Cell therapy in Huntington disease

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✓ Huntington disease (HD), caused by polyglutamate expansions in the huntingtin protein, is a progressive neurodegenerative disease resulting in cognitive and motor impairments and death. Neuronal dysfunction and degeneration contribute to progressive physiological, motor, cognitive, and emotional disturbances characteristic of HD. A major impetus for research into the treatment of HD has centered on cell therapy strategies to protect vulnerable neuronal cell populations or to replace dysfunctional or dying cells. The work underlying 3 approaches to HD cell therapy includes the potential for self-repair through the manipulation of endogenous stem cells and/or neurogenesis, the use of fetal or stem cell transplantation as a cell replacement strategy, and the administration of neurotrophic factors to protect susceptible neuronal populations. These approaches have shown some promising results in animal models of HD. Although striatal transplantation of fetal-derived cells has undergone clinical assessment since the 1990s, many cell therapy strategies have yet to be applied in the clinic environment. A more thorough understanding of the pathophysiologies underlying HD as well as the response of both endogenous and exogenous cells to the degenerating brain will inform their merit as potential therapeutic agents and enhance the framework by which the success of such strategies are determined.

Abbreviations used in this paper:BDNF = brain-derived neurotrophic factor; CNTF = ciliary neurotrophic factor; CNS = central nervous system; DARPP-32 = dopamine- and cyclic adenosine monophosphate–regulated phosphoprotein with MW 32 kD; DG = dentate gyrus; ESC = embryonic stem cell; GABA = γ–aminobutyric acid; GDNF = glial cell line–derived neurotrophic factor; HD = Huntington disease; MR = magnetic resonance; NPC = neural progenitor cell; NSC = neural stem cell; PD = Parkinson disease; PET = positron emission tomography; SVZ = subventricular zone.

✓ Huntington disease (HD), caused by polyglutamate expansions in the huntingtin protein, is a progressive neurodegenerative disease resulting in cognitive and motor impairments and death. Neuronal dysfunction and degeneration contribute to progressive physiological, motor, cognitive, and emotional disturbances characteristic of HD. A major impetus for research into the treatment of HD has centered on cell therapy strategies to protect vulnerable neuronal cell populations or to replace dysfunctional or dying cells. The work underlying 3 approaches to HD cell therapy includes the potential for self-repair through the manipulation of endogenous stem cells and/or neurogenesis, the use of fetal or stem cell transplantation as a cell replacement strategy, and the administration of neurotrophic factors to protect susceptible neuronal populations. These approaches have shown some promising results in animal models of HD. Although striatal transplantation of fetal-derived cells has undergone clinical assessment since the 1990s, many cell therapy strategies have yet to be applied in the clinic environment. A more thorough understanding of the pathophysiologies underlying HD as well as the response of both endogenous and exogenous cells to the degenerating brain will inform their merit as potential therapeutic agents and enhance the framework by which the success of such strategies are determined.

Huntington Disease Background

Huntington disease is a heritable neurodegenerative disease characterized by movement abnormalities, cognitive impairments, dementia, and affective disturbances.71 The disease presents in midlife, with progression over 20 years, eventually resulting in death.55 Pathological CAG expansions within exon 1 (the coding region) of the huntingtin gene (Htt) on the short arm of human chromosome 4 results in the progressive degeneration of basal ganglia (caudate nucleus and putamen), cerebral cortex, brainstem, spinal cord, thalamus, and hypothalamus (Fig. 1).6 Although the hallmark of HD is the progressive loss of medium spiny GABAergic neurons in the striatum,155,156 the degeneration of cortical and hippocampal neurons131,155 also contributes to disease progression and the cognitive deficits observed in HD and probably occurs in parallel with striatal loss from disease onset.

Fig. 1.
Fig. 1.

Diagram showing molecular disease progress in HD.

Although the HD gene was identified more than a decade ago,6 the function(s) of a normal htt and the biochemical processes through which mutant htt causes HD have not been fully elucidated. Whereas the aggregation of mutant htt appears to be cell autonomous,68 the persistent presence of the mutant htt protein and pathological cell–cell interactions are necessary for the development of significant neurodegeneration and functional deficits.68,69,159 Although HD appears to be a relatively simple model of neurodegeneration, its underlying cellular pathophysiologies and the consequences of mutant htt are complex.

