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Stem cell transplant therapy demonstrated high feasibility. The authors concluded that the NSCs derived from corrected HD-iPSCs differentiated to striatal fate in the R6/2 mouse model of HD. Thus, this therapeutic measure is able to operate in vivo.

IPSCs provide a human model of HD as well as a drug discovery platform. They arrived at this conclusion since human iPSCs recapitulate cellular phenotypes seen in other models of HD, and they can be reversed.

Human iPSCs can be a useful drug discovery platform. The normal and diseased cell lines have identical genetic profiles, thus, any differences in treatment outcomes observed should not be attributed to genetic confounds.

Autologous cell transplants are useful for screening multiple treatments for any specific patient. This is a step towards personalized regenerative medicine.

Lastly, the researchers' methods proved to be both effective and efficient in correcting the faulty gene.

The following image was created by Ronald (Wai) Li (2017).

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Bacterial Artificial Chromosome (BAC) Vector

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Bacterial Artificial Chromosome (BAC) Vector

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The BAC vector Mahru et al. (2012) used contained a CAG repeat sequence with a non-pathological 21 repeats, and a removable cassette encoding neomycin antibiotic resistance and enhanced green fluorescence protein genes.

This bacterial vector and homologous recombination were used to correct HD-iPSCs to generate corrected HD-iPSCs, used in all following experiments.

(adapted from Jen Philpot's image)

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Proposed Experiment: Measuring Behavioural Recovery in Mice Following Cell Replacement Therapy Using Corrected HD-iPSCs

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Proposed Experiment: Measuring Behavioural Recovery in Mice Following Cell Replacement Therapy Using Corrected HD-iPSCs

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Previous papers (Jeon et al.m 2012; Maucksch et al., 2013) have shown that HD mouse models (R6/2 and QA models) demonstrate behavioural rescue following transplantation of human-derived stem cells.

Previous studies observing behavioural phenotypes have used the stepping test to measure forelimb usage, the staircase test to measure grasping skills, the rotarod test to measure balance, and the open field test to measure anxiety-like behaviour.

Given the aforementioned literature, a future direction that tests behavioural recovery following stem cell transplantation is feasible.

Hypothesis: Corrected HD-NSC injection should improve behavioural phenotypes in R6/2 HD mice, because cellular phenotypes were shown to be reversed, and they likely underlie behavioural phenotypes.

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In the R6/2 HD mouse model, the following 3 experimental groups would be established:
1. Injection of corrected HD-NSCs
(Experimental Group)
2. Injection of healthy NSCs
(Control)
3. Injection of saline
(Control)

Protocol:
1. Obtain iPSCs, differentiate them into NSCs (as previously described).
2. Unilateral injections of NSCs into the striatum of the mice.
3. Randomize unilateral injection (left and right stratum).
4.  Control the injection apparatus, stereotaxic injection in same place with respect to Bregma and Lambda.
5. Conduct behavioural tests.:
1. Stepping test
2. Staircase test
3. Rotarod Test
4. Open Field Test

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Please turn on English subtitles!

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доклинические исследования

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Доклинические исследования: staircase test

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Установка "Staircase test" предназначена для изучения моторики передних конечностей у крыс. "Staircase" является высокочувствительным тестом, позволяющим оценить незначительные нарушения в работе самой конечности, а также кисти и пальцев. Тест широко используется для оценки неврологического дефицита у крыс при моделировании различных патологических состояний.

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A stepping test examines the forelimb functionality of mice on a moving conveyor belt. Mice injected with corrected HD-NSCs should use both limbs in equal proportion, while the mice with saline injections should show disproportionate usage of one limb, suggesting that HD-NSCs improve limb functionality.

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The staircase test measures the grasping capabilities by examining the number of food pellets collected on the stairs. Mice with corrected HD-NSCs should collect a larger quantity of food pellets compared to the saline condition, suggesting that HD-NSCs improve grasping ability. The amount of food pellets collected by mice injected with HD-NSCs should be comparable to the amount collected by mice injected with healthy NSCs.

The following image was created by Sierra LoMonaco (2017).

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The rotarod measures the balance, grip strength, and motor coordination of mice on a rotating rod. Mice with corrected HD-NSCs should remain on the rod longer than mice injected with saline, suggesting that HD-NSCs recover some motor behaviour. Mice with corrected HD-NSCs should stay on the rod for the same amount of time as mice with healthy NSCs.

The following image was created by Sierra LoMonaco (2017).

