Gonzalez-Cadavid, Nestor F., PhD
Pharmacological stem cell modulation for treating erectile dysfunction in type 2 diabetes
General Research Subject: Type 2 Diabetes
Focus: Complications, Complications\Macrovascular-Cellular Mechanisms of Atherogenesis in Diabetes, Genetics, Genetics\Type 2 Diabetes, Other
Type of Grant: Basic Science
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Erectile dysfunction (impotence) is a frequent complication of type 2 diabetes, that predicts cardiovascular disease and is usually due to the inability of the penis to retain blood in the corpora cavernosal tissue to maintain an erection ("corporal veno-occlusive dysfunction": CVOD). As diabetes progresses, CVOD fails to respond to medications, because the damaged corporal tissue that triggers erections cannot relax sufficiently. In type 2 diabetes animal models CVOD associates with high blood glucose (hyperglycemia) combined with obesity, but not with hyperglycemia alone. Stem cells are a promising treatment approach.
This project poses the hypotheses that muscle derived stem cells (MDSC) correct CVOD caused by diabetes/obesity by repairing the corporal tissue in a process stimulated by a class of anti-diabetic agents such as ACTOS, by modulating the interaction between implanted and endogenous stem cells. It is also proposed that long-term diabetes/obesity impairs the ability of MDSC to correct CVOD when reimplanted into the patient, but they may be reactivated in the laboratory by a process named "reprogramming". The goal is to investigate these hypotheses in cell culture, in the obese Zucker (OZ) diabetic rat, and in an engineered diabetic mouse where stem cells produce green fluorescence, by determining whether: 1. Treatment of OZ rats with MDSC prevents and/or cures CVOD. 2. MDSC are stimulated by ACTOS by modulating their interaction with penile stem cells. 3. ACTOS protects MDSC from hyperglycemia, and the "reprogramming" of MDSC reactivates them. This project has potential significance for the clinical cure/prevention of an important diabetes complication.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project is within the broad area of diabetic complications, and more specifically covers the very significant problem of erectile dysfunction (ED) associated with type 2 diabetes (T2DM). ED is highly prevalent in T2DM and metabolic syndrome with insulin resistance, that severely impairs the quality of life of patients, is a sentinel of cardiovascular disease, poses a severe burden on public health costs, and fails to respond in a large fraction of patients to glycemic control or oral phosphodiesterase 5 inhibitors. The prevalent form of ED in diabetes is vasculogenic, in part because the penis is an extension of the vascular system, but essentially due to the fact that hyperglycemia and dyslipidemia as well as other unknown factors, lead to the loss of penile corpora cavernosal smooth muscle cells responsible for penile erection and also tissue fibrosis, thus impairing corporal relaxation. The result is a venous leakage in the penis when an erection is induced that is named corporal veno-occlusive dysfunction (CVOD), and is responsible for an inadequate or short-term erection in T2DM patients, causing male impotence.
The focus of this project is on a therapeutic approach that may eventually ameliorate or cure ED associated with T2DM, by studying in an animal model of T2DM, insulin resistance and obesity, whether implantation into the corpora cavernosa of stem cells obtained from the adult skeletal muscle (MDSC) can repair the defective corporal tissue and correct ED, and whether treating concurrently with a drug that is clinically applied for glycemic control in T2DM (pioglitazone or Actos) may stimulate these effects by both acting directly on the MDSC and protecting the tissue at low doses that do not exert glycemic control. Stem cells have the ability to replicate indefinitely and then generate the different types of cells that need to be replaced in a damaged tissue. The project will also investigate whether the potential senescence of these stem cells when obtained from aged T2DM subjects (that would reduce their repair capacity) may complicate treatment, and whether this may be counteracted by their "rejuvenation" or reactivation, through molecular and cellular biology approaches, including the iPS (induced pluripotent stem cell) technology. The latter method allows differentiated cells, and potentially senescent stem cells too, to acquire or regain their full stem cell features and therefore their tissue repair capacity.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Despite the fact that this is a basic laboratory study performed in animal models and cell cultures, this project has a very high translational impact to the clinic, since once the project is completed it will open up the possibility of pilot clinical trials where the knowledge gained experimentally can be used for testing the treatment with human MDSC obtained from the leg muscles of the same T2DM patient who is being treated for his ED. In fact, a phase I clinical trial (safety) is already ongoing overseas for ED, but with other types of stem cells (bone marrow stem cells) and in non-diabetic patients.