As no cure is currently available, management of symptoms is the primary goal in treating HD. Disease-modifying therapies—for example, small interfering RNA, pharmacological intervention, and modulation of autophagy—target pathogenic pathways, whereas cell replacement therapies attempt to replace dysfunctional or dying cells primarily through transplantation (Fig. 2). Cell therapy strategies in HD have traditionally been aimed at replacing or protecting cells lost during the course of the disease and thereby preventing or retarding disease progression. Current work in HD cell therapy is broadly classified into 1 of 3 aims: 1) to harness the ability of the brain to self-repair through the upregulation of endogenous stem cells/neurogenesis; 2) to replace dead and/or dying neurons through fetal or stem cell transplantation; and 3) to protect neurons vulnerable to disease progression through the administration of neuroprotective trophic factors via cell or viral delivery. Although the manipulation of endogenous self-repair has garnered attention only recently, clinical trials of fetal-derived cell transplantation in the striatum have been performed since the 1990s in patients with HD. However, a more cogent understanding of the pathological processes that give rise to HD and the behavior of both endogenous and exogenous cells in the diseased brain will contribute to not only additional or improved therapeutic strategies, but also a better context through which the success of therapeutic manipulations can be analyzed and understood.

Fig. 2.
Fig. 2.

Drawing illustrating therapies in HD. Sites of cell degeneration (caudate and putamen) in HD appear in red, and ongoing adult neurogenesis in the human brain appears in green. Target of fetal-derived cell transplantation into the diseased striatum is represented by the syringe. CoQ10 = coenzyme Q10; iRNA = interfering RNA. Illustration by Mick Cafferkey.

Restoring or Manipulating Neurogenesis as Endogenous Cell Therapy in HD

One focus of cell therapy has been to understand the deficits in endogenous stem cell regulation in HD, primarily in the adult hippocampal DG and SVZ, with the aim that restoring or upregulating endogenous neurogenesis may partially ameliorate disease symptoms and repair the damaged brain.

Neurogenesis occurs in the hippocampus and SVZ of adult mammals, including humans (Fig. 3).2,3,53 Neural stem cells in the SVZ–olfactory bulb and DG can differentiate into all lineages of the adult CNS including neurons.61,82,95,116 Furthermore, endogenous NSCs outside the 2 standard neurogenic regions have been shown, in some instances, to have the capacity to differentiate into neurons and integrate appropriately in regions undergoing cell death.10,30,104 Neurodegeneration or injury can upregulate proliferation11,80,119 and promote the migration of newborn cells to the site of damage.10,99,119 However, it is not clear if this increase in cell genesis is neuroprotective and/or linked to functional recovery, if the increase is of a magnitude to be of therapeutic value, or if this upregulation in proliferation represents pathological network reorganization (as some seizure models have indicated).120,135

Fig. 3.
Fig. 3.

Drawing depicting sites of neurogenesis in the rodent brain. A: Newborn hippocampal neurons (blue) are born in the subgranular zone of the hippocampus and migrate into the granule cell layer of the DG as they mature and integrate. B: Neurons (blue) originate in the SVZ lining the lateral ventricles and migrate via the rostral migratory stream (RMS) to the olfactory bulb. CA1 = cornu ammonis 1 of the hippocampus proper; CA3 = cornu ammonis 3 of the hippocampus proper; GCL = granule cell layer; GL = glomerular layer.

Neural stem cells in the SVZ and hippocampal subgranular zone develop into electrically mature and fully integrated neurons.28 In the subgranular zone of the hippocampus, progenitor cells become neurons predominantly and functionally integrate into the DG.27,78,151 Neural precursor cells originating in the SVZ of the lateral ventricle migrate tangentially through the rostral migratory stream, guided by astrocytes34,100,158 to the olfactory bulb where they become fully differentiated and electrically competent.96 Neurogenesis has been implicated in learning and memory65,138,150,151 and may be necessary for the functional integrity of the circuits into which new cells generate.34,138 The rate of neurogenesis in adult mammals is dynamically regulated by a variety of physiological and pathological factors.11,80,119,150 The microenvironment plays a key role in maintaining the neurogenic potential of the adult brain;19,117,136 it also plays a role in the fate restriction of endogenous NSCs in neurogenic regions.95,137,145

Abnormalities in adult neurogenesis as exhibited in both HD transgenic mice63,64,89,90,124,146 and humans35–37 may have clinical relevance for patients afflicted with HD. Although striatal pathophysiology contributes to some motor and cognitive defects in patients with HD,5 nonstriatal pathology, especially of the hippocampus, may mediate aspects of affective and cognitive deficits in HD.35,121,131 Neural progenitor cell proliferation, survival, and structure are abnormal in the DG of mice transgenic for the human HD gene,63,64,89,90,124 an effect that can be partially restored by environmental enrichment.90 Environmental enrichment or physical activity, which modulates the proliferation and survival of newly formed neurons, improves motor and cognitive deficits in HD transgenic mice models.118,143,148 However, it remains to be clearly determined whether a partial restoration of neurogenesis following environmental enrichment directly contributes to behavioral changes in HD mice.