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Hunting's disease (HD) is a progressive, autosomal dominant disorder. It is a neurodegenerative disorder that is genetically-linked and results in severe motor and cognitive impairment. Its symptoms are often described as a combination of Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis (ALS/Lou Gehrig's/motor neuron disease) symptoms.

The following video provides a concise overview of HD.

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The genetic defect that causes HD occurs within the IT15 (interesting transcript) gene on chromosome 4.

Individuals with HD express an abnormal CAG repeat expansion in the IT15 gene, which produces an aberrant form of the huntingtin protein (Htt). These CAG repeats are repeated from 36 (the pathological threshold) to 120 times. The aberrant Huntingtin protein is prone to being cleaved, and the fragment containing the CAG repeat aggregates, causing cell death.

To put this into perspective...
Normal DNA contains 10-28 CAG repeats . As you can see, there is a huge discrepancy in CAG repeats between healthy individuals and people with HD!

Does the number of repeats play a role in the severity of HD? Interestingly, as the gene is passed down from generation-to-generation, the number of CAG repeats increases. If inherited, future generations have a greater risk of developing HD symptoms at an even earlier age! Research has indicated a strong correlation between the number of CAG repeats in DNA and the age of onset for Huntington's Disease.

INCREASE repeats = EARLIER onset

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Previous studies were conducted using fetal neural transplants. Tissues from human embryos between 5-9 weeks old were implanted in the caudate nucleus and putamen in the hopes of improving HD symptoms. Motor and cognitive improvements were observed after only 2 years, however, these improvements were short-lived as no permanent cure was established.

The following image was created by Sierra LoMonaco (2017).

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One of the indicators for HD is programmed cell death (apoptosis) in the cortex and striatum. Apoptosis can be measured by the terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay. The TUNEL assay is a technique used to measure levels of cell degradation during apoptosis. The author's results showed that HD-NSCs had a much greater increase in TUNEL-positive cells compared to the normal and corrected NSCs.

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The Apo3HTS

high throughput screen for Caspase 3/7 detection was used as the caspase activity assay in our study. Caspases are endoproteases that are involved in controlling cell inflammation and cell death.
The results demonstrated that when growth factor was removed, only HD-NSCs showed increase in caspase-3/7 activity.

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Brain-Derived Neurotrophic Factor (BDNF) Levels In HD-NSCs

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Brain-Derived Neurotrophic Factor (BDNF) Levels In HD-NSCs

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Mahru et al. (2012) used quantitative reverse transcription PCR (RT-qPCR) in order to quantify the expression levels of BDNF mRNA and protein. BDNF is a growth receptor that is found primarily in the CNS. It is responsible for numerous important nervous system aspects such as synapse formation, dendritic growth, neuronal survival and proliferation.
Correction of the CAG expansion in HD-NSCs led to increased levels of BDNF.

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Bachoud-Lévi, A., Gaura, V., & Brugières, P, et al. (2006). Effect of fetal neural transplants in patients with Huntingtons disease 6 years after surgery: a long-term follow-up study. The Lancet Neurology, 5(4), 303-309.
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Rotarod. (2011, August 14). Retrieved December 04, 2017, from https://www.youtube.com/watch?v=TDJZ_SmGwQc

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Takahashi, K., & Yamanaka, S. (2006). Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell, 126(4), 663-676. doi:10.1016/j.cell.2006.07.024

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Zhang, N., An, M. C., Montoro, D., & Ellerby, L. M. (2010).  Characterization of Human Huntington’s Disease Cell Model from  Induced Pluripotent Stem Cells. PLoS Currents, 2, RRN1193. http://doi.org/10.1371/currents.RRN1193

Доклинические исследования: staircase test. (2015, April 6). Retrieved December 04, 2017, from https://www.youtube.com/watch?v=NEkB6Jtcvmw&

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To measure mitochondrial bioenergetics, the authors measured oxygen consumption rate (OCR or mitochondrial respiration) using an XF24 extracellular flux analyzer.

Their results show that maximum respiration was higher in corrected NSCs compared to uncorrected NSCs. This suggests that correcting the CAG repeat that produces Htt is what improves mitochondrial function and maximum respiration in NSCs.

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Transforming growth factor beta 1 (TGF-β1) Levels in HD-NSCs

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Transforming growth factor beta 1 (TGF-β1) Levels in HD-NSCs

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The authors again used RT-qPCR to measure mRNA and protein expression levels, but now of TGF-β1. TGF-β1 is a growth factor that regulates cell differentiation, growth and proliferation. It is also able to affect activation and expression of other growth factors.
They found that TGF-β1 levels in corrected NSCs were higher than in uncorrected NSCs.

