Three Targeted Diseases Involving Protein Kinases
Our research is focused on protein kinases and their pharmacological inhibitors.
Kinases are responsible for phosphorylation, the addition of a phosphate group to a biological molecule. This reaction is involved in essentially all physiological and cellular events and abnormalities in phosphorylation are observed in many human pathologies, notably proliferation-associated diseases and neurodegenerative diseases.
As a consequence, research projects carried out by ManRos Therapeutics on cystic fibrosis, polycystic kidney disease, Down syndrome and Alzheimer’s disease are highly complementary and synergistic. They share several common targets and similar mechanisms.
Cystic Fibrosis (CF)
A rare orphan disease…
CF is a life-threatening and chronically debilitating condition affecting people from very early in the childhood with a frequency of about 1 in 2,500 live births among Caucasians.
- It affects more than 80.000 patients in the world
- 33.000 in the USA
- 40.000 in Europe
- 6.500 in France.
CF is a genetic disease (autosomal recessive disorder) caused by different mutations of the CF transmembrane conductance regulator (CFTR) gene. There are currently over 2,000 mutations affecting CFTR, many of which give rise to a disease phenotype. The most commonly observed mutation in the world – including the European community – is F508del-CFTR. Indeed, around 75% of CF alleles contain the ΔF508 mutation in which a triplet codon has been lost, leading to the deletion of phenylalanine at position 508 in the protein.
… that affects respiratory functions
Patients suffering from CF develop debilitating lung function disorders. Many patients with CF develop also secondary chronic bacterial pulmonary infections among which Pseudomonas aeruginosa infections are the more frequently reported – 70 to 80% CF patients being primarily infected by their teen years – and, allergic fungal infections such as bronchopulmonary aspergillosis. In the early 2000, 80 to 95% of patients with CF still succumbed to respiratory failure brought on by chronic bacterial infection and concomitant airway inflammation.
Among CF complications, the most frequently reported are cystic fibrosis-related diabetes (CFRD) (20-50% of CF adolescents and adults) and liver (30%) and pancreatic enzyme production (5-10 %) related diseases.
Polycystic Kidney Disease (PKD)
The most common human genetic disease…
Autosomal dominant polycystic kidney disease (ADPKD) is the most common human genetic disease.
Its prevalence is approximately 1 case per 500-1000 births.
- 650,000 in the USA
- more than 800.000 in Europe
- 80.000 in France
- and 12 million worldwide.
… against which no effective treatment is available
It is characterized by the development of fluid-filled cysts in kidneys, liver, pancreas and other organs. PKD is due to mutations in the PKD1 gene (85%) or PKD2 gene (15%) which respectively encode the polycystin-1 and polycystin-2 proteins. About half of the ADPKD patients progress to end-stage renal disease (ESRD) by age 60. No fully effective therapy is available although significant progress has been made recently in identifying new potential treatments. In human, the growth rate of renal cysts is about 5% per year. Reduction of this rate by half would probably be sufficient to postpone ESRD and to largely benefit to most PKD patients.
Alzheimer’s Disease (AD) & Down Syndrome (DS)
A major health issue…
According to the AD International Association the number of AD patients is expected to almost double in 20 years in the world, from 35.6 million in 2011 to 65.7 million in 2035. In Europe, the prevalence of AD is ~6.4% over 65 years and ~20% over 80 years (EURODEM estimates). Women are three times more affected than men. Life expectancy of patients at diagnosis is estimated at 3-8 years. AD is one of the most costly diseases for developed economies. The global total estimated cost for dementia (of which AD is the most common form) was 604 billion $ in 2010 (70% in Western Europe and North America) (cost of illness EU27: 160 billion € (1.3% of GDP) in 2008 of which 55% as informal care; 2.2 million life years lost due to disability; considerable weight for patients caregivers; annual cost of 22 K€ per patient (2005), including 26% in medical expenses).
… linked to the DYRK1A kinase
Understanding the functions and regulations of the DYRK1A kinase is expected to have a direct impact in four major diseases with defect in cognition: Down syndrome (DS), rare Intellectual Disabilities (ID), Autism spectrum Disorders (ASD) and Alzheimer’s disease. All these conditions induce a strong burden at the social and economic level. DS is due to the presence of 3 copies of human chromosome 21 (where the DYRK1A gene is located). It still represents the most common form of intellectual disabilities with a prevalence of 1 in 2000 newborns in developed countries, where prenatal diagnosis is implemented, and 1 out of 700 newborns in other parts of the world. A few rare intellectual conditions, both ID and ASD, are due to mutations in DYRK1A. In addition several key proteins contributing to AD, such as Tau, PSEN1 and APP are modified through controlled splicing or phosphorylation by DYRK1A. Thus, having a better understanding of the molecular and cellular function of DYRK1A in the adult brain should certainly help to improve the treatment of rare or more common diseases sharing abnormal regulation of this kinase and its interacting proteins.