Induced pluripotent stem cells model spinal muscular atrophy

5 January 2009

A paper in Nature reports on the creation of an in vitro model of the genetic disease spinal muscular atrophy (SMA) using skin cells from an affected child (see also BBC news). SMA is an autosomal recessive genetic disorder caused by mutations in the SMN1 or SMN2 (survival motor neuron 1 or 2) genes, which leads to degeneration of specific motor neurons and progressive paralysis. Patients with SMA 1 typically die by age 2; SMA2 is generally less severe as low levels of functional SMN2 protein are still produced. A team of American researchers sought to create a human cell-based system to study the mechanisms by which motor neurons degenerate and how the SMN proteins function [Ebert AD et al. (2008) Nature doi:10.1038/nature07677].

Using fibroblast cells from an SMA1 patient and his unaffected mother, they generated induced pluripotent stem cells (iPS cells) using vectors based on lentiviruses to introduce the necessary genes OCT4, SOX2, NANOG and LIN28. Both wild-type and SMA cell-lines were established, and showed normal replication and growth. Analysis of RNA from the original fibroblast and iPS cells showed that intact (full-length) SMN1 transcripts were present in both forms of wild-type cells, but neither the original nor the induced pluripotent SMA cells.

The researchers next generated neurons and astrocytes from the iPS-SMA and iPS-WT cells; 4 weeks after differentiation was induced, both types of cell-lines had given rise to similar numbers of neurons, including motor neurons. However, 6 weeks after differentiation, the number and size of motor neurons was significantly reduced in the iPS-SMA cells compared with the iPS-WT cells, although the overall growth of other neuronal cells was not affected. This suggests that the disease-phenotype of the iPS-SMA initially allowed normal growth and differentiation of neuronal cells, but later shows selective loss of motor neurons compared with the wild-type cells.

Finally, treatment of the iPS cells with compounds known to increase production of SMN protein from the functional SMN2 gene showed evidence of increased SMN production similar to that observed in fibroblasts, suggesting that the system could be suitable for screening potential drugs to ameliorate the disease. Referring to the development, research lead Clive Svendsen of the University of Wisconsin-Madison commented: "Now you can replay the human disease over and over in the dish and ask what are the very early steps that began the process. It's an incredibly powerful new tool" (see press release).

Comment: Previous research created patient-specific induced pluripotent stem cells from individuals with different genetic diseases (see previous news); this paper is new not only with respect to the disease studied, but also in demonstrating disease-specific loss of cell function and survival when compared with equivalent cells from a healthy patient, lending weight to the assertion that iPS cells can reproduce elements of pathology. Although further investigation will be required to determine whether or not the cell-based system is definitely reproducing the actual disease processes (as opposed to some effect arising from the processes used to induce pluripotency and neuronal differentiation leading to loss of motor neurons), it is likely to prove valuable both for further investigation of disease processes, and for in vitro screening of potential therapeutics. It is sad to think that the trial subject is unlikely to benefit directly from the research, given the typically rapid progression of disease, but shows how families affected by serious diseases may chose to participate in clinical trials in the hope that others may benefit in the future.

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