unheard of, and there are already some previous successes. Historic example are the use of thalidomide as a treatment for leprosy as well as for multiple myeloma. Or niclosamide, a worm-fighting drug, has been discovered a couple of years ago to be an almost non-toxic option against certain leukemias. Or metformin, widely used to treat type 2 diabetes, which is under investigation to treat conditions like polycystic ovary syndrome (PCOS), some cancers, metabolic syndrome or autoimmunities like rheumatoid arthritis.

Time will be the final judge on the bench of knowledge.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Karasozen Y et al. Am J Hum Genet. 2019; 104(5):968-76. 

Scullen T et al. World Neurosurg. 2018 Mar; 111:349-357. 

Arts FA et al. et al. Hum Mol Genet. 2017; 26(10):1801-810.

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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