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To measure the mRNA and protein levels of N-cadherin, the authors used RT-qPCR. N-cadherin is a transmembrane protein that is important for tissue tissue homeostasis and morphogenesis by mediating cell to cell adhesion in animals.
The results showed that N-cadherin levels in corrected NSCs were higher than in uncorrected NSCs.

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In Vivo Striatal Differentiation (STEM121-Positive Cells)

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In Vivo Striatal Differentiation (STEM121-Positive Cells)

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Researchers performed confocal imaging, a technique that is highly useful in generating 3-dimensional images of specimens. Using this technique, they found high levels of STEM121-positive cells (a marker for human cytoplasmic protein) in the striatum of mice that received corrected HD-NSC injection. This result suggests that corrected NSCs survived the transplantation in vivo.

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The open field test looks at the locomotive activity of mice in an enclosed space. Mice injected with corrected HD-NSCs should spend more time in the centre of the box compared to the saline condition, suggesting that corrected HD-NSCs are anxiolytic. Mice injected with corrected HD-NSCs and mice injected with healthy NSCs should exhibit similar behaviour.

The following image was created by Sierra LoMonaco (2017).

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Alternative Explanation of Predicted Results

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Alternative Explanation of Predicted Results

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Injecting NSCs in and of itself could have improved behavioural function. A previous paper showed that injection of HD-NSCs differentiated into GABAergic striatal neurons which are susceptible to degeneration in HD. Despite containing the faulty HTT gene, restoration of these cells improved scores on the staircase and apomorphine-induced rotation tests.

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In Vivo Straital Differentiation (DARPP-32, GABA, MAP2)

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In Vivo Straital Differentiation (DARPP-32, GABA, MAP2)

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Using confocal imaging, Mahru et al. (2012) showed that the

medium spiny neuron marker

DARPP-32 (Image J and K),

the GABAergic neuron marker

GABA (Image H and I), and the

neuronal marker MAP2 (Image E and F) were all co-labeled with human cells (STEM121).

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Mice with corrected HD-NSCs perform at the same level as mice injected with saline.

NSCs that differentiate into human striatal neurons in mice may not have all the synapses, since they are not present during neurodevelopment. Furthermore, newly-formed synapses may not be potentiated (via long-term potentiation), and therefore the presence of striatal neurons alone would be insufficient for behavioural outputs.

Alternatively, the protocol as previously described may not have measured the reversal of all cellular changes associated with HD. These unmeasured changes might be essential for performance in these behavioural tests, i.e. essential for motor functions.

Mice with corrected HD-NSCs perform worse than the mice injected with saline in behavioural tests.

Injection might have caused lesioning and damage to neurons, impairing performance in behavioural tests.

NSCs have been previously shown to have higher rates of apoptosis following injection, and this apoptosis can spread to nearby healthy neurons.

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Other experiments that could strengthen the present paper's findings include performing follow-up histological examinations post-transplantation. Doing so would establish that the reversal of cellular phenotypes are retained after transplantation. This could be done after behavioural testing, as animals must be sacrificed for staining of brain sections.

Lastly, since a drug discovery platform was established, future studies could test therapies on these autologous HD-iPSCs, in which both diseased cell lines and normal cell lines are genetically identical. Differences observed would more likely be due to the therapy, and not due to genetic differences.

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Both in vitro and in vivo evidence strengthen the results. Why?

They effectively showed that these cells can be genetically manipulated outside of the organism, then introduced to the organism without complication.

Their rationale was solid.

Mouse models of HD have well-studied cellular phenotypes and the authors of this paper utilized this information to guide their investigation.

Gene targeting protocols in human iPSCs were lacking, and there was untapped potential for the use of stem cell therapy. Furthermore, in vivo evidence was lacking. Thus, the authors sought to investigate how iPSCs could be utilized in established mouse models of HD.

The following image was created by Ronald (Wai) Li (2017).

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1. Lack of control groups when testing for differentiation to striatal fate in vivo.

They only examined in vivo differentiation of neurons derived from corrected HD-NSCs. Therefore, no conclusions regarding differences between corrected HD-iPSC-derived neurons and the healthy-control-iPSC-derived neurons could be made. For example, the number of surviving cells may differ between the two groups.

2. Did not measure cellular phenotypes after in vivo transplantation.

Although they showed differentiation, it is possible the neurons were not functioning at the level of endogenous, healthy (non-HD) striatal neurons. The measurement of cellular phenotypes typically associated with HD would also be most informative in context, compared to control groups. They also could not show that these effects lasted overtime.

