ABSTRACT
The core loss of dopaminergic neurons in the substantia nigra in Parkinson's disease (PD) coupled to the therapeutic benefits of dopaminergic therapies in patients, simplifies the treatment strategy for this disease. In the context of neurotrophic factors, this distils down to the simple question as to whether a factor exists for these cells that can promote their survival in the face of the degenerative disease process. If such a factor exists, and GDNF seems a strong candidate, then one could anticipate that this treatment would be as effective as L-dopa therapy. However it would not be better than this, nor curative, given the extensive pathology in PD. To date a number of clinical trials have been undertaken in which GDNF has been directly delivered to the PD brain. In addition there have been studies in which neurturin (part of the GDNF family) has also been delivered to the CNS using a viral vector delivery system. These trials have produced mixed results. Importantly though, some patients have shown a sustained clinical response to this treatment which correlates with evidence of increased dopaminergic activity in the brain at the site of delivery using F-dopa PET as well as in a single post-mortem study. The challenge therefore is not whether this approach works, because it self-evidently does in some patients, but rather how we can do this more consistently.
Subject(s)
Intercellular Signaling Peptides and Proteins/administration & dosage , Parkinson Disease/drug therapy , Animals , Fluorodeoxyglucose F18 , Glial Cell Line-Derived Neurotrophic Factor/administration & dosage , History, 20th Century , History, 21st Century , Humans , Intercellular Signaling Peptides and Proteins/classification , Intercellular Signaling Peptides and Proteins/history , Multicenter Studies as Topic , Neurons/drug effects , Parkinson Disease/diagnostic imaging , Positron-Emission Tomography , Randomized Controlled Trials as TopicABSTRACT
The clinical and experimental transplantation of bone dates back to the seventeenth century and human allogeneic (homogeneic) bone has been successfully used as an alternative to autogenous bone since 1878, when Sir William Macewen reconstructed the right humerus of William Connell. This review describes how subsequent studies of bone transplantation led to the eventual discovery of a new family of secreted signalling molecules--the bone morphogenetic proteins (BMPs), and the realisation of the important role of polypeptide growth factors in mediating the growth, remodelling and regeneration of the skeleton. The development of suitable alternatives to both autogenous and allogeneic bone has been a goal of bone and biomaterials research for more than 30 years. The first requirement is a biocompatible, bioresorbable, osteoconductive framework supporting the ingrowth of host cells from the recipient bed. Many materials including collagen, calcium phosphate ceramics and synthetic polymers have been widely tested experimentally with varying success. The discovery of osteoinductive BMPs and their availability in recombinant human forms has given considerable impetus to the field. However, progress to date in engineering significant quantities of functional bone tissue in vivo has been disappointing; finding suitable carriers for BMPs has proven to be a greater challenge than expected. The dilemma for the clinician and the biotechnology industry, at present, is that, while recombinant human growth factors are readily available for clinical use, the lack of delivery systems that can adequately mimic both the physical properties and release kinetics of bone matrix remains a major handicap.
