The Australian government has recently given its approval for a clinical trial of what is almost certainly a medical first. The Carlsbad-based stem cell company, International Stem Cell Corp. (ISCO), a publicly traded biotechnology company, has developed a unique stem cell technology to address particular conditions.
The clinical trial that has been approved will examine the use the ISCO’s unique stem cell products in the treatment of Parkinson’s disease. Twelve Parkinson’s patients will receive implantations of these cells sometime in the first quarter of 2016, according to Russell Kern, ISCO’s chief scientific officer. The implanted cells will be neural precursor cells, which are slightly immature neurons that will complete their maturation in the brain, hopefully into dopamingergic neurons, which are the precise kind of neurons that die off in patients with Parkinson’s disease.
Parkinson’s disease (PD) is a progressive disorder of the nervous system that affects voluntary movement. PD develops gradually and sometimes begins with a slight tremor in only one hand, but PD may also cause stiffness or slowing of movement. PD worsens over time.
PD patients suffer from tremor, or shaking of the limbs, particularly when it is relaxed and at rest. Over time, PD reduces the ability to move and slows movement (bradykinesis) which makes simple tasks difficult and time-consuming. Muscle stiffness may occur and this limits the range of motion and causes pain. PD patients also suffer from stooping posture and balance problems and a decreased ability to perform unconscious movements. For example, they have trouble swinging their arms while they walk, blinking, or smiling. They might also experience speech problems that can range from slurring of the speech to monotone speech devoid of inflexions, or softer speech with hesitations before speaking. Writing might also become problematic.
PD is caused by the gradual death of neurons in the midbrain that produce a chemical messenger called dopamine. The drop in dopamine levels in the system of the brain that controls voluntary movement leading to the signs and symptoms of Parkinson’s disease.
Several different animal experiments with a variety different cell types have established that transplantation to dopamine-making neuronal precursors into the midbrains of laboratory animals with artificially-induced PD can reverse the symptoms of PD. Dopaminergic neurons can be derived from embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), umbilical cord blood hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and NSCs (see Petit G. H., Olsson T. T., Brundin P. Neuropathology and Applied Neurobiology. 2014;40(1):60–67). Also, since the 1980s, various cell sources have been tested, including autografts of adrenal medulla, sympathetic ganglion, carotid body-derived cells, xenografts of fetal porcine ventral mesencephalon, and allografts of human fetal ventral mesencephalon (fVM) tissues have been implanted into the midbrains of PD patients (Buttery PC, Barker RA. J Comp Neurol. 2014 Aug 15;522(12):2802-16). While the results of these trials were varied and not terribly reproducible, these studies did show that the signs and symptoms of PD could be reversed, in some people, by implanting dopamine-making neurons into the midbrains of PD patients.
ISCO has derived neural precursor cells from a completely new source. ISCO scientists have taken unfertilized eggs from human egg donors and artificially activated them so that they self-fertilize, and then begin dividing until they form a blastocyst-stage embryo from which stem cells are derived. This new class of stem cells, which were pioneered by ISCO, human parthenogenetic stem cells (hpSCs) have the best characteristics of each of the other classes of stem cells. Since these stem cells are created by chemically stimulating the oocytes (eggs) to begin division, the oocytes are not fertilized and no viable embryo is created or destroyed. This process is called parthenogenesis and parthenogenetic stem cells derived from the parthenogenetically-activated oocytes, are produced from unfertilized human egg cells.
Why did ISCO decide to do this trial in Australia? According to Kern, ISCO chose to conduct their clinical trial in Australia because its clinical trial system is more “interactive,” which allows for better collaboration with Australia’s Therapeutic Goods Administration on trial design. This clinical trial, in fact, is the first stem cell trial for PD according to the clinical trial tracking site clinicaltrials.gov. The test will be conducted by ISCO’s Australian subsidiary, Cyto Therapeutics.
The approach pioneered in this clinical trial might cure or even provide an extended period of relief from the symptoms of PD. If this clinical trial succeeds, the stem cell clinical trial dam might very well break and we will see proposed clinical trials that test stem cell-based treatments for other neurodegenerative diseases such as Huntington’s disease, Lou Gehrig’s disease (ALS), frontotemporal dementia, or even Alzheimer’s disease.
ISCO has spent many years developing their parthenogenetic technology with meager financing. However the company’s total market value amounts to something close to $11.1 million, presently.
hpSCs are pluripotent like embryonic stem cells. Because they are being used in the brain, they will not be exposed to the immune system. Therefore an exact tissue type match is not necessary for this type of transplantation. In their publications, ISCO scientists have found their cells to be quite stable, but other research groups who have worked with stem cells derived from parthenogenetically-activated embryos have found such cells to be less stable than other types of pluripotent stem cells. The stability of the ISCO hpSCs remains an open question. The lack of a paternal genome might pose a safety challenge for the use of hpSCs.
Rita Vassena and her colleagues in the laboratory of Juan Carlos Izpisua Belmonte at the Salk Institute for Biological Studies in La Jolla, CA examined the gene expression patterns of mesenchymal stem cells derived from hpSCs and found that the overall gene expression patterns were similar to MSCs made from embryonic stem cells or induced pluripotent stem cells. However, upon further differentiation and manipulation, the gene expression patterns of the cells began to show more variability and further depart from normal gene expression patterns (Vassena R, et al Human Molecular Genetics 2012; 21(15): 3366-3373). Therefore, the derivatives of hpSCs might not be as stable as cellular derivatives from other types of stem cells. The good news about hpSCs established from parthenogenetic ESCs were reported to be morphologically indistinguishable from embryonic stem cells derived from fertilized embryos, and seem to show normal gene expression or even correct genomic imprinting in chimeras, when pESCs were used in tissue contribution (T.Horii, et al Stem Cells, vol. 26, no. 1, pp. 79–88, 2008).
For those of us who view the early embryo as the youngest members of the human community who have the right not to be harmed, hpSCs made by ISCO remove this objection, since their derivation does not involve the death of any embryos.
The ISCO approach to Parkinson’s is similar to that of a San Diego group called Summit for Stem Cell, which is going to use induced pluripotent stem cell derivatives. This nonprofit organization is presently raising money for a clinical trial to test the efficacy of their treatment.
Both groups intend to transplant the cells while they are still slightly immature, so that they can complete their development in the brain. Animal studies suggest that implanting immature precursors are better than transplanting mature dopaminergic neurons into the midbrain. The precursors then differentiate into dopamine-making neurons, and other cells differentiate into supportive glial cells, which support the dopamine-making neurons.
“It’s a dual action,” Kern said. “Also, neural stem cells reduce inflammation, and inflammation is huge in Parkinson’s.”
Summit 4 Stem Cell will also take a similar approach, according to stem cell scientist Jeanne Loring, a leader of the Summit 4 Stem Cell project. The cells make proper connections with the brain better when they are still maturing, said Loring, who’s also head of the regenerative medicine program at The Scripps Research Institute in La Jolla. This is all provided that Summit 4 Stem Cell can raise the millions of dollars required for the clinical trial and secure the required approvals from the U.S. Food and Drug Administration.
Loring said she views ISCO as a partner in fighting Parkinson’s. One of her former students is working for the company, she said. “The whole idea is to treat patients by whatever means possible,” Loring said.
ISCO’s choice of Australia for its streamlined regulatory process makes sense, Loring said. Her team, with U.S.-based academics and medical professionals, doesn’t have the same flexibility as ISCO in looking for clinical trial locations, she said.