3. Did not perform behavioural tests on mice after transplantation.

Functional differences at the behavioural level may have shown these corrected HD-NSCs to be a viable therapeutic intervention, such as in cell replacement therapy.   Possible improvements would include reduction in motor deficits associated with HD; a detailed account of an experiment that would resolve this limitation is covered under Future Directions.

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1. Treatments may not generalize to humans

The described HD-iPSCs may be used as a successful model for therapeutic interventions in animals (e.g. to test drug treatment). However, that may not be the case in the context of the human brain.

2. Phenotypic analysis was well-controlled for.

It is highly unlikely that the rescue (decrease) in apoptosis after HD-iPSC correction was due to changes in the expression of OTHER proteins/genes related to apoptosis. The authors conducted a gene expression analysis (RT-qPCR) that did not show drastic changes in gene expression.

3. Included control groups for in vitro striatal differentiation

Incorporating uncorrected HD-iPSCs as well as iPSCs from healthy controls provided a baseline to compare the cellular phenotypic rescue after HD-iPSC correction. This was only done in vitro and not in vivo.

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NOVEL FINDINGS

1. Correction in HD-iPSC

Only correction of HD in hESCs have been explored in previous research. Correction of HD in iPSCs has never researched until now.

2. Striatal differentiation in vivo

Previously, researchers only showed differentiation of HD-iPSCs in vitro. However in the current paper, they were also able to demonstrate differentiation of HD-iPSCs in vivo.

RELEVANCE OF FINDINGS

1. Potential use of HD-iPSC to test therapeutic interventions

Gene-corrected iPSCs would function as more closely-matched controls. They can be used to study the efficacy of treatments on patients with HD. Since they are derived from the same patient, they have the same genetic background. Thus, changes following therapeutic intervention in corrected-HD controls would serve as a genetically-matched control.

2. Further clinical trials could lead to the development of cell replacement therapies for the treatment of genetic diseases, like HD, in humans.

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Previously Established Models of Huntington's Disease

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Previously Established Models of Huntington's Disease

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HD has a large genetic component, thus its cellular and behavioural phenotypes are more likely to be recapitulated in models that introduce this faulty HTT gene. Several models have already been utilized but modelling potential in hiPSCs has not yet been thoroughly explored.

Animal Models

Rats, chemically lesioned through quinolinic acid (QA mice), have previously been used as a mouse model of HD. Injection of QA induces neurological damage through hyperactivation of N-methyl-D-aspartate (NMDA) receptors, and subsequent influx of calcium ions. QA also induces mitochondrial damage, producing reactive oxygen species. This pattern is observed in patients with HD.

Mouse ES cells utilize highly optimized gene targeting techniques to introduce defective genes. Introducing the defective HTT gene recapitulates cellular phenotypes seen in patients with HD.

Human Models
Human ES cells have been used to model HD and is a potential therapy, but gene targeting protocols in human contexts are not as well-established as mouse protocols.

The present paper utilizes iPSCs as a potential model of HD.

The following image was adapted from Auditory Brain Stem Response. (n.d.).

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Generation of Induced Pluripotent Stem Cells (iPSCs) from HD Patient Fibroblasts

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Generation of Induced Pluripotent Stem Cells (iPSCs) from HD Patient Fibroblasts

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iPSCs are generated by the use of Yamanaka factors in embryonic stem (ES) cell culture conditions. Using skin fibroblast cells from human HD patients, Zhang et al. (2010) generated neural stem cells (NSCs) using Yamanaka factors: nestin, Pax6, and Sox1. They differentiated the HD-iPSCs to striatal fate by combining specific neurotrophins and morphogens.

In the following video, Shinya Yamanaka briefly explains what iPSCs are, and their potential uses.

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While the use of ES cells has provided scientists with the ability to develop new treatments and therapies in the field of regenerative medicine, there are still a contingent that opposes it's application.

Some ethical concerns surrounding embryonic stem cell research include:
- Religious Beliefs
- Efficacy and Rejection
- Informed Consent

Some benefits of embryonic stem cell research include:
- Vast cell differentiation
- Functional repair
- Nerve regeneration
- Potential personalized medicine

It is important to consider both the benefits of ES cell application and it's consequences before making a judgement call on where you stand.

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Given the genomic basis of HD and the drawbacks of previous models, the authors sought to establish a robust gene targeting protocol for human iPSCs (hiPSCs), and a potential treatment discovery platform.