Stem Cell Autopsy: Survival and fate of fetal neural stem cells in NeuralStem ALS trial

by Alexey Bersenev on November 16, 2014 · 0 comments

in pathology and autopsy

I’ve written two years ago about autopsy findings from ALS patients, treated by neural stem cell product candidate, commercialized by NeuralStem. Recently, company published an update on pathology of spinal cords and donor cell fate after transplantation. The article is freely available online.

PRIME-XV-Expansion-Banner-550x80

The authors analyze 6 postmortem cases of transplantation investigational product NSI-566 into spinal cord of ALS patients. Knowing DNA sequence of donor cell line, they were able to trace cells in the sites of implantation. In all 6 cases donor’s DNA was detected (0.67–5.4% of total tissue DNA) in patients survived up to 3 years after surgery. Based on donor’s DNA detection, the authors made a conclusion that transplanted cells survived long-term, without any correlation with course of immunosuppression. From press release:

… researchers found no correlation of DNA content to survival period after immunosuppressant medications had been discontinued. These data demonstrate that transplanted HSSCs can survive for a prolonged period, even in the absence of immunosuppression.

The question is that whether detection of donor DNA equivalent of cell survival? The authors said YES, and, most likely they are right. However, we cannot exclude horizontal transfer of donor’s DNA with apoptotic bodies, described before as phenomenon of chimerism.

The real gem of the study is the case of sex-mismatch transplant. If male neural cell line was transplanted in female recipient, we can detect donor cells by difference in X and Y chromosomes, using fluorescence in situ hybridization (FISH analysis). Detection of XY+ (male) cells (64% in injection sites and nothing in other regions) was a definitive proof of donor’s cell survival and persistence (for 196 days after transplant in this particular patient). By adding immunohistochemistry to FISH analysis, researchers able to show neuronal differentiation (by coexpression of NeuN marker) of XY+ cells. The area of injections were stained negatively for glial markers. So, there was no evidence for glial differentiation (read multipotentiality) of transplanted cells. Undifferentiated SOX2+ cells were co-located with XY+ cells in areas of injections. Morphologically similar “nests of non-native” non-glial cells were identified in all other cases. Based on these observations, the authors “suspect” long-term survival of donor cells in all cases.

The biggest outstanding question remain: “Is donor cell long-term engraftment linked to therapeutic benefit”? It’s unclear from the pathology studies, but company believes that cell survival and efficacy are linked:

“The success of our therapy is predicated upon our cells ability to survive long-term and differentiate, providing neurotrophic support in the spinal cord and acting as ‘nurse’ cells for the patients’ own motor neurons that are attacked by the disease,” said Karl Johe, PhD, Neuralstem Chairman and Chief Scientific Officer.

I’d definitely avoid some strong claims in press release at this point.

{ 0 comments… add one now }

Leave a Comment

Previous post:

Next post: