Comment
Stem cell therapy for Alzheimer’s disease: hope or hype? Alzheimer’s Disease International estimated that, in 2015, 46·8 million people worldwide are living with Alzheimer’s disease, with a global cost of US$818 billion.1 At present, no disease-modifying therapies are available; this unmet need, combined with failures of several recent clinical trials, highlights a need for improved disease models and novel approaches for therapeutic intervention. In The Lancet Neurology, Joshua Hunsberger and colleagues2 review progress in the use of stem cells for disease modelling, drug discovery, and therapeutic intervention in Alzheimer’s disease, and make a case for the acceleration of clinical trials in this area. It is the use of stem cells as disease models that perhaps has the most to offer in terms of immediate gain, and the most exciting development is the potential to assay potential therapeutics with induced pluripotent stem cells (iPSCs). The generation of iPSCs from patients with genetic lesions in the disease-related genes APP and PSEN1 has revolutionised in-vitro modelling of dementia, providing a limitless source of patient-specific neurons that can feature disease-linked genotypes.3 As reviewed by Hunsberger and colleagues,2 several independent groups have established Alzheimer’s disease-relevant phenotypes in vitro with this approach, and the identification of both amyloid-β (Aβ) and downstream tau pathologies in neurons generated from patients with mutations in APP or PSEN1 is especially encouraging, since recapitulation of these two pathological hallmarks in murine disease models has been difficult without overexpression of multiple mutated genes.4 These iPSC-derived neurons can now be used in detailed mechanistic studies to understand the earliest molecular signatures of disease, and as a drug-screening platform to identify small molecules that modify well established cellular phenotypes linked to Aβ and tau pathologies. The results obtained with iPSC disease models have generally been positive, but several shortcomings remain. Accumulating evidence from neuropathological studies and the identification of microglial-enriched genes such as TREM2 as risk factors5 lend support to a non-cell-autonomous cause for Alzheimer’s disease with astrocyte and microglial involvement. Co-culture models that allow the contribution of different cell types to the disease process to be investigated will be
necessary. Further, the maturity of neurons generated from iPSCs is widely debated in the context of both gene expression and electrical activity. Of particular relevance to Alzheimer’s disease is the finding that the expression profile of tau remains fetal-like in iPSC-derived neurons until 1 year in culture.6 Even in cases of familial disease with the earliest onset, the disease only manifests clinically several decades after the onset of pathology and structural changes—how effectively will iPSCs recapitulate the full time course of disease-associated molecular changes? The potential of iPSCs to model sporadic Alzheimer’s disease, which represents the majority of cases, is also understudied, although early reports have shown in-vitro phenotypes in neurons from patients with sporadic disease and preliminary evidence that iPSC-derived neurons could be used to stratify patients according to differential drug responsiveness.7 Emerging evidence from preclinical models supports further investigation of stem cells as therapeutics. The therapeutic potential of several cell types, including bone marrow-derived mesenchymal stem cells, adipose-derived stem cells, and neural stem cells, has been studied in animal models of Alzheimer’s disease, and beneficial outcomes include the removal or reduction of disease pathologies, reversal of memory deficits, integration of donor cells into host neuronal circuitry, and provision of trophic support from donor cells to remaining neuronal circuits. Hunsberger and colleagues2 conclude that replacement of widespread neuronal loss is unlikely, but the potential benefit of stem cell therapies to reinforce remaining circuits and slow disease progression remains great enough to warrant further study. Ongoing multicentre initiatives to coordinate clinical trials of stem cell therapies for other neurological disorders such as Parkinson’s disease will help to inform some of the key questions regarding safety, delivery, dosage, and efficacy.8 Despite promising preclinical data, numerous challenges need to be overcome before stem cell therapies for Alzheimer’s disease can become a reality in the clinic. Safety concerns include rejection of transplants and the proliferative capacity of stem cells, which increases the risk of tumorigenicity. These concerns could potentially be addressed by the
www.thelancet.com/neurology Published online December 15, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00382-8
Lancet Neurol 2015 Published Online December 15, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00382-8 See Online/Personal View http://dx.doi.org/10.1016/ S1474-4422(15)00332-4 For Alzheimer’s Disease International see https://www. alz.co.uk/
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Comment
generation of a HLA haplobank of cell lines to minimise rejection risk, and by harnessing the cells’ apoptotic machinery to trigger autodestruction if proliferation becomes excessive.9 The cost of production of clinical-grade cells for therapy is likely to be prohibitive to widespread use, making the approach to identify small molecules with iPSC models more attractive. Finally, a key remaining question is how would one identify which patients should receive cell-based therapies? It is clear that the development of disease pathology and associated neuronal loss occur years before symptom onset, and data suggest that unsuccessful therapies in phase 3 trials might in fact be beneficial if intervention occurs earlier in the disease process.10 Whatever approach is taken, early and accurate diagnosis leading to early intervention will be essential. In conclusion, although many questions remain, stem cells have great potential to enhance our understanding of the molecular basis of Alzheimer’s disease and provide a platform for the discovery of novel therapeutics. Long-term studies will ascertain whether stem cell therapies will contribute to the growing arsenal of potential therapeutics at our disposal, but these prospects are unlikely to be realised in the short term despite the hype.
