Insights into Neurogenesis and Aging: Potential Therapy for Degenerative Disease?

Robert A Marr; Rosanne M Thomas; Daniel A Peterson

Disclosures

Future Neurology. 2010;5(4):527-541. 

In This Article

Limitations to Developing Therapies for Neurodegenerative Diseases

Animal Models of Disease

When developing new therapeutic approaches to neurodegenerative diseases the type of model used to approximate the disease is a key component. This is particularly true when one is dealing with complex process such as aging, neurogenesis and idiopathic neurodegenerative diseases. There are two major classes of disease models. The first is genetically modified organisms carrying the mutant human gene associated with heritable forms of the disease (examples below). The majority of these models are in mice as they can be genetically manipulated relatively easily. Examples include mice carrying mutant forms of the human amyloid-precursor protein (APP) and presenilin (PS) genes associated with early-onset autosomal dominant AD (familial-AD).[104] For Parkinson's disease (PD), an example would be mice that overexpress the mutant form of human α-synuclein associated with familial PD.[105] There are similar examples for many other diseases including Huntington's disease and prion disease. These are very useful genetic models; however, they do not necessarily replicate all the idiopathic changes that occur in clinical cases. In addition, in some cases not all the pathological features are present. For example, there is a lack of tau pathology in mutant APP transgenic (AD-like) mice unless an additional mutant tau gene is present.[106] It should be noted, however, that this mutant tau gene is not associated with AD but instead with fronto–temporal dementia. Lesion models of neurodegenerative disease are the second major class of animal model that can be used in multiple species. For PD, these include 6-OHDA and MPTP used primarily in rats and mice, respectively, to kill dopaminergic neurons. The lesion approach has also been used to model AD through the use of a cholinergic basal forebrain neuron toxin (e.g., 192 IgG-saporin).[107] These models lack the progressive age-related nature of most neurodegenerative diseases and are static in terms of pathology over the long term. Lesion models also lack the 'toxic environment' present in most age-related neurodegenerative diseases.

Obstacles to Cell-mediated Therapies

The therapeutic use of stem cells could be pursued through two different strategies.[108] The first strategy is the derivation, isolation and expansion in vitro of a suitable stem cell population. Once obtained, this population could be banked and samples used over time for therapeutic delivery (Figure 2A). Alternatively, cultured stem cell populations could be genetically modified in vitro to express suitable therapeutic or instructional transgenes following engraftment (Figure 2B). The second strategy would not utilize exogenous stem cells, but rather recruit local stem cells already present within the brain. As most of the brain does not support neurogenesis, a suitable environmental niche will need to be created through delivery of genes encoding for the necessary signals or factors (Figure 2C). Engineering a niche may also be a suitable strategy when paired with grafting of exogenous stem cells to areas where endogenous signals to support differentiation and functional integration are diminished or nonexistent. As detailed below, each of these approaches faces some obstacles that will need to be overcome to facilitate clinical application.

A fundamental challenge to using exogenous stem cells is the source of those cells. Human embryonic stem cells (hESCs) have received the most attention as a source of therapeutic stem cells. As a result of their pluripotency, hESCs have the promise of the greatest flexibility for repair as they could be used for potentially any organ system. However, the process of isolating cells of the inner cell mass destroys the embryo, resulting in ethical considerations that have placed limits on this approach. More recently, it has been found that differentiated somatic cells could be induced back to a pluripotent state to essentially mimic the embryonic stem cells.[109,110] These so-called induced pluripotent cells (iPSCs) would theoretically be superior to hESCs for therapeutic delivery as they would be autologous cells and should not elicit immunogenicity. However, their therapeutic utility may be limited owing to the fact that they are genetically equivalent to the patient and any dysfunction or pathology due to genetic influences would still be present in the iPSCs. Nevertheless, iPSCs provide a valuable new tool to study neurodegenerative disease as patient somatic cells, such as skin cells, can be induced to pluripotency with subsequent differentiation into neurons in vitro. Access to iPSC-derived neurons from patients with specific neurodegeneration will provide unprecedented opportunities to study disease etiology and progression and to screen for therapeutic agents in vitro.

Another limitation of using truly pluripotent stem cells for therapeutic delivery derives from their potential to form teratomas. The probability of teratoma formation can be reduced by specifying lineage commitment prior to engraftment,[111] but the presence of even a single, true pluripotent stem cell within the transplant population carries risk. As a result, considerable focus has been placed on using stem or progenitor cells with more restricted fate potential isolated from tissue. Some of these cell populations, such as the hematopoietic stem cells of the bone marrow, retain a considerable range of multipotentiality and contribute both to hematopoietic and mesenchymal stem cell lineages. Bone marrow-derived mesenchymal stem cells, as well as mesenchymal stem cells derived from other sources such as umbilical cord, are being intensely investigated for their efficacy in tissue repair.[112–115] Interestingly, the ability of mesenchymal stem cells to affect repair may derive from their ability to support an environmental niche rather than directly participate in restoration by neuronal differentiation.

