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Lock E.,Liverpool John Moores University | Ranganath L.R.,University of Liverpool | Timmis O.,AKU Society
Current Rheumatology Reports | Year: 2014

Nitisinone 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione (NTBC), an effective herbicide, is the licensed treatment for the human condition, hereditary tyrosinaemia type 1 (HT-1). Its mode of action interrupts tyrosine metabolism through inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD). Nitisinone is a remarkable safe drug to use with few side effects reported. Therefore, we propose that it should be investigated as a potential treatment for other disorders of tyrosine metabolism. These include alkaptonuria (AKU), a rare disease resulting is severe, early-onset osteoarthritis. We present a case study from the disease, and attempts to use the drug both off-label and in clinical research through the DevelopAKUre consortium. © 2014, Springer Science+Business Media New York. Source


Gallagher J.A.,University of Liverpool | Dillon J.P.,University of Liverpool | Sireau N.,Findacure | Timmis O.,AKU Society | Ranganath L.R.,University of Liverpool
Seminars in Cell and Developmental Biology | Year: 2016

"Fundamental diseases" is a term introduced by the charity Findacure to describe rare genetic disorders that are gateways to understanding common conditions and human physiology. The concept that rare diseases have important lessons for biomedical science has been recognised by some of the great figures in the history of medical research, including Harvey, Bateson and Garrod. Here we describe some of the recently discovered lessons from the study of the iconic genetic disease alkaptonuria (AKU), which have shed new light on understanding the pathogenesis of osteoarthritis. In AKU, ochronotic pigment is deposited in cartilage when collagen fibrils become susceptible to attack by homogentisic acid (HGA). When HGA binds to collagen, cartilage matrix becomes stiffened, resulting in the aberrant transmission of loading to underlying subchondral bone. Aberrant loading leads to the formation of pathophysiological structures including trabecular excrescences and high density mineralised protrusions (HDMPs). These structures initially identified in AKU have subsequently been found in more common osteoarthritis and appear to play a role in joint destruction in both diseases. © 2016. Source


Gallagher J.A.,University of Liverpool | Dillon J.P.,University of Liverpool | Sireau N.,Findacure | Timmis O.,AKU Society | Ranganath L.R.,University of Liverpool
Seminars in Cell and Developmental Biology | Year: 2016

"Fundamental diseases" is a term introduced by the charity Findacure to describe rare genetic disorders that are gateways to understanding common conditions and human physiology. The concept that rare diseases have important lessons for biomedical science has been recognised by some of the great figures in the history of medical research, including Harvey, Bateson and Garrod. Here we describe some of the recently discovered lessons from the study of the iconic genetic disease alkaptonuria (AKU), which have shed new light on understanding the pathogenesis of osteoarthritis. In AKU, ochronotic pigment is deposited in cartilage when collagen fibrils become susceptible to attack by homogentisic acid (HGA). When HGA binds to collagen, cartilage matrix becomes stiffened, resulting in the aberrant transmission of loading to underlying subchondral bone. Aberrant loading leads to the formation of pathophysiological structures including trabecular excrescences and high density mineralised protrusions (HDMPs). These structures initially identified in AKU have subsequently been found in more common osteoarthritis and appear to play a role in joint destruction in both diseases. © 2016 Elsevier Ltd. Source


Hall A.K.,CUDOS | Sireau N.,AKU Society | Raffai F.,Findacure
Expert Opinion on Orphan Drugs | Year: 2014

There is a large unmet need for helping rare disease patient groups and Findacure aims to empower these groups to become effective campaigners for change. Through its scientific meetings, Findacure also aims to gain the support of the scientific community in recognizing the importance of 'fundamental diseases' (conditions that manifest themselves as extreme and rare genetic disorders that offer a unique opportunity to better understand other diseases, including many common ones) and help to create a receptive research environment. Since it may often be commercially unattractive to develop treatments for many fundamental diseases, Findacure helps facilitate patient groups to themselves drive the development of treatments for fundamental diseases, using multi-stakeholder collaborative models. © 2014 Informa UK, Ltd. Source


Nemethova M.,Slovak Academy of Sciences | Radvanszky J.,Slovak Academy of Sciences | Kadasi L.,Slovak Academy of Sciences | Kadasi L.,Comenius University | And 31 more authors.
European Journal of Human Genetics | Year: 2016

Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy. © 2016 Macmillan Publishers Limited. Source

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