Local conditions of the microenvironment, including factors released by astrocytes, play a crucial role in neurogenesis.94,139 Dysregulation of this environment in the degenerating brain can result in a nonpermissive environment for neurogenesis.8,73 Despite the expression of mutant htt, the proliferation, longevity, differentiation, and survival of NPCs derived from the hippocampus and SVZ of HD transgenic mice are similar to those of wild-type–derived NPCs in vitro,67,124 suggesting that abnormalities in neurogenesis in vivo are due to the microenvironment in which the NPC resides and not the intrinsic properties of the precursor itself. Although there is no change in basal SVZ NPC proliferation or maturation in a rodent model of HD, the absence of increased proliferation of SVZ NPCs in response to quinolinic acid indicates deficits in the SVZ microenvironments.124 However, Phillips and colleagues (unpublished data, 2007) have demonstrated that adult neurogenesis in the SVZ is responsive to the induction of stroke in an HD model in rodents.

Although little work has been done on the effect of HD on adult human hippocampal neurogenesis, the SVZ in adult humans with HD has been well characterized. Increased cell proliferation in, and the thickness of, the SVZ correlate with pathological grade and CAG repeat length.35 It is unclear whether this increase in proliferation is a protective response by the CNS to replace or protect damaged cells in the striatum or whether the upregulation in neurogenesis contributes to pathology in the striatum. Most of the cells born in the diseased SVZ exhibit phenotypes of glial cells (progenitors or mature glial fibrillary acidic protein–positive astrocytes) with fewer neurons.35,37 Furthermore, this effect is region specific—there is increased proliferation in the central and ventral regions of the SVZ, whereas striatal atrophy occurs mostly in the dorsal region.36 The birth site of new neurons in proximity to the degenerating striatum as well as the upregulation of neurogenesis in this region in response to damage in HD raises the possibility that the brain can at least partially compensate for neurodegeneration. Indeed, in a rat lesion model of HD, SVZ progenitor cells have been shown to migrate from the site of their inception toward the lesion.146 A better understanding of the mechanisms underlying adult neurogenesis within the context of HD would contribute to our ability to harness the therapeutic potential of these cells.

Strikingly, the beneficial impact on cognitive and motor behavioral measures through the restoration of adult neurogenesis in rodent models of HD has revealed the therapeutic potential of endogenous NPCs. The induction of neurogenesis through trophic factors or antidepressant treatment has alleviated motor and cognitive deficits in rodent models of HD. In a mouse model of HD, treatment with fibro-blast growth factor–2, a neuroprotective growth factor, increased cell proliferation by 150% in the SVZ (compared with 30% in wild-type littermate controls) and was accompanied by an increase in immature doublecortin-positive neurons and a decrease in aggregations formed by mutant huntingtin protein. These cells migrated to the striatum (the primary site of pathology) and formed projections. Improved motor performance on a test for motor coordination (rotarod) and extended lifespan were also observed.79 Cognitive and hippocampal neurogenic deficits in HD transgenic mice can be rescued (that is, return to normal or near-normal levels of behavior) by chronic administration of the antidepressant fluoxetine without affecting motor deficits characteristic of HD67 and thus suggesting that in addition to striatal pathology, secondary abnormalities in adult hippocampal neurogenesis play a role in the affective symptoms of HD. This finding is in line with the dependency of behavioral outcomes on hippocampal neurogenesis following antidepressant treatment.134 Finally, the forced induction of neostriatal neurogenesis also slows disease progression and alleviates motor and cognitive impairments in a mouse model of HD.32

By correcting abnormalities in adult hippocampal neurogenesis or manipulating endogenous neurogenic regions to contribute to the repair of degenerating neuronal populations, it is theoretically possible to nonsurgically treat both the underlying pathologies and the cognitive and motor symptoms of HD.