The second therapeutic repair strategy described above, recruiting endogenous stem cells, has an advantage over the delivery of exogenous stem cells in that cell source and immunogenicity are no longer problems. However, the major limitation of this approach centers upon our limited understanding of the signals and factors that stimulate endogenous stem cells to proliferate and regulate their subsequent differentiation. While the identification of these signals are beginning to be elucidated for neurogenic regions of the adult brain, relatively little is known regarding environmental cues that will need to be supplied to recruit stem or progenitor cells in the majority of the brain that is non-neurogenic. There is also a need to refine knowledge of the age-related changes in environmental cues[21,28] and the effect of degenerative neuropathology[116,117] that further reduce endogenous neurogenesis so that appropriate strategies to prepare the aged and/or diseased brain to accept stem cell therapies can be developed.

Obstacles to Gene Therapy

Obstacles to the successful therapeutic modulation of neurogenesis by viral gene transfer include first and foremost the need for a sufficient understanding of the genes regulating key stem cell properties (e.g., proliferation, survival, specific differentiation, recruitment). Also, one may need to know precisely which therapeutic gene is required to overcome the pathology. In addition, the changes in stem cells and their niche that occur during aging must also be understood as they could impose limitations on therapies and require approaches that compensate for age related deficiencies. Finally, an understanding of the toxic effects of the particular pathology on stem cells is critical to the development of gene therapy approaches (discussed below). Concerning technical issues related to the use of gene therapy, there are several considerations. Multiple administrations of the gene transfer vector may be necessary to maintain long-term transgene expression creating technical and immunological problems.[118] However, in the vast majority of cases this should not be an issue. This is because the nature of the currently available mainstream vectors allows for continuous transgene expression if used on long-lasting (terminally differentiated) cell populations (e.g., neurons).[119–121] If permanent transgene expression is required from replicating stem cells then integrating retroviral vectors (e.g., lentiviral) would be required.[122,123] In this case, insertional mutagenesis and oncogenesis is a variable to consider. In some cases, the use of 'suicide genes' (e.g., HSV-TK) that can be used to kill the transduced cell in the presence of an inducer (e.g., ganciclovir) may be advantageous. Finally, immune-mediated elimination of transgenic cell populations can be avoided by using current generation viral vectors (i.e., non-immunogenic) and human transgenes (i.e., self antigens).

Obstacles to Therapeutic Efficacy

Neurodegenerative diseases may share many common features, but they are not monolithic and each disease will require a tailored therapeutic approach that addresses all facets of neurological impairment. The challenges associated with developing stem cell therapies for neurodegenerative diseases is well illustrated with AD. There are two facets to understanding the stem cell therapies in AD as there exists both a widespread neuronal dysfunction and/or loss to address as well as the observation that neurogenesis is reduced in AD. It appears that the reduced neurogenesis with AD can largely be accounted for by a significant decline in both the number of neuroblasts and their proliferative capacity (reviewed in [117]). Studies in transgenic mouse models of AD showed mixed effects on neurogenesis, reflecting the plethora of transgenic models and nature of the neurogenic analyses. Regardless, a majority of studies reported reduced neurogenesis (reviewed in [117]). While AD may appear amenable to stem cell therapy, there are several obstacles to overcome. First, it is primarily a disease of synaptic loss, with neural cell death as a later stage characteristic of the disease. Therefore, delivering or inducing stem cells in the brain will not directly address the most significant aspect of AD pathology. Second, there are underlying causes of this disease that produce a toxic environment leading to neuronal dysfunction and death. Therefore, replacing lost or dysfunctional neurons in this toxic environment could be compared with pumping air into a flat tire without first patching the hole. Third, the area of degeneration in AD is very large affecting the majority of the cerebral cortex and limbic system. It is difficult to imagine how so many neurons could be properly replaced. However, it should be noted that minor regional improvements in pathology (e.g., hippocampal) could still positively affect cognition and quality of life. Furthermore, these obstacles do not mean that a therapy related to neurogenic stimulation would not be successful for AD. Indeed, it may be the case that a proneurogenic environment reduces pathogenesis (toxicity) in AD (reviewed in [117,124]). Unlike AD, PD is presumably more amenable to treatment with a stem cell (cell replacement) approach. This is primarily because it is widely believed that the cause of PD is due to neuronal cell loss in a relatively small region known as the substantia nigra, pars compacta. Assuming cell replacement would result in proper reinnervation of the striatum, cell replacement seems to be a more reasonable goal for PD. However, the problem of a toxic environment that results in cell loss would presumably persist. It is unclear if neurogenesis is suppressed or stimulated in PD and the potential of NSCs to differentiate into dopaminergic neurons in the absence of genetic or pharmaceutical manipulations is also in question. A similar conclusion can be derived for amyotrophic lateral sclerosis where the effects on neurogenesis are not clear, including the potential of natural NSCs to replace motor neurons (reviewed in [124]). Perhaps the condition most amenable to treatment using a stem cell approach is acute neuronal damage as the aforementioned caveats would not apply. This is perhaps reflected in the large number of research groups exploring stem cell approaches for more acute injury including stroke and epilepsy. Furthermore, neurogenesis is clearly upregulated in models of stroke (reviewed in [124]) suggesting that augmenting the natural response may be an appropriate therapeutic strategy.

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