Role of Lipid Mediators in Metabolic Diseases & Malignant Tissue Growth – Two Distinct Diseases, One Common Denominator

Dr. Ayala Luria, scientist in the Department of Urology and Institute for Regenerative Cures at UC Davis Medical Center, and a Consultant in a startup company, Adipocyte Therapeutics, discussed about the role of lipid mediators in various diseases, at www.bio2devicegroup.org event.

Diabetes is a disease of glucose homeostasis.  We need glucose for brain activity, energy for muscles etc.  But too much glucose can cause osmosis and affect the vessels and organs.  Under normal circumstance, the body can balance the amount of glucose, or sugar, in the blood with the amount of glucose that the cells need for fuel. The hormone insulin, produced by the pancreas, helps transport the glucose into the cells.  However, under diabetic conditions, the insulin secretion is not sufficient or is not working properly.  There is a strong correlation between obesity, particularly abdominal fat and diabetes.   Adipose tissue is implicated in the development of a systemic inflammatory state that contributes to obesity-associated coronary heart disease.

Dr. Luria’s research project relies on the concept of small lipid mediator, the autacoids that are metabolites of arachidonic acid. About 40% of the drugs in the market targeted towards treatment of inflammatory diseases, asthma and allergy are based on the a class of chemical compounds or small molecules of the archidonic acid pathway.  This small molecule can be diverted to prostaglandins and thromboxanes to treat inflammation and blood clothing.  It can also be diverted to leukotrienes to target asthma, allergies and so on.  There is however, yet another pathway through epoxyeicosatrienoic acids (EETs).  Luria’s research indicated that increasing EETs either pharmacologically or through genetically modified animals, helped obese mice regulate glucose levels.

Luria then discussed her work in angiogenesis.  Angiogenesis refers to the formation of growth of blood vessels, which is at the core of sustaining life.  Without blood, without oxygen, we cannot survive.  In diabetics, impaired wound healing, retinopathy etc. are caused due to impaired angiogenesis.  Insufficient angiogenesis also is considered to be one of the causes in stroke, CHS and so on.  Whereas in cancer, excessive angiogenesis causes malignant tumor growth and many drugs on the market are targeted towards killing angiogenesis.    Luria’s collaboration research indicated that (EETs) stimulate angiogenesis, although the mechanisms involved are not entirely understood.  She tried to use angiogenesis as a vehicle for chemotherapy drugs in low doses.  Combining EETs with inhibitors, led to stark decline in tumors.  She arrived at the conclusion that it might be interesting to target diabetes treatment as benign tumor growth by inhibiting angiogenesis and further use angiogenesis as a vehicle to target tissue growth.

This interesting talk generated lot of response and was followed by Q&A.

Please join us on this Tuesday, April 21, 2013 for continuing discussion on metabolic diseases.  Next week’s talk is titled “Obesity 360” and panelists include – Dr. Darshana Nadkarni, Dr. Alex Nedvetsky, and Mr. Nat Bowditch –  http://bit.ly/ZExFfQ

Wet AMD – Leading Cause of Blindness: Symptoms, Causes, & Innovative Treatment Options

Dr. Mark Shusterman, Medical Director at Oraya Therapeutics, discussed new treatment options for Wet Age Related Macular Degeneration, at http://www.bio2devicegroup.org .

AMD is a leading cause of blindness for seniors, worldwide. In the US, it impacts more people than cataracts and glaucoma combined. It affects 9.1 million people in the U.S. and 10 to 30 million people worldwide. Almost entire medical budget could be consumed by AMD, if the current paradigm for AMD is not solved, said Shusterman.

Biology of the eye is interesting. Normal human eye has two chambers, the anterior and the posterior chamber. Retina has photoreceptors, with the highest concentration of cons that allow us to see color. These are lined at the back of the eye and create electrical impulses that travel through the optic nerve to the brain. The Macula is an oval shaped spot near the center of the retina and is responsible for high resolution central vision. More specifically, it is the fovea, a dimple shaped central part of the macula that produces the highest resolution vision. Retina is the thinnest at this region and most serious forms of macular degeneration affects this area. Risk factors for macular degeneration include, age (60+ years), race (Caucasians and Asians are at greater risk), gender (women are at higher risk), genetics (probability increases, if someone in the family has it), and life style issues (smoking, diet, obesity, and high blood pressure).

