Advantages and Recent Developments of Autologous Cell Therapy for Parkinson’s Disease Patients

Abstract

Parkinson's Disease (PD) is a progressive degenerative disease characterized by tremor, bradykinesia, rigidity and postural instability. There are approximately 7-10 million PD patients worldwide. Currently, there are no biomarkers available or pharmaceuticals that can halt the dopaminergic neuron degeneration. At the time of diagnosis about 60% of the midbrain dopamine (mDA) neurons have already degenerated, resulting in a depletion of roughly 70% of striatal dopamine (DA) levels and synapses. Symptomatic treatment (e.g., with L-dopa) can initially restore DA levels and motor function, but with time often lead to side-effects like dyskinesia. Deep-brain-stimulation can alleviate these side-effects and some of the motor symptoms but requires repeat procedures and adds limitations for the patients. Restoration of dopaminergic synapses using neuronal cell replacement therapy has shown benefit in clinical studies using cells from fetal ventral midbrain. This approach, if done correctly, increases DA levels and restores synapses, allowing biofeedback regulation between the grafted cells and the host brain. Drawbacks are that it is not scalable for a large patient population and the patients require immunosuppression. Stem cells differentiated in vitro to mDA neurons or progenitors have shown promise in animal studies and is a scalable approach that allows for cryopreservation of transplantable cells and rigorous quality control prior to transplantation. However, all allogeneic grafts require immunosuppression. HLA-donor-matching, reduces, but does not completely eliminate, the need for immunosuppression, and is currently investigated in a clinical trial for PD in Japan. Since immune compatibility is very important in all areas of transplantation, these approaches may ultimately be of less benefit to the patients than an autologous approach. By using the patient's own somatic cells, reprogrammed to induced pluripotent stem cells (iPSCs) and differentiated to mDA neurons immunosuppression is not required, and may also present with several biological and functional advantages in the patients, as described in this article. The proof-of-principle of autologous iPSC mDA restoration of function has been shown in parkinsonian non-human primates (NHPs), and this can now be investigated in clinical trials in addition to the allogeneic and HLA-matched approaches. In this review, we focus on the autologous approach of cell therapy for PD.

Autologous Induced Pluripotent Stem Cell–Based Cell Therapies: Promise, Progress, and Challenges

“…Postmortem analysis of the brain at 2 years post‐surgery showed survival of the engrafted dopaminergic neurons and expression of important markers. Isacson and Hallett's team also demonstrated functional improvement post‐transplantation in non‐human primate models with 8 years of chronic PD as part of preclinical studies toward developing an autologous iPSC‐based cell therapy for PD (Osborn et al., 2020). They were recently awarded a $6M grant from the NIH to support their in‐human studies, which will use autologous iPSCs as a starting material for the cell therapy product.…”

Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain

“…Finally, the recognition that metabolism takes center stage in the regulation of NSC function and adult neurogenesis is expected to improve the generation and amplification of patient-derived (autologous, non-immunogenic) iPSC and iPSC-derived neuroblasts and neurons for transplantation into areas of neurodegeneration or the injured brain [ 207 , 208 , 209 , 210 , 211 , 212 ]. Conditions that favor glycolysis and fatty acid metabolism should facilitate de-differentiation of adult somatic cells to iPCS and amplification of iPSC, while conditions that suppress glycolysis and induce mitochondrial metabolism should promote efficient differentiation of iPSC to neurons.…”

Stem Cell Therapy: A Promising Treatment of Parkinson’s Diseases

“…Furthermore, a clinical trial was initiated in Japan, Takahashi's lab, where PD patients have received human leukocyte antigen (HLA) matched iPSCs derived dopamine neurons. All these researches can be used as assistance for future approach 3 ; however, it has limitations due to the high risk of teratoma formation after transplantation 9 .…”

“…Pharmacological treatment can be advantageous for many years but prolong use of pharmacological treatment had produced many side effects including, on-off fluctuations and wearing-off phenomenon 3 , confusion, hypotension, hallucination, orthostatic hypotension, fatigue, brain hemorrhage, infarction, and seizures 4 .…”