Patient-derived Cell Models Created for SMA-LED Research
Four lines available for studies into rare SMA form and its possible treatments
Researchers have developed and validated four new cell lines derived from four patients with spinal muscular atrophy (SMA) with lower extremity predominance (SMA-LED) that can be used as a tool in studies of this rare form of spinal muscular atrophy.
With the characteristics of the patient it was derived from, each cell line houses a different mutation associated with SMA-LED.
The generation of these cell lines was described in “Generation of FOUR iPSC lines (CRICKi004-A; CRICKi005-A; CRICKi006-A, CRICKi007-A) from Spinal muscle atrophy patients with lower extremity dominant (SMALED) phenotype,” published as a lab resource in Stem Cell Research.
Lines derived from patients with DYNC1H1, BICD2 gene mutations
As with other types of SMA, SMA-LED is marked by the loss of motor neurons, the nerve cells that communicate with muscles to control voluntary movements, resulting in muscle weakness and wasting.
But the legs are particularly affected in SMA-LED patients, with symptoms appearing in infancy or childhood and progressing slowly. It also is caused by mutations in the DYNC1H1 or BICD2 genes.
Ultimately, these mutations impair the body’s ability to transport chemical messengers among motor neurons, preventing their communication and causing muscle weakness. Still, it isn’t established why only lower limbs are affected in SMA-LED.
These four cell lines, called induced pluripotent stem cells (iPSC), are being made available for use as a research tool for scientists investigating the mechanisms underlying this disease.
To generate each line, fibroblasts — a type of connective tissue cell — were obtained from four SMA-LED patients, three with DYNC1H1 mutations and one with a BICD2 mutation.
These fibroblasts were then reprogrammed in the lab to put them in a pluripotent state. Essentially, pluripotency means that the cells, now in an immature form, are capable of giving rise to virtually any cell type in the body under the right conditions.
In the lab, the cells can be treated with certain chemicals to induce the transformation to a particular cell of interest to researchers, such as motor neurons.
Since these iPSCs and the cells they give rise to will have the same characteristics as the cells of the person they came from, the lines offer a way to more directly examine this rare disease.
For example, researchers could use the iPSCs from the person with a BICD2 mutation to generate motor neurons with that mutation. They can then use these patient-derived cells to more closely examine the cellular mechanisms underlying that person’s disease.
“Here we report the generation and validation of four iPSC lines derived from four patients with SMALED,” the U.K. research team wrote.
In additional experiments, the team validated that the cells were indeed pluripotent, and could be differentiated into other cell types. Moreover, “identical genetic identity to the donor” was confirmed, the scientists noted.
Ultimately, these types of human-derived cell lines are thought to be a promising way of better understanding — and testing potential therapies for — rare diseases like SMA-LED.
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