Wet form of macular degeneration is a more serious form which is preceded by Dry AMD. Dry AMD is characterized by drusen in the retina and takes years or even decades to develop. It can remain stable or can progress to Wet AMD. About 10-15% of Dry Amd converts to Wet AMD. In Wet AMD, abnormal blood vessels behind the retina start to grow under the macula and these vessels are very fragile and leaky. The oozing blood and fluids accumulate, eventually scarring the rods and the cons. If untreated, it progresses to loss of central vision within 2 years. Signs and symptoms of AMD include, wavy appearance of straight lines, foggy or blurry central vision, difficulty distinguishing colors, development of central blind spot, difficulty reading, and difficulty recognizing faces. Some of the possible ways to prevent AMD are, eating diet rich in vitamins C & E, selenium and carotenoids, taking prescription vitamins indicated for eye health that includes antioxidants and zinc, exercise, not smoking, and maintaining normal BP, weight, and cholesterol.

Often however, there is a disease progression and until now few viable and cost effective treatment options existed. Initially, there were attempts to treat AMD with laser. But it seemed that laser did not just burn scarred tissue, but some good tissue and nerves as well. It appeared, that with laser, slightly less vision loss in the immediate future was traded with more significant vision loss, a year or two later. Another photodynamic therapy or PDT is still around but only seems to work well in certain forms of AMD, but is not effective for most forms of AMD. Anti-VEGF injections, Lucentis, Avastin, Macugen, and Eylea are all in use and have been a standard form of suggested treatment for AMD, since Lucentis was introduced in 2006. Anti-VEGF drugs work by targeting VEGF (Vascular Endothelial Growth Factor), a protein responsible for creation of new blood vessels. But cost and frequency of injections required are major inhibiting factors. For instance, an injection of Avastin costs $50. An injection of Lucentis costs between $1200 and $1400. Most of these anti-vitreal injections work best when given routinely on a monthly basis. Eylea can be given bi-monthly. While the efficacy of anti-VEGF compounds has prolonged and saved the eyesight of millions of patients worldwide, it has also placed a huge new burden on patients who require costly, regular injections, as well as on the ophthalmic practice and on the healthcare systems. And cost constraints render this form of treatment unavailable to many people, across the world. Additionally, although greatly beneficial in stabilizing the progression of wet AMD, and decreasing resulting vision loss, the use of anti-VEGF agents carries significant known risks, such as infection (endopthalmitis), increase in intraocular pressure (glaucoma), stroke and others.

Oraya therapy is a new breakthrough treatment, intended as one-time, non-invasive procedure for Wet AMD. Oraya Therapy uses highly targeted, low-voltage X-rays to inhibit and prevent the growth of abnormal blood vessels under the macula (choroidal neo-vascularization) that is most often associated with wet AMD. Radiation is a useful modality because it targets rapidly proliferating and late responding tissues and cells and unlike ablative therapies like laser photocoagulation, it can deliver small amount of energy to the targeted area like the Endothelium (anti-angiogenic), Fibroblasts (anti-fibrotic), and Inflammatory cells (anti-inflammatory). Non-mitotic cells (such as nerve cells) are left largely unaffected. Slowly replicating cells (such as normally proliferating vascular endothelial cells) generally have time to repair the damage or to be replaced by recruitment from outside the target region.

Oraya Therapeutics I-Ray System comprises of Precision-controlled X-ray tube, Patient interface, patented Eye stabilizing device, Eye tracking module, and Intuitive operator interface. The IRay System is designed to deliver three overlapping X-ray beams to the macula, each 4 mm in diameter. The beams are directed into the eye while the patient sits comfortably in a chair, with the head positioned on a chin rest. The entire procedure takes about 20 minutes and the patient can go home after the appropriate post-treatment evaluations are made. Clinical data indicates that the use of radiation in conjunction with existing pharmacologic therapies may have beneficial results in terms of improved disease control with a decreased need for recurrent intra-ocular injections. Examination of the effects of radiotherapy on wet AMD, in more than one thousand patients, indicated that patients treated with radiotherapy were two times more likely to require no further injections and were overall more likely to require fewer than 4 treatments in a year. The radiotherapy was delivered using high-energy external beam systems (with the exception of one study that used brachytherapy), and doses ranged from 7.5 to 24 Gy. The analysis also determined that no patients suffered radiation retinopathy, optic neuropathy, or malignancy. The presentation was followed by Q&A.