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*Selina Wray, Nick C Fox Department of Molecular Neuroscience (SW) and Dementia Research Centre, Department of Neurodegeneration (NCF), UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [email protected] We declare no competing interests. 1
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Prince M, Wimo A, Guerchet M, et al. World Alzheimer Report 2015—The global impact of dementia: an analysis of prevalence, incidence, cost and trends. London: Alzheimer’s Disease International, 2015. https://www.alz. co.uk/research/WorldAlzheimerReport2015.pdf (accessed Dec 1, 2015). Hunsberger J, Rao M, Kurtzberg J, et al. Accelerating stem cell trials for Alzheimer’s disease. Lancet Neurol 2015; published online Dec 15. http://dx.doi.org/10.1016/S1474-4422(15)00332-4 Livesey FJ. Human stem cell models of dementia. Hum Mol Genet 2014; 23: R35–39. Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles. Neuron 2003; 39: 409–21. Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 2013; 368: 117–27. Sposito T, Preza E, Mahoney CJ, et al. Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Hum Mol Genet 2015; 24: 5260–69. Kondo T, Asai M, Tsukita K, et al. Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell 2013; 12: 487–96. Barker RA, Studer L, Cattaneo E, Takahashi J, G-Force PD consortium. G-Force PD: a global initiative in coordinating stem cell-based dopamine treatments for Parkinson’s disease. NPJ Park Dis 2015; 1: 15017. Barry J, Hyllner J, Stacey G, Taylor CJ, Turner M. Setting up a haplobank: issues and solutions. Curr Stem Cell Rep 1: 110–07. Liu-Seifert H, Siemers E, Holdridge KC, et al. Delayed-start analysis: mild Alzheimer’s disease patients in solanezumab trials, 3·5 years. Alzheimer’s Dement Transl Res Clin Interv 2015; 1: 111–21.
www.thelancet.com/neurology Published online December 15, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00382-8
Stem cell therapy for Alzheimer’s disease: hope or hype? Alzheimer’s Disease International estimated that, in 2015, 46·8 million people worldwide are living with Alzheimer’s disease, with a global cost of US$818 billion.1 At present, no disease-modifying therapies are available; this unmet need, combined with failures of several recent clinical trials, highlights a need for improved disease models and novel approaches for therapeutic intervention. In The Lancet Neurology, Joshua Hunsberger and colleagues2 review progress in the use of stem cells for disease modelling, drug discovery, and therapeutic intervention in Alzheimer’s disease, and make a case for the acceleration of clinical trials in this area. It is the use of stem cells as disease models that perhaps has the most to offer in terms of immediate gain, and the most exciting development is the potential to assay potential therapeutics with induced pluripotent stem cells (iPSCs). The generation of iPSCs from patients with genetic lesions in the disease-related genes APP and PSEN1 has revolutionised in-vitro modelling of dementia, providing a limitless source of patient-specific neurons that can feature disease-linked genotypes.3 As reviewed by Hunsberger and colleagues,2 several independent groups have established Alzheimer’s disease-relevant phenotypes in vitro with this approach, and the identification of both amyloid-β (Aβ) and downstream tau pathologies in neurons generated from patients with mutations in APP or PSEN1 is especially encouraging, since recapitulation of these two pathological hallmarks in murine disease models has been difficult without overexpression of multiple mutated genes.4 These iPSC-derived neurons can now be used in detailed mechanistic studies to understand the earliest molecular signatures of disease, and as a drug-screening platform to identify small molecules that modify well established cellular phenotypes linked to Aβ and tau pathologies. The results obtained with iPSC disease models have generally been positive, but several shortcomings remain. Accumulating evidence from neuropathological studies and the identification of microglial-enriched genes such as TREM2 as risk factors5 lend support to a non-cell-autonomous cause for Alzheimer’s disease with astrocyte and microglial involvement. Co-culture models that allow the contribution of different cell types to the disease process to be investigated will be
necessary. Further, the maturity of neurons generated from iPSCs is widely debated in the context of both gene expression and electrical activity. Of particular relevance to Alzheimer’s disease is the finding that the expression profile of tau remains fetal-like in iPSC-derived neurons until 1 year in culture.6 Even in cases of familial disease with the earliest onset, the disease only manifests clinically several decades after the onset of pathology and structural changes—how effectively will iPSCs recapitulate the full time course of disease-associated molecular changes? The potential of iPSCs to model sporadic Alzheimer’s disease, which represents the majority of cases, is also understudied, although early reports have shown in-vitro phenotypes in neurons from patients with sporadic disease