Our project may have the following advantages: 1) despite using MDSC, the concepts of prior biological "rejuvenation" of the stem cells and concurrent pharmacological treatment for both stem cells stimulation and direct improvement of the host penile tissue, are applicable to other types of stem cells that may soon be tested clinically; 2) stem cells and their pharmacological modulation are aimed for a long-term "curative" approach of the penile corporal histopathology underlying ED and hence of the disorder itself, in contrast to the current pharmacological therapy that is simply palliative, seeking to facilitate a sporadic erection for a few hours to couple of days after taking the pill of PDE5 inhibitors like Viagra or Cialis; 3) the procedures to obtain the MDSC are less invasive to the patient than with other types of stem cells, and the class of pharmacological drugs investigated (Actos, and other compounds in the same family) is widely used in the clinic for T2DM patients, and may be applied at much lower doses than those inducing overweight or potential side-effects; 4) there are other stem cells that have FDA approval for other conditions and may be approved for ED, but the human MDSC have been well characterized and may be isolated and prepared for injection in the same institutions that treat the patients.
In summary, the translation from an animal model to the treatment of T2DM patients with ED is likely to be tested, at least for safety, in the next 2-3 years, and even its main concepts may be applicable to other cardiovascular complications of T2DM.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
For the last two decades I have been working in experimental molecular/cellular pathology and therapy in an Urology department (UCLA), focusing on many aspects of conditions affecting the urogenital tract and the vascular system, mainly ED, Peyronie’s disease, vaginal and kidney damage, arteriosclerosis, and related. The more recent common denominator of these interests has been the use of gene and adult stem cell therapy to treat tissue damage, mainly cell death and fibrosis, and their resulting dysfunctions. One of the main factors in inducing cell loss and fibrosis in tissues is the combination of hyperglycemia (high blood glucose), dyslipidemia (alteration of blood lipids), oxidative stress, and inflammation that characterize diabetes mellitus. So, using models of T1DM and T2DM, I have explored different pathological and therapeutic aspects of the impact of diabetes into some of their complications, such as ED, vaginal dystrophy, nephropathy, and more recently on the extreme form of peripheral arterial disease that is named critical limb ischemia. The ADA helped previously with the funding of some stages of this research
I do not have any family disease motivation to work on diabetes, but as my scientific interests drove me more and more into what I know better (not being a diabetologist), i.e, the vascular and renal complications of diabetes, I started to learn the human impact of the more serious epidemics that the world faces: the combination of diabetes and obesity. Having also a part-time appointment in a minority school of medicine (Charles Drew University) allowed me to become acquainted with the relationship of these conditions and health disparities, which is particularly severe in limb ischemia and diabetic nephropathy. So, my new ADA grant will allow me to focus further into this area, and I hope to be lucky enough as being eventually funded by other agencies for related aspects of ED in T2DM, and on the limb ischemia in diabetes project.
In what direction do you see the future of diabetes research going?
I cannot foresee the research advancement on the purely metabolic and etiologic aspects of diabetes, other than the use of stem cells for the treatment of insulin deficiency in T1DM, or advanced T2DM, which I believe will soon render some effective clinical translation. However, because of my interest on some diabetes vascular and renal complications, I firmly believe that research on these areas not only should address the main causes of death in diabetic patients, or the substantial impact on health care (in the case of ED in T2DM), but should help to advance two areas: 1) the general pathology and treatment of the vascular and renal dysfunctions caused by other non-diabetic risk factors such as aging, where the end-points of the chronic insult are often quite similar, and 2) the examination of how unknown factors other than hyper-glycemia per se, or more presumable factors, such as dyslipidemia and obesogens acting in concert with hyperglycemia, may impact the smooth muscle tissue in the vascular wall, the corpora cavernosa, or the kidney to cause a histopathology and dysfunction that often does not respond to glycemic control.
The identification of these factors, or at least how they work locally at the level of target tissues not related to metabolic control, is of potential great importance. In this respect, the dual differential action of thiazolidenediones (pioglitazone and others), as well as other drugs, at the systemic metabolic or the local levels and their potential effects on endogenous stem cells contributing to tissue repair, and the role of endogenous stem cells per se or their cross talk with implanted stem cells, may also be novel areas in diabetes complications that are worth exploring. Whether diabetes research would actually move actively in these directions is much more difficult to predict since it depends on funding priorities.
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