Chapter 9 - Neurotrophic Factors and Neurodegenerative Diseases: A Delivery Issue

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Abstract

Neurotrophic factors (NTFs) represent one of the most stimulating challenge in neurodegenerative diseases, due to their potential in neurorestoring and neuroprotection. Despite the large number of proofs-of-concept and evidences of their activity, most of the clinical trials, mainly regarding Parkinson's disease and Alzheimer's disease, demonstrated several failures of the therapeutic intervention.

A large number of researches were conducted on this hot topic of neuroscience, clearly evidencing the advantages of NTF approach, but evidencing the major limitations in its application. The inability in crossing the blood–brain barrier and the lack of selectivity actually represent some of the most highlighted limits of NTFs-based therapy. In this review, beside an overview of NTF activity versus the main neuropathological disorders, a summary of the most relevant approaches, from invasive to noninvasive strategies, applied for improving NTF delivery to the central nervous systems is critically considered and evaluated.

Introduction

Due to their potential in providing symptomatic relief and in acting disease's modifying agents, neurotrophic factors (NTFs) are potentially major players in therapeutic interventions for neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and many other neurodegenerative pathologies. Despite the incomplete understanding of the NTF role in neurological diseases, several neurotrophins (as nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF; neurotrophin-3, NT-3; neurotrophin-4; NT-4), glial cell line-derived neurotrophic factor (GDNF), and neurokines (as ciliary neurotrophic factor, CNTF) belonging to the wide NTF family, were described in several in vitro and in vivo experiments of different pathologies aiming to obtain prevention and therapeutic efficacy on neuronal survival (Aron and Klein, 2011). These molecules, due to their distinct neuroprotective properties, demonstrated the cumulative effect of curbing the disease progression and allaying existing symptoms. An extensive literature is given regarding NTF application (as single molecule or in mixture, commercially named Cerebrolysin®) in spinal cord brain injury (Sharma, 2007, Sharma et al., 2010), showing high potential in neurorestoration.

Due to the NTF limits, such as their inability to cross the blood–brain barrier (BBB), their poor stability in fluid environment, the limited diffusion through the brain parenchyma, and the side effects associated with the binding with extra-target receptors, a numbers of papers and researches aimed to find a potentially efficacious strategy for NTF application in therapy.

This review will focalize the discussion on the evolution of the delivery strategies of NTFs on brain, underlining the merits and limits of technological–biotechnological–pharmaceutical research over the past 10–15 years.

Initially, we start discussing the first experiments by using direct free NTF intracerebroventricular (ICV) or intrastriatal administration in different neurodegenerative diseases. In the second section, we analyzed the literature data on the biotechnological “ex vivo” gene therapy approach and pharmaceutical technological approach by using nonviral exogenous transporters.

Section snippets

HD and NTFs

HD is an autosomal dominant hereditary neurodegenerative disorder characterized by chorea (excessive, spontaneous, irregularly timed abrupt movements), disturbed voluntary motor performance, cognitive impairment, and dementia. With an incidence of 4–10 per 100,000, Huntington afflicts approximately 50,000 patients both in Europe and in the United States and another 250,000 persons are genetically at risk. Although the average age of onset is approximately 40 years, the disease may begin at any

NTF Delivery Approaches: Evolution in Therapies

Whereas the attractiveness of NTFs as preventive and curative for a wide range of neurodegenerative diseases, researchers are proposing the application of new and more effective strategies to improve the release of these factors. Besides the application of viral vectors, which are deeply discussed in other chapters (Bjorklund and Kirik, 2009, Bjorklund and Kordower, 2010, Deierborg et al., 2008), naked and/or encapsulated cells secreting NTFs (ex vivo gene therapy/cell-based therapy) and

Conclusion

The extreme large number of experiments on AD, PD, HD, ALS, and other neurodegenerative diseases produced a plethora of data on the efficacy, the safety, and the potential applicability of NTF approach as therapeutic treatment. If it is clear that NTF strategies really represent a tremendous option for neuroregeneration at various levels of neuropathology, several drawbacks in their applicability will be demonstrated and recorded. These limitations, ranging from NTF side effects to their poor

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