Transplantation of Fetal-Derived Cells as Exogenous Cell Therapy in HD

One of the most studied areas of HD cell therapy is the transplantation of fetal-derived cells into the brain of a symptomatic patient with HD. Extensive work on the safety and efficacy of the transplantation of fetal striatal allografts into a diseased adult brain has been completed in both rodent and primate models, and several clinical trials have been performed since the 1990s. Although full recovery has not been observed following fetal allografts in the striatum of humans with HD, some suggestions of delayed disease progression indicate positive functional outcomes.12,13 The contribution of these grafts to functional recovery is enhanced by the fact that implanted cells, lacking the disease-causing gene, do not themselves appear vulnerable to neurodegenerative processes,56,83 an effect that is also seen in transplants in patients with PD.86,87,126

All clinical trials to date have been focused on the transplantation of fetal-derived cells into the diseased striatum. Because HD pathophysiology involves several brain regions, including nonstriatal sites, cell implantation into the striatum alone may limit the ability of grafts to address or reverse HD symptoms. Whereas grafted regions are relatively spared from neurodegeneration, surrounding brain regions continue to degenerate,13 which may limit the functional outcome of transplantation. Furthermore, the timing of transplantation may be crucial to the functional benefits of the graft; the majority of patients involved in clinical transplantation trials have had mild to moderate HD, and the impact of the disease stage on transplant efficacy remains to be measured.

Much evidence has accumulated about the efficacy of fetal-derived cell transplantations in animal models of HD. All striatal cell types from the allo-and xenotransplantation of fetal- or embryonic-derived striatal tissue have been shown to survive, grow, and establish functional afferent and efferent connections to host tissue25,98,101,126 and display appropriate electrophysiological properties25,29,113 in both rodent25,45,77,113 and primate models70,84 of HD. Although the authors of 1 study have reported no clinically relevant behavioral improvements following striatal grafting in a transgenic mouse model of HD,45 others have demonstrated that behavioral motor deficits18,54 are improved by the transplantation of striatal tissue into the degenerate striatum of rodents113 and primates.70,84 Both pre- and postoperative motor training in animal models of HD have also had a significant impact on functional recovery, presumably by enhancing the plasticity of grafts and host circuitry.41–44 In primates, striatal allografts and xenografts survive, differentiate into mature DARPP-32–positive striatal cells, and receive dopaminergic innervation.70,84,115 These changes are correlated with improvements in both motor performance,70,84 including recovery in a test of skilled motor performance,84 and cognitive function.115 Cellular and behavioral improvements following fetal-derived striatal cell transplantation are thought to occur through circuit reconstruction, the normalization of neurotransmitter release, and/or the production of trophic factors.25,47,92,113

Transplantation to regions outside the striatum has garnered little attention even in animal models of HD. Whereas medium spiny striatal neurons degenerate early in HD, pronounced degeneration is also observed in cortical areas, which densely innervate the striatum.147 In this respect, van Dellen and colleagues149 have demonstrated the potential therapeutic benefit of targeting the host cortex as a site of transplantation. Wild-type fetal cortical cells were transplanted into the anterior cingulate cortex of neonatal HD transgenic mice. This therapy delayed the onset of an overt motor deficit (rear paw clasping) but did not enhance motor coordination as assessed with a rotarod. This study highlights the potential benefit of targeting the widespread pathophysiology of HD, not just neurodegeneration in the striatal regions, as it may allow preservation of striatal function through the delivery of neuroprotective trophic factors, such as BDNF, from spared nonstriatal regions that project to the striatum.

Clinical trials involving the transplantation of fetal striatal tissue in humans were begun in the late 1990s. As in animal models of HD, most transplanted tissue was derived from the human fetal striatum (whole or partial ganglionic eminence) and transplanted into the host striatum.72,133,157 The amount and cellular composition of the transplanted cells must be regulated, as transplants with < 30% striatal content are ineffective, and the selective dissection of striatal primordial tissue (that is, the lateral region of the lateral ganglionic eminence) has proven disappointing from a functional perspective.23 As in PD,97,142 the safety of allografts of fetal striatal neural tissue has been demonstrated in HD.12,72,85,133 Similar to its successful use in cell therapy for PD,87 hibernation medium used to store harvested cells for up to 8 days has allowed the collection of adequate amounts of tissue and the flexibility to prepare tissue at sites and times other than the site and time of transplantation surgery.74,76 The use of tissue previously stored in hibernating medium has had no major adverse effects on subsequent transplantation performed according to this validated protocol.133

