Rick: They actually are not sure how and why the microcarriers seem to enhance implanted-cell survivability. With this as a start, you can undoubtedly come up with a far more sophisticated immunological hypothesis than I can. But the conjectures are as follow, again from the Oct98 NI:
"Cell Coated Microcarriers (CCM): This is Theracell's most advanced implant technology, the adhesion of therapeutic cells to microcarriers (made of glass, gelatin, polymers, or other vehicles) for stereotaxic implantation. This is being developed as an 'off-the-shelf', cryopreserved, prepackaged treatment. It is not totally clear how the microcarriers' effect occurs, it is believed that the microcarrier substrate shields the implanted cells from immunological detection, and may also precipitate the release of endogenous neurotrophic factors (CNTF and BDNF in particular) that foster the growth of these cells. It does appear that the size of the microcarriers interferes with detection, and that astrocyte cells in the host tissue grow around these microcarriers, providing a natural 'semi-permeable membrane' similar in its function to the semipermeable sheath developed by CytoTherapeutics. The most advanced component of this program is Spheramines, the microcarrier delivery of human retinal epithelial cells which secrete dopamine. Dopamine is released, but T-cells and microglia cannot access the implanted cells. These can be grown in culture. Thus far the program has relied upon fetal cells, which are difficult to obtain in quantity (and will stir some controversy even at best), the fact that one fetal eye is expected to provide enough cells to ultimately treat 5000 patients or so is a plus (compared to the original fetal cells implants in Sweden, where 6-12 fetuses were required per patient). However, Titan has evidence that cells from the retinas of subjects up to young adulthood are viable for these implants, thus the supply issues problematic for programs completely reliant upon fetal tissue may not be problematic.
Titan has shifted the bulk of its preclinical energy to the Spheramine program, and is currently carrying out primate studies using the MPTP model of Parkinson's. The percentage of implanted cells surviving after 8 months is reportedly quite high, consistent percentage- wise with the 60-80% improvement in Parkinsonian motor symptoms shown by monkeys receiving the implants. Histological examination indicates that the implanted cells (which were of fetal origin) not only survived, but grew together. A final primate trial is underway, and toxicology studies planned, in anticipation of an IND for human studies in mid-99. This would allow the start of a Phase I/II study in advanced Parkinson's patients. Titan is also beginning preliminary animal studies in a model of spinal cord injury. Epilepsy, Alzheimer's, and chronic pain are other possible targets, based on the ability of microcarriers to stabilize other cell types, those producing GABA, acetylcholine, and analgesic enkephalins respectively." |