and preliminary evidence that iPSC-derived neurons could be used to stratify patients according to differential drug responsiveness.7 Emerging evidence from preclinical models supports further investigation of stem cells as therapeutics. The therapeutic potential of several cell types, including bone marrow-derived mesenchymal stem cells, adipose-derived stem cells, and neural stem cells, has been studied in animal models of Alzheimer’s disease, and beneficial outcomes include the removal or reduction of disease pathologies, reversal of memory deficits, integration of donor cells into host neuronal circuitry, and provision of trophic support from donor cells to remaining neuronal circuits. Hunsberger and colleagues2 conclude that replacement of widespread neuronal loss is unlikely, but the potential benefit of stem cell therapies to reinforce remaining circuits and slow disease progression remains great enough to warrant further study. Ongoing multicentre initiatives to coordinate clinical trials of stem cell therapies for other neurological disorders such as Parkinson’s disease will help to inform some of the key questions regarding safety, delivery, dosage, and efficacy.8 Despite promising preclinical data, numerous challenges need to be overcome before stem cell therapies for Alzheimer’s disease can become a reality in the clinic. Safety concerns include rejection of transplants and the proliferative capacity of stem cells, which increases the risk of tumorigenicity. These concerns could potentially be addressed by the
www.thelancet.com/neurology Published online December 15, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00382-8
Lancet Neurol 2015 Published Online December 15, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00382-8 See Online/Personal View http://dx.doi.org/10.1016/ S1474-4422(15)00332-4 For Alzheimer’s Disease International see https://www. alz.co.uk/
1
Comment
generation of a HLA haplobank of cell lines to minimise rejection risk, and by harnessing the cells’ apoptotic machinery to trigger autodestruction if proliferation becomes excessive.9 The cost of production of clinical-grade cells for therapy is likely to be prohibitive to widespread use, making the approach to identify small molecules with iPSC models more attractive. Finally, a key remaining question is how would one identify which patients should receive cell-based therapies? It is clear that the development of disease pathology and associated neuronal loss occur years before symptom onset, and data suggest that unsuccessful therapies in phase 3 trials might in fact be beneficial if intervention occurs earlier in the disease process.10 Whatever approach is taken, early and accurate diagnosis leading to early intervention will be essential. In conclusion, although many questions remain, stem cells have great potential to enhance our understanding of the molecular basis of Alzheimer’s disease and provide a platform for the discovery of novel therapeutics. Long-term studies will ascertain whether stem cell therapies will contribute to the growing arsenal of potential therapeutics at our disposal, but these prospects are unlikely to be realised in the short term despite the hype.
2
*Selina Wray, Nick C Fox Department of Molecular Neuroscience (SW) and Dementia Research Centre, Department of Neurodegeneration (NCF), UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK [email protected] We declare no competing interests. 1
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3 4 5 6
7
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9 10
Prince M, Wimo A, Guerchet M, et al. World Alzheimer Report 2015—The global impact of dementia: an analysis of prevalence, incidence, cost and trends. London: Alzheimer’s Disease International, 2015. https://www.alz. co.uk/research/WorldAlzheimerReport2015.pdf (accessed Dec 1, 2015). Hunsberger J, Rao M, Kurtzberg J, et al. Accelerating stem cell trials for Alzheimer’s disease. Lancet Neurol 2015; published online Dec 15. http://dx.doi.org/10.1016/S1474-4422(15)00332-4 Livesey FJ. Human stem cell models of dementia. Hum Mol Genet 2014; 23: R35–39. Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles. Neuron 2003; 39: 409–21. Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 2013; 368: 117–27. Sposito T, Preza E, Mahoney CJ, et al. Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Hum Mol Genet 2015; 24: 5260–69. Kondo T, Asai M, Tsukita K, et al. Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell 2013; 12: 487–96. Barker RA, Studer L, Cattaneo E, Takahashi J, G-Force PD consortium. G-Force PD: a global initiative in coordinating stem cell-based dopamine treatments for Parkinson’s disease. NPJ Park Dis 2015; 1: 15017. Barry J, Hyllner J, Stacey G, Taylor CJ, Turner M. Setting up a haplobank: issues and solutions. Curr Stem Cell Rep 1: 110–07. Liu-Seifert H, Siemers E, Holdridge KC, et al. Delayed-start analysis: mild Alzheimer’s disease patients in solanezumab trials, 3·5 years. Alzheimer’s Dement Transl Res Clin Interv 2015; 1: 111–21.
www.thelancet.com/neurology Published online December 15, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00382-8
