traditional hormone replacement therapy
The standard of care for hormone deficiency in men ('hypogonadism'), which increases as a function of age, is supplementation with testosterone. This treatment only partially corrects the condition since it does not address important deficits in other gonadal hormones, including inhibin B, inhibin A, and anti-Müllerian hormone. There are no pharmacological sources of these protein hormones and they cannot be easily administered orally, transdermally, or sub-cutaneously, as with sex steroids. Further, hormone monotherapy can cause significant side-effects, including carcinogenesis resulting from the imbalance with inhibins (known tumor suppressors) and other testicular hormones. From a practical perspective, it is difficult to ascertain an appropriate dose of sex steroid because in most cases there is no data available regarding a patient's baseline (young adult) circulating levels. Typically, therefore, testosterone treatment results in supraphysiological concentrations that do not replicate the normal, time-variant release and interaction, of hormones. Ongoing treatment with testosterone can also lead to suppression of endogenous testosterone production and testicular shrinkage and infertility.
Post-menopausal women were historically administered estrogen, progesterone, or both, in order to replace the hormones no longer produced by the ovaries. Unfortunately, rather than using physiologically identical human hormones (17β-estradiol and progesterone), most HRT in the US was derived from horse (mare) urine (conjugated equine estrogens; 'CEE') or produced synthetically (medroxyprogesterone acetate; 'MPA'). Structural differences between endogenous sex hormones are already quite subtle, and neither horse- nor synthetic-derived hormones have precisely the same structure as human estrogen or progestagen, respectively. Human estrogen and human testosterone differ by a single functional group (aldehyde vs hydroxyl), yet they produce vastly different outcomes in human development and physiology. It is therefore not surprising that there are major biological differences in the efficacy of these unnatural versus natural forms of steroids. Supplementation with 17β-estradiol post-menopause has been shown to delay the onset, decreases the incidence, and improve the course of age-related diseases, including Alzheimer’s disease, coronary heart disease, osteoporosis, obesity, and type II diabetes, although an increase in reproductive cancers is suggested by some studies. By comparison, supplementation with CEE and MPA increase risk for breast cancer, coronary heart disease, stroke and Alzheimer's disease. In any case, substitution of one or a few hormones at artificial doses cannot be expected to restore the complex milieu of hormonal interactions that existed prior to menopause or andropause, ultimately limiting the medical utility of this approach.
next-generation Hormone replacement therapy
Our solution to the limitations of traditional hormone replacement therapy is to develop stem cell-based therapeutics intended to replace or regenerate gonadal cells that have been lost or are no longer functioning properly. Rejuvenating the gonads with those cells that produce sex hormones allows for the rebalancing of the entire sex hormone axis (the hypothalamic-pituitary-gonadal (HPG) axis). We are advancing candidate cell therapies that are fit-for-purpose to the tissue into which they will be transplanted, and capable of producing the milieu of hormones needed under the natural conditions within the body. Unlike chemical or biologic drugs, cells are complex machines able to sense their environment, integrate a wide range of signals, and perform appropriate functions in response. Arguably, cells are better suited than drugs to restoring tissue function. Delivery of the cells will be designed for outpatient clinics, to be performed by physicians specifically trained to administer the therapy. Gonadal tissues are known to be among a few privileged sites within the body that are protected from the immune system, thus we are exploring use of cells that are either derived from the patient ('autologous') or from another common source ('allogeneic').
Each individual’s body requires continuously varying levels of numerous sex hormones that can only be regulated by the person’s own glandular tissues when functioning correctly. Pharmacological solutions, as indicated above, cannot rebalance all the hormones of the hypothalamic-pituitary-gonadal (HPG) axis. Our approach, repopulating the gonads with those cells that normally produce sex hormones, is expected to offer multiple advantages. These include: holistic hormonal rebalancing in accordance with the individual's specific endocrine requirements; long-term, possibly permanent, restoration of circulating hormone levels, obviating the need for regular supplementation treatments; re-establishing the cyclical interactions of the HPG axis; utilization of the body's own endocrine organs to drive the differentiation and maturation of stem cells into those cell types required to restore gonadal function.
relevance to aging and age-related diseases
Due to the limitations of hormone replacement, conditions such as hypogonadism that result from andropause, menopause and numerous other deficiency syndromes remain major unmet medical needs. But what does this have to do with aging and age-related disease? The premise of our technology platform is the following assertion: dysregulation of the endocrine system that accompanies aging is not merely a symptom, but a cause of aging and consequent age-related diseases. It is, however, impractical for a biotech with limited resources to develop a product aimed directly at treating aging. The necessary scope and duration of clinical trials to address effects on aging would be prohibitive. Instead, we have elected to focus on specific indications that are within reach, and with large market demographics, where we expect to achieve clinical success. Yet the underlying treatment would fundamentally be the same as that which could also address aging and be expected to improve healthspan. Specifically, we intend to look for co-morbidities of age-related diseases within our initial clinical cohorts, and use these signals as cues for further clinical studies targeting aging.
In summary, JangoBio’s research will be directed towards an innovative stem cell-based therapy for the hormone replacement therapy market. This approach aligns with our ultimate goal to develop a treatment for aging in that our cell therapy has the potential to restore health and delay diseases of aging, including heart disease, stroke, COPD, cancer, dementia, and type 2 diabetes, among others. During our initial clinical studies, we expect to see effects on co-morbidity of these conditions, and (if so) this data will offer the opportunity to establish subsequent clinical trials to gain indications of our cell therapy for numerous diseases of aging.