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HD InsightsStem Cells to Model or Treat Huntington’s Disease

Treating a mouse model of HD with neurons made from stem cells

Cell replacement holds significant potential for treating Huntington’s disease (HD). This involves implantation of healthy neurons into the brain where mutant huntingtin (mHtt) has caused neuronal degeneration. Human pluripotent stem cells (hPSC) derived from embryos or stem cells developed from a patient’s blood or skin sample represent an ideal source of cells to make neurons. Stem cells can be expanded and turned into any cell type in the body by a process called differentiation. Scientists can differentiate hPSC into neurons, and there are currently clinical trials applying this approach in Parkinson’s disease.

Stem cells can be reliably differentiated into human neural stem cells (hNSC), which are immature neurons. There is a theory that when these cells are implanted into the correct region of the brain, they will mature into the correct cell type and make connections with neighboring cells, correcting the defects caused by loss of neurons. This would be a downstream therapy for HD.

A recent study group implanted hNSC into an HD mouse model expressing humanized Q175 mHtt.1 This study examined the long-term survival of these implanted hNSC and evaluated mouse HD symptoms after transplant.

The mice were injected at 2 1/2 months of age and analysis was done at 10 months of age. The group found that some of the hNSC differentiated into resident neurons, including mature medium spiny neurons (MSN), the neurons that are primarily affected in HD.

After employing an electrophysiology technique, the researchers found that some were able to function as expected and to connect to other neurons in the brain.

The mouse model behavioral and phenotypic symptoms improved post-transplant and known brain functions, and signals that are affected by mHtt were rescued by these implanted neurons.

Notably, most of the hNSC maintained their immature cell properties, meaning that not all neurons matured. In the future, it may be possible to further differentiate the neurons towards mature MSN prior to transplantation to get a better response. Further studies will help determine if this is a plausible course of treatment for human HD.

stem cells

Directly reprogramming HD patient fibroblasts in neurons for drug discovery and personalized medicine

Usually, when scientists want to make neurons for transplantation or to study disease, blood or skin is taken from patients and it is first made into stem cells prior to differentiating the stem cells into neurons. Making stem cells is time-consuming and expensive.There are certain methods where the skin biopsy from patients can be directly reprogrammed into neurons, skipping the stem cell stage. The caveat to this method is that, historically, direct reprogramming to make neurons is much less efficient than differentiation of neurons from stem cells. 

Regardless of how patient-specific neurons are made, they can be used to study patient-specific phenotypes and test drugs in a patient-specific manner. If direct reprogramming is successful and efficient, it would be a more cost-effective way to make neurons for study or transplant.

Therefore, researchers recently conducted a study to improve the direct differentiation of human skin samples into neurons.2 They performed direct differentiation on samples from both HD patients and control patients to see if neurons produced from HD patients recapitulated HD phenotypes.

Their paper describes the direct reprogramming process and shows that the neurons derived from the HD cells show aggregated mHtt, whereas neurons derived from the control patient cells do not show this phenotype. The group suggests using this process on HD samples as a method to test drugs in a patient-specific matter for a personalized medicine approach.

Future work assessing the phenotypes of these neurons and their response to drugs, as well as further improving the direct reprogramming efficiency, will need to be done to capitalize on the promise of this approach.

1. Holley, S.M. et al (2023) Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington’s disease mice and innervate the striatum. Molecular Therapy: Vol. 31
No 12: 3545 – 3563

2. Kraskovskaya, N et al. (2023) Direct Reprogramming of Somatic Skin Cells from a Patient with Huntington’s Disease into Striatal Neurons to Create Models of Pathology. Doklady Biological Sciences: ISSN 0012-4966