Graft survival has been reported in several clinical trials.85,132 Magnetic resonance imaging has been successfully used to locate and monitor the growth of grafted tissue,125 and metabolic assessment has also been effective in evaluating the efficacy of transplantation. Tissue at the site of grafting has been shown on MR imaging to increase in growth by 6 months posttransplantation, without overgrowth.133 Furthermore, inferences regarding the health of the graft, based on MR spectroscopy and PET, suggest that graft sites are populated by adult neurons that are metabolically active.59,132 For example, the maturation of transplanted cells led to the stabilization of brain striatal and cortical metabolism in 3 of 5 patients receiving bilateral fetal striatal grafts in an open-label study. In the remaining 2 patients, striatal and cortical hypometabolism progressed.62 However, reductions in metabolic activity, including a significant loss of dopamine receptor binding, have been documented in patients 2 years following intrastriatal transplantation of fetal-derived cells.59 A 7% decline in striatal metabolism was observed on fluorine-18–labeled fluorodeoxyglucose–PET over a 6-year period in patients who had received functional benefit from the transplants;13 although not significantly different, this decline was lower than the average for patients with HD who did not receive implants.88 On average, dopamine receptor (D2) binding declines by 5–15% in control patients with HD as measured on PET.121 In general, increases in hypometabolism in patients with HD who have received transplants are consistent with those in control patients with HD, although 1 patient showing clinical improvement after transplantation also showed improvement on striatal raclopride PET scans (unpublished data, 2008). In addition, postoperative FLAIR imaging showed a persistent signal that could represent grafted tissue, host reaction (gliosis), or both (Fig. 4).

Fig. 4.
Fig. 4.

Fluid attenuated inversion recovery MR image obtained in a patient with HD who had received a graft of fetal-derived striatal tissue into the caudate and putamen, showing the patient's status 3 (A), 8 (B), 13 (C), and 32 months (D) after transplantation. The origin of the apparent persistent signal along the impact tract is unknown but may represent surviving donor tissue or host glial reaction.

Postmortem histological evidence for the survival and integration of fetal-derived cell striatal transplantation has also been reported in 3 patients who died between 18 and 79 months after the procedure.72,83 Fetal lateral ganglionic eminence was bilaterally grafted into striata with HD. Autopsy results revealed that grafts were clearly demarcated83 and grew to 5–10% of the normal human caudate putamen tissue volume after 18 months in 1 patient.72 Grafted cells displayed morphological features characteristic of both the developing and the mature striatum72,83 and were innervated by appropriate host target regions,72 although the presence of efferents was very limited in the tissue from patients surviving > 6 years after transplantation, despite minimal gliosis within the grafted tissue.83 Notably, grafted fetal striatal cells survive, develop, and integrate into host tissue without being affected by the disease process itself; that is, no mutant huntingtin aggregates were observed within the transplanted region, and the graft showed no signs of immunological rejection.56 The sparing of grafted tissue from disease progression has also been reported in other transplant cases, including in patients with PD.86,87,126

The success of allografts of fetal-derived striatal tissue in patients with HD hinges on motor and cognitive improvements following transplantation.12–15,85,103,125 Improvements on the Unified Huntington's Disease Rating Scale motor score have been reported as early as 1 month after unilateral grafting of fetal-derived striatal tissue12 and have stabilized between 6 months85 and 2 years13 after transplantation. Patients assessed up to 6 years after bilateral transplantation have demonstrated that immediate improvements in motor scores (between 6 months and 2 years) may not persist long term. However, the rate of motor and cognitive decline may be reduced in some patients who have undergone transplantation. Of those patients exhibiting initial functional and metabolic benefits from transplantation in the Creteil clinical trial, clinical improvement reached a plateau after 2 years and declined variably from 4 to 6 years. Dystonia progressed more rapidly and consistently than other motor symptoms, but transplantation of fetal-derived striatal tissue appeared to alleviate choreatic symptoms. Cognitive performance was also stabilized on nontimed tests in these patients. The remaining 2 patients who showed neither metabolic nor functional improvement at the initial 6 month follow-up continued to decline over the 6-year course of study at a rate similar to that seen in patients with HD who had not received transplants.13–15 Variability in graft integration and functional recovery has been a common feature in HD transplant trials.

