In addition to renal/cardiovascular diseases, preclinical studies strongly suggest
that AIMs are active in a number of other diseases that are linked with inflammation, oxidative stress, and aging. These include applications in
Respiratory Disease, Neurodegenerative Diseases,
Autoimmune, Transplants, and Cancer.
Major respiratory diseases including asthma, chronic obstructive pulmonary disorder (COPD), and cystic fibrosis all involve chronic oxidative stress and inflammation. Recent research has highlighted the importance of the Nrf2 pathway in protecting the lungs against inflammatory insult, and highlighted Nrf2 activation as a promising therapeutic strategy for treating major respiratory disorders.
AIM molecules have shown significant activity in preclinical models of asthma, acute lung inflammation, COPD, and cystic fibrosis. AIMs are in preclinical development for respiratory indications.
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Neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and ALS are now understood to have a significant inflammatory component. Chronic oxidative stress and activation of inflammatory signaling pathways (including the NF-kB pathway) are believed to play a major role in the pathology of these disorders. For example, NF-kB activation has been shown to increase the production of beta-amyloid, the suspected pathogenic protein in Alzheimer’s disease, and brains of Alzheimer’s patients have been shown to contain highly elevated levels of inducible nitric oxide synthase (iNOS), a major NF-kB target gene. Similarly, Nrf2 activation has produced beneficial effects in models of
Alzheimer's Disease, Parkinson's Disease, Huntington’s disease and ALS.
Because AIMs are known to activate Nrf2 and inhibit microglial activation, NF-kB activation, and iNOS expression, they have the potential to become significant new treatments for these intractable diseases. Preclinical studies have identified AIMs that are particularly efficient in reaching effective concentrations in the CNS, and several of these have shown significant activity in models of Alzheimer’s, Parkinson’s, and Huntington’s diseases,
as well as ALS. These molecules are in preclinical development.
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Autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, lupus, psoriasis, type I diabetes, and Crohn’s disease, are fundamentally inflammatory diseases in which the body mistakenly mounts an immune response against its own tissues. Although the etiology of these diseases is not completely understood, they share certain common features including elevated circulating and tissue levels of inflammatory cytokines such as TNF-alpha, elevated levels of molecules indicating oxidative stress, and damage to specific tissues caused by hyperactivity of immune cells such as macrophages and T cells. Failure of antioxidant systems has been implicated in the pathology of these diseases. For example, mice lacking functional Nrf2 develop a syndrome that closely resembles human lupus. Furthermore, chronic activation of NF-kB and JAK/STAT signaling is also associated with autoimmunity.
Several different AIM molecules have demonstrated substantial activity in a variety of validated preclinical models of autoimmune diseases, including rheumatoid arthritis,
lupus, multiple sclerosis, and inflammatory bowel disease.
Several AIMs that cross the blood-brain barrier
are in preclinical development for multiple sclerosis. Reata also plans to complete preclinical development on one or more additional AIM molecules for other autoimmune indications.
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Transplanted organs are at risk of failure due to ischemia-reperfusion injury associated with the transplantation process, as well as rejection by the recipient’s immune system. Conversely, patients receiving bone marrow transplants may suffer from graft-versus-host disease, in which transplanted immune cells attack normal tissues of the recipient. Consequently, transplant patients routinely take immunosuppressive drugs, which increase the patient’s susceptibility to infection and are frequently associated with kidney damage.
In preclinical studies, AIMs provided potent protection against renal ischemia-reperfusion injury and against graft-versus-host disease, suggesting they may be useful in preventing both acute and chronic transplant failure. AIM molecules are in preclinical development for transplant indications. Multiple AIMs have proven effective in animal models of graft versus host disease.
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Cancer cells are characterized by well-known hallmarks: limitless and self-promoting growth, avoidance of programmed cell death (apoptosis), stimulation of new blood vessel growth (angiogenesis), and the ability to remodel surrounding tissues to facilitate invasion and metastasis. Many of these same characteristics are present in inflamed tissue on a temporary basis, allowing the host to fight off infection and heal damaged tissue. Avoidance of apoptosis prevents host cells from being killed by high levels of reactive oxygen species (ROS), such as hydrogen peroxide, that are generated by macrophages and other immune cells to kill invading pathogens. Rapid cell growth, angiogenesis, and tissue remodeling are vital for wound repair and recovery of normal tissue function. In normal tissue these processes are eventually turned off, whereas in cancer or chronic inflammation and autoimmune diseases they are continually active. This has led to the classic description of cancer as "a wound that does not heal."
Many of these tumor-promoting inflammatory processes are regulated by NF-κB and STAT3, which are constitutively activated in many cancers
and are, in part, regulated by Nrf2. When activated, both NF-kB and STAT3 increase the expression of a wide variety of anti-apoptotic proteins such as BCL-XL, angiogenic factors such as VEGF, inflammatory cytokines such as IL-6, and tissue remodeling enzymes such as MMP-9. In addition, chronic activation of STAT3 is believed to play a critical role in the ability of tumors to evade detection and destruction by the immune system. Consequently, each of these proteins is a major target for the development of new cancer therapies. By inhibiting both, AIMs offer a particularly attractive profile of activity. An extensive series of published studies has shown that they are potent inhibitors of angiogenesis, processes of invasion and metastasis, cell proliferation, and chemically induced carcinogenesis. In addition, they have been shown to enhance the tumor-killing properties of standard chemotherapy drugs, radiation, and a number of targeted therapies. This profile, combined with their outstanding tolerability in human clinical studies, shows great promise for the use of AIMs in combination therapy.
Clinical proof of concept for AIMs in the treatment of cancer
has been achieved in Phase 1 studies of bardoxolone methyl in
patients with advanced cancers. Results were selected for an oral presentation at the 2008 American Society of Oncology annual
meeting. Follow-on AIMS are in preclinical
development for cancer.
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