Endogenous tissue generation and restoration: Maximizing our human potential.

Objectives:* Review the types of stem cells used in preclinical research and clinical trials.* Discuss pharmacologic strategies that facilitate endogenous repair, stem cell upregulation and functional restoration following injury (emphasis on hearing loss as an exemplar).* Brief review of adult CNS stem cell clinical trials and their success to date.* Identify clinical trials using hESC and why this approach advances neither the science or society.Overview;For the first time in history, elderly (> 65 years old) adults outnumber young (Since the 1998 discovery that neurogenesis is operant in adult humans, there has been an explosion in our understanding of how to exploit this process for repair of the central nervous system (CNS). Initially, human embryonic stem cells (hESCs) were advanced as the primary means for achieving cell replacement and regenerative tissue repair. More recently (2006), the ability to re-introduce a pluripotent state in differentiated adult cells was established, using genes important to embryonic stem cell function. Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. In 2012 John Gurdon was awarded, jointly with Shinya Yamanaka, the Nobel Prize for Physiology or Medicine "for the discovery that mature cells can be reprogrammed to become pluripotent."Since these discoveries, the number of neurorestorative CNS clinical trials has been steadily increasing. In periodically reviewing the CNS clinical trial space (2010, 2012 and 2015), the ratio of cellular: non-cellular (primarily growth factors) regenerative approaches remains at ~ 2:1. This has been increasingly dominated by autologous stem cell approaches with few ongoing CNS hESC clinical trials, although the absolute number of hESC trials has increased from 2 in 2010 to 8 in 2015 (N= 3 stroke, N= 3 ALS and N= 2 spinal cord injury). Sponsors of CNS hESC include ReNeuron (CTX), StemCells Inc (HuCNS-SC®), NeuralStem (NSI-566) and In Vivo (HFB 2050 line). The scientific reason for this increase is unclear, especially given the wide range of adult autologous and allogenic stem cell options in development and the lack of a therapeutic advantage for hESCs. Other companies such as Q Therapeutics, Life Technologies, Novogenix and ReNeuron are suppliers of hNSC. Academia is also a key participant is these activities, as universities and academic medical centers are the primary sites for conducting most research on human disease, including trials using hNSC. Should they remain agnostic to this strategy?Going forward, the field of hearing loss is particularly poised for the introduction of therapeutic clinical trials that build upon and augment the successes of devices (e.g., hearing aids and cochlear implants). While devices are clearly a therapeutic advance, they do not perform well in "real world" noisy environments where speech discriminator is more challenging. Hearing loss represents one of the most neglected human diseases, affecting up to 10% of the entire world and is increasingly associated with the development of other significant pathology such as dementia and depression. The number of Americans with hearing loss has evidentially doubled during the past 30 years. Hearing loss, primarily sensorineural hearing loss (SNHL), disproportionally affects the youngest and the oldest segments of society. The prevalence of newborns with congenital hearing loss is ~ 1:500 and approximately 14.9% of U.S. children have low-frequency or high-frequency hearing loss of at least 16-dB hearing level in one or both ears. In both noise-induced and age-related SNHL, the earliest pathology is at the inner hair cell-auditory neurite ribbon synapse, with hair cell and spiral ganglion neuron death a later consequence. …