iRND3's goal is to help identify new medicines for patients with rare and neglected diseases. While having an interest to address opportunities for all rare and neglected diseases, we realize the need to focus our efforts. To this end our current focus is on eukaryotic pathogens including Trypanosoma brucei, Trypanosma cruzi, Leishmania, Cryptosporidium, and the fungus aspergillus fumigatus, and cancers, specifically pediatric cancers including neuroblastoma.
What do cancer and infectious diseases have in common besides being rare and/or neglected diseases? From a pharmacological perspective we are looking to identify medicines that kill the cells, either cancer cells for cancer, or infectious cells from the pathogens. iRND3 has expertise and platforms to identify medicines with pharmacological mechanisms that will selectively kill these unwanted cells. Our strategy is to identify these compounds in our laboratory in Mountain View, CA and then have the molecules tested for efficacy in the appropriate animal models for proof of concept (POC) in the laboratories of disease area experts. Molecules that show proof of concept will be subject to pre-clinical development as therapeutic candidates towards the goal of enabling an Investigational New Drug (IND) application. We look to fund this work through grants, partnerships, collaborations and donations.
Infectious diseases caused by eukaryotic pathogens result in significant morbidity and mortality worldwide. Treatment of these diseases is often compromised by limited therapeutic options and/or development of resistance. Despite increased emphasis on development of new drugs and therapeutic approaches to augment clinical options and combat antimicrobial resistance, development of new or novel therapeutics against eukaryotic pathogens lags behind that for other pathogens.
Human African trypanosomiasis (HAT)
is endemic to parts of sub-Saharan Africa. During the most recent epidemic the prevalence reached 50% in several villages in Angola, the Democratic Republic of the Congo, and South Sudan. Sleeping sickness was the first or second greatest cause of mortality in those communities, even ahead of HIV/AIDS. In 2009, after continued control efforts, the number of cases reported dropped below 10 000 (9878) for the first time in 50 years. This decline in number of cases has continued with 6314 new cases reported in 2012. However, the estimated number of actual cases is about 20,000 and the estimated population at risk is 65 million people. HAT is a progressive and fatal disease caused by the protozoan parasites Trypanosoma brucei gambiense and T. b. rhodesiense, which are transmitted to the human host by the bite of the tsetse fly. If left untreated the parasite enters the central nervous system and the disease is ultimately fatal. HAT is not a priority for the pharmaceutical industry and thus the NIH and WHO categorized it as a neglected tropical disease (NTD).
is endemic in 21 countries across Latin America and kills more people in the region than any other parasite-borne disease, including malaria. In total, 70 million people are at risk worldwide and patient numbers are growing in non-endemic countries such as the United States, Australia, and Europe. The disease is transmitted by an insect known as the “kissing bug” and, without treatment, is potentially fatal. Existing treatments have an unsatisfactory cure rate and can have toxic side effects.
occurs in 98 countries with 350 million people living at risk worldwide. The parasite that leads to infection is called Leishmania and transmitted by sandflies. Leishmaniasis is a poverty-associated disease with several different forms; visceral leismaniasis, which is fatal without treatment, and cutaneous leshmaniasis are the most common. Existing treatments are difficult to administer, toxic, and costly. Drug resistance is also an increasing problem.
is a genus of apicomplexan protozoans that can cause a respiratory and gastrointestinal illness that primarily involves watery diarrhea with or without a persistent cough in both immunocompetent and immunodeficient humans. Cryptosporidium is one of the leading causes of waterborne disease, or disease caused by contaminated drinking water or recreational water. Recreational water is water from swimming pools, hot tubs, fountains, lakes, rivers, springs, ponds, or streams that can be contaminated with sewage or feces from humans or animals. In most healthy people, a cryptosporidium infection usually goes away within a week or two. If you have a compromised immune system, a cryptosporidium infection can become life-threatening without proper treatment.
Fungal infections- aspergillus fumigatus
is the most frequent cause of invasive fungal infection in immunosuppressed individuals, which include patients receiving immunosuppressive therapy for autoimmune or neoplastic disease, organ transplant recipients, and AIDS patients. A. fumigatus primarily causes invasive infection in the lung and represents a major cause of morbidity and mortality in these individuals. Additionally, A. fumigatus can cause chronic pulmonary infections, allergic bronchopulmonary aspergillosis, or allergic disease in immunocompetent hosts.
is the most frequently occurring solid extra-cranial tumor of childhood and accounts for approximately 10-15% childhood deaths from cancer. Despite intensive therapy with conventional drugs, prognosis remains poor for advance-stage cases and the chance of long-term survival is < 30%. More than 50% of these tumors occur in children less than 2 years of age. The incidence of neuroblastoma has increased in recent years and it continues to carry a poor prognosis in children over two years of age with a survival of only 38%. The disease displays a remarkable clinical diversity, ranging from spontaneous regression to fatal progression and dissemination to privileged sites, such as bone-marrow and liver.
is the most dangerous type of skin cancer. It is the leading cause of death from skin disease and its incidence is on the rise, with over 76,250 new cases and approximately 9,000 deaths in 2012. The mainstay of targeted therapy for melanoma, BRAF inhibitors, has significantly improved the survival of patients with advanced stages of the illness. The first-in-class BRAF-specific inhibitor vemurafenib (PLX4032) was approved in 2011 and extends melanoma survival by 4 to 6 months compared with standard chemotherapy. But resistance to therapy develops in most patients, causing them to stop therapy or switch to another agent. Recent basic research has revealed one way in which resistance works. Researchers have found that the BRAF inhibitors cause the melanoma cancer to change its source of energy (ATP) in a process called metabolic reprogramming. They have found that resistant tumors have a greater oxidative phosphorylation capacity that results in the mitochondria providing the primary source of energy. Activated BRAF promotes metabolic reprogramming by suppression of oxidative phosphorylation through the actions of the melanocyte lineage factor MITF and the mitochondrial master regulator PGC1α. BRAF inhibitors, which transiently suppress melanoma growth in vitro and in patients, induce PGC1α and oxidative phosphorylation. This addiction to oxidative phosphorylation in melanomas treated with BRAF targeted therapy therefore suggests that mitochondrial inhibitors should be evaluated in combination with BRAF pathway inhibitors in vivo.
The World Health Organization list of neglected tropical diseases
Information about specific diseases can be obtained at:
- National Institute for Health Office of Rare Diseases.
- National Organization for Rare Diseases