In addition to the risk of host rejection,17,133 the main surgical risk to cell transplantation in HD has been subdural hemorrhages, which have occurred in 1 clinical trial.72 Of the 7 patients in this trial, all receiving bilateral implants of fetal-derived striatal tissue, 3 had subdural hemorrhages and 2 required surgical drainage.72 It is important to note that this study involved patients with more advanced symptomatic HD than in other analyses, as well as an increased surgical risk and complications due to greater degeneration and increased atrophy of the brain. However, the role of atrophy as a risk factor for complications from neural grafting in HD or any neurodegenerative disorder remains speculative. Other clinical trials have included patients in earlier stages of the disease, which reduces the risks of this complication.133 Complications from immunosuppressive drug treatment following transplantation have been generally predictable with largely reversible side effects133 and thus have not been a major safety concern. However, the issues of whether immunosuppressive therapy is needed for intracerebral transplantation and the optimal duration of immunosuppressive treatment have not been resolved.17

The use of fetal-derived striatal cells for transplantation has shown that grafts into the degenerative adult brain are safe and at least partially efficacious in terms of some immediate functional response. However, this approach seems to be less viable over the long term. In addition to the ethical and practical considerations regarding the source of cells for human fetus–derived allografts and the limited repair potential of striatal-only grafts, many groups have turned to alternative strategies for obtaining cells for therapy in HD, the most notable of which has been the utilization of stem cells.

Stem Cell–Based Cell Therapy in HD

Stem cell therapy in the adult brain with HD has received increasing attention for its potential to mitigate pathological neurodegeneration by replacing lost neuronal and/or nonneuronal populations, by triggering endogenous repair mechanisms, or by protecting existing cells primarily through trophic support.57,58,75,106 Stem cell transplantation is a promising field in cell therapy for HD as stem cells are relatively easy to obtain compared with primary fetal tissue and have the potential to be manipulated to eliminate possible problems of host rejection. Neural stem cells can be isolated from the fetal, neonatal, and adult brain and propagated in culture.24,129 Like ESCs, NSCs can give rise to all 3 major cell types of the CNS; unlike ESCs, however, NSCs exhibit little risk of tumor formation following transplantation. Grafted NSCs can develop both morphological and electrical properties of mature neurons and integrate into host circuitry.52 Transplanted immature neurons or embryo-derived NPCs have been shown to migrate toward the site of degeneration, differentiate, and form synaptic connections in several models of neurodegeneration.46,106,149 Transplanted ESCs can differentiate into neurons in the HD-affected striatum and appear to migrate to nearby cortical regions where they have been found to express markers of immature neurons.141

Most of the recent work in stem cell therapy has been conducted in animal models of HD. However, protocols and procedures developed from trials of fetal-derived cell transplantation in humans with HD will lay the groundwork to move stem cell therapy into the clinic. One of the first challenges to stem cell therapy in HD is to determine which source of stem cells is most efficacious, and many sources have been examined. In addition to human ESCs (discussed later), stem cells derived from mesenchyme in adults have been investigated as a readily available source of stem cells in HD.51,91,152 Whereas few neurons have been formed from mesenchyme-derived stem cell grafts, transplantation of these grafts has elicited some behavioral recovery.91,152 Similarly, xenotransplantation of adult peripheral precursor cells originating from porcine Sertoli cells of the testes has shown the rescue of locomotor impairments in an HD lesion model in rats, probably acting through neuroprotection given the effectiveness after only a short time.130

Murine and human NSCs have also been utilized as cell therapy sources for rodent and primate models of HD, with varying degrees of success. After grafting, mouse- and human-derived cells have differentiated into cell types appropriate to the site of transplantation in several degenerative models, including rodent models of HD, predominantly forming astrocytes with a small number of neurons.46,81,106,141,154 Neural stem cell treatments have resulted in either full106,141 or partial154 functional recovery in tests of lesion-induced impairment. Transplanted human- and mouse-derived NPCs in an excitotoxic HD lesion model not only have survived in the striatal site of implantation, but also have migrated81 and stained for markers of immature neurons in cortical regions.141 Following transplantation into a mouse model of HD, murine ESC-derived NPCs, genetically modified to promote neuronal differentiation, formed GABAergic neurons with appropriate outgrowth. The grafts were also functionally beneficial given that the animals showed improvement in rotational behavior.21 Human NSCs appear to behave similarly to murine-derived NSCs in rodent models of HD. Intravenously transplanted human NSCs migrate to the striatum, reduce striatal atrophy, and contribute to functional improvement in a rodent lesion model of HD.109,141 Note that DARPP-32 medium spiny neurons and fiber outgrowth have also been observed following transplantation of human NPCs in an animal model of HD.9

The differentiation of stem cells or treatment with growth factors in vitro prior to implantation may facilitate fate determination while mitigating the risk of tumor formation posed by stem cells.39,106,141 A protocol in which mouse embryonic cells directed toward a GABAergic fate retain their neuronal identity after transplantation into a rodent lesion model of HD has proven successful. However, undifferentiated ESCs show little differentiation over a 6-week time course.40 Additionally, stem cell therapy has the potential to alleviate cognitive deficits in degenerative disease, such as memory impairment,160 through the replacement of degenerating cells and the restoration or preservation of proper network function.

