Cancers, Alzheimer’s disease, PKD: three severe pathologies with unmet medical needs.

Protein phosphorylations are involved in essentially all physiological and cellular events. It is therefore not surprising that abnormal phosphorylations are found as a cause or consequence of human diseases. A high number of diseases actually result from mutations in particular protein kinases and phosphatases.

ManRos Therapeutics targets are of considerable interest because of their numerous essential physiological functions such as regulation of cell division cycle, apoptotic cell death, multiple neuronal functions, pain signaling, insulin release by pancreatic cells, transcription, RNA splicing. Among the associated pathologies, ManRos Therapeutics has chosen to focus its efforts on three major diseases: cancers, neurodegenerative disorders, and polycystic kidney disease.

Cancer & Leukemias

Image: Chronic lymphocytic leukemia cells. (c) 2007 Rector and Visitors of the University of Virginia Charles E. Hess, M.D. and Lindsey Krstic, B.A.

Despite recent therapeutic successes, cancer remains one of the largest causes of deaths in industrial nations. Approximately 10.5 million Americans have or have had cancer. It is also estimated that about 560,000 Americans and 6.2 million people worldwide died of cancer in 2007.

Cancers comprise more than 200 different diseases characterized by uncontrolled cell growth. Prostate, breast, lung and colorectal cancers are still the most common forms (50% of all cases). Although average survival after diagnosis has improved dramatically, a strong R&D effort is still needed to improve the survival of patients in many cancers.

Until now, antineoplastic agents and older chemotherapeutics are used to treat cancer. The majority of cancer drugs are “non specific” to cancer cells, and thus highly toxic drugs with undesirable associated side effects (nausea, hair loss, etc.). Recently, a number of drugs with novel targeted mechanisms (including kinase inhibitors) have emerged, providing hope for improved efficacy and reduced side effects. Targeted therapies are changing the landscape of cancer treatment and likely will be used in most cancer patients in 5-10 years.

There are numerous examples of the direct involvement of kinases and their regulators in the development of cancers: breast cancer, prostate cancer, melanoma and chronic lymphoid leukemia are among the representative examples.

Alzheimer’s disease

As the average life expectancy of the population rises, AD represents an ever-growing healthcare issue. It is a devastating disease without a cure, and the economic impact to society is huge: AD afflicts 4-5 million people in the U.S. and approximately 15 million people worldwide. In the US, the cost of caring for these patients amounts to $80-$100 billion each year. AD is expected to become a major global health care resource problem.

Currently available AD treatments provide only symptomatic relief, temporarily improving brain function in patients with mild-to-moderate disease. Effective drugs are urgently needed to fight the disease.

Numerous kinases (CDKs, GSK3s, CK1, etc.) are involved in AD and chronic neurodegenerative diseases. Considerable data support the critical role of abnormal activation of CDK5 and CDK1 in the brains of Alzheimer’s disease patients. CDK5 is also involved in Parkinson’s disease. There is also strong evidence for kinase implication in “acute” neuronal disorders and neurodegeneration: stroke, traumatic brain injury and pain signaling.

Polycystic Kidney Disease

Polycystic kidney disease (PKD) is the most common genetic disease, affecting 600,000 Americans and 12.5 million people worldwide. PKD affects more people than Down syndrome, cystic fibrosis, muscular dystrophy and sickle cell anemia combined! 6,000 new cases are diagnosed each year in the US alone.

PKD is a progressive genetic disorder of the kidneys. The causes of the disease are mainly inheritable genetic DNA mutations. PKD is characterized by the presence of multiple cysts in both kidneys, and in other organs (e.g. liver, pancreas). These cysts grow and multiply over time, also causing the mass of the kidney to increase.

Whereas some treatments aim at the reduction of symptoms and the prevention of complications, to ease the PKD symptoms and prolong life, no effective treatment is available today to prevent the onset of the disease.

CDKs appear to play a key role in the development of PKD and are relevant targets for treating PKD. Other kidney diseases where CDKs are involved comprise glomerulonephritis, lupus nephritis, collapsing glomerulopathy and Pt-induced nephrotoxicity.

Other diseases

The interest of CDK, GSK-3 or CK1 inhibitors has also been validated in other pathologies, including:

• Inflammation: arthritis represents a good example of an inflammatory disease with CDK activity abnormalities.
• Type 2 diabetes: CDK5 prevents insulin secretion by pancreatic cells, and its inhibition favors glucose-dependent secretion. CDK inhibition reduces the loss of beta cell function under glucotoxic conditions.
• Unicellular parasites: Unicellular organisms (Plasmodium, Leishmania, etc…) are responsible for devastating diseases such as malaria and leishmaniosis. They have CDK homologs involved in their proliferation and differentiation.

ManRos Therapeutics is seeking to collaborate with academic or industrial teams to further progress in such areas.