Although the gold standard in stem cell treatment has been the production of neurons, the differentiation of transplanted cells into nonneuronal lineages, such as astrocytes, may serve neuroprotective or regenerative roles in degenerative environments. Additionally, there is at least corollary evidence that diseased glial cells contribute to HD pathophysiology.147,161 Endogenous or transplant-derived nonneuronal cells must be included in any consideration of the efficacy of stem cell therapy in HD. In neurogenic regions, astrocytes interact with NSCs and NPCs136,139 to promote proliferation and fate determination139 and may stimulate the maturation and integration of newly formed neurons.139,140 The contribution by nonneuronal cells may be particularly relevant in regions affected by HD in which it is hypothesized that abnormalities in the microenvironment, rather than neuron intrinsic properties, primarily contribute to the degenerative environment.124

Taken together, results from initial stem cell therapy investigations have indicated that stem cells are viable cell sources for transplantation in animal models of HD. However, factors that control the differentiation, survival, and maturation of stem cells in the context of a host degenerative brain must be more thoroughly understood before stem cell therapy will prove to be a robust and safe strategy that can be transferred to the clinic.

Manipulation of Endogenous or Exogenous Trophic Factors in HD Cell Therapy

A concurrent aim of stem cell therapy in HD is the use of growth factors or transplanted cells to protect neurons susceptible to disease and/or death. Because trophic factors are large molecules that do not readily cross the blood-–brain barrier, stem cell transplantation and viral delivery of trophic factors have been investigated as means of delivering support to cells susceptible to degeneration. Transplanted stem and progenitor cells can promote the survival of host cells by releasing neuroprotective trophic factors such as BDNF, CNTF, and GDNF.102,114

Brain-derived neurotrophic factor plays a role in HD neuronal degeneration and the survival and differentiation of endogenous and exogenous NSCs. Neural stem cells are responsive to BDNF,20,33 and BDNF itself participates in cell differentiation.112,153 Cortically derived BDNF is an important survival molecule for striatal projection neurons,123,144 and BDNF is responsive to lesioning of the rodent striatum.16,26 Reductions in cortical BDNF mRNA164 and defective transport60 underlie decreased striatal BDNF and correlate with HD progression in a transgenic mouse model of HD164,165 and brain tissue in humans with HD.163 Furthermore, BDNF knock-out models recapitulate HD pathogenesis in humans,144 suggesting a key role for BDNF in HD progression. Virally overexpressed BDNF enhances proliferation of endogenous precursor cells and protects against subsequent toxic insult to striatal neurons.19 Similarly, environmental enrichment was shown to rescue striatal and hippocampal BDNF deficits in a transgenic mouse model of HD and to improve motor functioning.143 Taken together, these results are encouraging in that the regulation of abnormal BDNF production, either through endogenous or exogenous manipulations, may improve motor function in HD models.

Ciliary neurotrophic factor is a neuroprotective cytokine that protects striatal neurons—particularly vulnerable GABAergic striatal neurons—from excitotoxic lesions while simultaneously preventing behavioral deficits in both rodent and nonhuman primate excitotoxic lesion models of HD.4,38,48,49 Cellularly delivered CNTF may also have neuroprotective benefits to neurons wired to the site of delivery, such as cortical neurons, or those of the globus pallidus and substantia nigra pars reticulata, 2 regions receiving striatal efferents.50 The intrastriatal infusion of CNTF via baby hamster kidney–1 cells engineered to produce CNTF through semipermeable membranes protects cells from degeneration and restores cognitive and motor functions in a lesion model of HD in primates.110 Because these cells are encapsulated, this method is particularly creative in that it allows for the continuous production and release of growth factor(s) without the risks of tumor formation and immune rejection. Similarly, the use of cells engineered to produce CNTF has been assessed in Phase I trials in humans with HD. However, clinical improvements were not observed in patients receiving this treatment, although the technical issues of maintaining sustained release and adequate levels of CNTF may underlie this result.22 Finally, adeno- and lentiviral delivery of CNTF preserves striatal neurons and circuits when the factor is injected prior to excitotoxic injury in rodents.111,128 However, conflicting results have been found in a progressive model of HD in mice by using a viral CNTF strategy.162 Ciliary neurotrophic factor is thus likely to be most beneficial as a neuroprotective agent when delivered prior to the onset of degeneration. In the clinical setting, however, treatment prior to the onset of disease raises a host of ethical questions.

Astrocytes can rescue damaged neurons,31 and such protection is thought to involve the release of growth factors, such as GDNF.93,105 Neurons and astrocytes are responsive to GDNF, especially after injury,105 and GDNF protects striatal medium spiny GABAergic neurons from excitotoxic injury in rodent models of HD.66,107,122 Neural stem cells and fibroblasts genetically modified to deliver GDNF and transplanted into sites of excitotoxic lesions protect striatal neurons from degeneration,7,122,127 an effect similar to that observed in PD models.1 Glial cell line–derived neurotrophic factor–secreting NSCs also partially restore functional deficits in neurotoxic lesioned mice.127 Viral GDNF delivery into the striatum of presymptomatic transgenic mice with HD preserves striatal neuronal cells from degeneration, decreases the percentage of neuronal cells with mutant htt inclusions, and ameliorates behavioral deficits (hand clasping and accelerating rotarod).107,108

The use of growth factors, administered virally or through transplanted engineered cells, has the potential to protect vulnerable neuronal cells in the degenerative HD-affected brain. Brain-derived neurotrophic factor, CNTF, and GDNF have been investigated for their neuroprotective effects, primarily in animal models of HD, with promising results. Except for 1 clinical trial in which there was no clinical improvement, the use of growth factors as a clinical therapy has not yet been addressed.

Conclusions

In addition to research exploring the pathological processes underlying HD, ongoing studies of the benefits of cell therapy inform potential therapeutic strategies to manage and understand this neurodegenerative disease. Cell therapies in HD are intended to protect neuronal populations susceptible to disease and/or replace dysfunctional or dying neurons. Clinical progress in HD cell therapy to date has been centered on establishing protocols for transplanting fetal-derived cells into the diseased striatum; however, this strategy is laying the foundation for stem cell therapy in the clinic. Although both exogenous stem cell therapy and the manipulation of endogenous cells for self-repair are in inchoate stages, these strategies create new and promising approaches to both the treatment and management of HD. By ameliorating or reversing abnormalities in adult neurogenesis or harnessing endogenous stem cells to participate in the self-repair of degenerating neuronal populations, it is theoretically possible to treat both underlying HD cellular pathophysiologies and symptoms. Transplantation of fetal-derived cells into degenerative striatal regions has proven safe and at least partially effective in patients with HD. However, the benefits of fetal-derived cell transplantation in HD seem to center around delaying, rather than reversing, disease processes. The use of both stem cell– and growth factor–based therapies, although in its early stages, appears likely to contribute to future clinical strategies, including, but not limited to, neuroprotective and neuron replacement approaches.

Acknowledgments

We thank Keaton Norquist, James Kelly, and Fardad Afshari for their helpful comments on our manuscript.

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The HD work was supported by grants from the Hereditary Disease Foundation and Medical Research Council (R.A.B. and C.W.) as well as The HighQ Foundation (R.A.B.). This work was also supported in part by a Marshall Scholarship and a Jack Kent Cooke Fellowship (C.D.C.).

Article Information

Address correspondence to: Colin Watts, M.B, B.S, Ph.D., F.R.C.S., Cambridge Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 2PY, United Kingdom. email: cw209@cam.ac.uk.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Diagram showing molecular disease progress in HD.

  • View in gallery

    Drawing illustrating therapies in HD. Sites of cell degeneration (caudate and putamen) in HD appear in red, and ongoing adult neurogenesis in the human brain appears in green. Target of fetal-derived cell transplantation into the diseased striatum is represented by the syringe. CoQ10 = coenzyme Q10; iRNA = interfering RNA. Illustration by Mick Cafferkey.

  • View in gallery

    Drawing depicting sites of neurogenesis in the rodent brain. A: Newborn hippocampal neurons (blue) are born in the subgranular zone of the hippocampus and migrate into the granule cell layer of the DG as they mature and integrate. B: Neurons (blue) originate in the SVZ lining the lateral ventricles and migrate via the rostral migratory stream (RMS) to the olfactory bulb. CA1 = cornu ammonis 1 of the hippocampus proper; CA3 = cornu ammonis 3 of the hippocampus proper; GCL = granule cell layer; GL = glomerular layer.

  • View in gallery

    Fluid attenuated inversion recovery MR image obtained in a patient with HD who had received a graft of fetal-derived striatal tissue into the caudate and putamen, showing the patient's status 3 (A), 8 (B), 13 (C), and 32 months (D) after transplantation. The origin of the apparent persistent signal along the impact tract is unknown but may represent surviving donor tissue or host glial reaction.

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