Frontiers in Clinical Drug Research - Central Nervous System: Volume 2

Atta-ur-Rahman

• Publisher: Bentham Science Publishers
• Year: 2016
• ISBN:
  9781681081892
• Topic: Physical Sciences
• Subtopic: Clinical Chemistry

Frontiers in Clinical Drug Research – Central Nervous System presents the latest researches and clinical studies on the central nervous system (CNS). It covers a range of topics such as the development and pathophysiology of the brain and spinal cord, physiological sites of drug action in the CNS and clinical findings on drugs used to treat CNS defects due to injury or impaired development. In addition to clinical research on humans, the book also highlights other avenues of CNS medicine and research such as pain medicine, stem cell research, pharmacology, toxicology and translational models in animals.
The second volume of the series features chapters on the following topics:
- Nucleic acids as drugs for neurodegenerative diseases
- Cellular Cysteine Network (CYSTEINET):
- Non-motor Symptoms in Parkinson's Disease and drug therapies
- Multi-modal pharmacological treatments for major depressive disorder

Nucleic Acids as Drugs for Neurodegenerative Diseases

INTRODUCTION

Neurodegenerative diseases are a broad spectrum of central nervous system (CNS) disorders that are characterized by a chronic and progressive course, and share a common hallmark consisting of the selective death of specific neuronal populations. The clinical manifestation of each neurodegenerative disease depends on the specific type of neurons that is involved. These disorders include both inherited diseases caused by single gene mutations (e.g., Huntington’s disease and several spinocerebellar ataxias) and common diseases of more complex origin (e.g., Alzheimer’s disease and Parkinson’s disease).

Common age-related neurodegenerative diseases, along with cerebrovascular disorders, are currently among the leading causes of death and morbidity in Western countries, and their prevalence is destinated to further rise as a consequence of average lifespan increase. This type of diseases exerts a growing impact from the societal and economic point of view, which makes the development of strategies for early detection as well as effective and safe treatments more important than ever.

Notwithstanding the significant advance made in recent years towards the elucidation of the pathogenic mechanisms underlying these various neurological disorders, no cures currently exist and therapeutic interventions are still limited to palliative and symptomatic treatment. Therefore, much effort is being made to develop innovative therapeutic strategies, and, among these, nucleic acid-based strategies may have the potential for substantial advancements.

Nucleic acid-based therapeutic strategies, collectively known as gene therapy, refer to the delivery of nucleic acid molecules to target cell populations in order to achieve either the over-expression of a therapeutic gene, or inhibit the expression of an endogenous harmful gene, or even restore the function of a defective gene [1].

It was around the 1970s when the idea to deliver a therapeutic gene to treat human diseases came out [2], and the first foreseen application was the treatment of recessively inherited diseases by delivering a wild type copy of the defective gene responsible for the disease. Since then, the potential of gene therapy approach has been considerably increased by the development of novel kinds of therapeutic nucleic acids. Moreover, the range of candidate diseases for this treatment modality has expanded beyond that of inherited diseases to include more common diseases, such as cardiovascular disorders, cancer, and degenerative disorders of CNS.

Two main nucleic acid-based approaches, “gene addition” and targeted inhibition of gene expression, are currently investigated for the treatment of neurodegenerative diseases. The earliest attempts at neurodegenerative disease gene therapy focused on the “gene addition” approach. Independent of the actual cause of neuron depletion, a therapeutic goal common to most neurodegenerative diseases is to preserve the viability and function of the residual neurons. Delivery of genes coding for neurotrophic factors as neuroprotective/neurorestorative agents is therefore an intensely investigated strategy. Further candidate therapeutic genes are chosen for each specific disease on the basis of available knowledge about the disease causing mutation or the pathogenetic mechanism underlying the disease.

More recently, advances in gene silencing technology have led to the evaluation of strategies aimed at selectively interfering with the pathogenetic mechanisms underlying disease phenotype. These strategies are applied to the targeting of gain-of-function mutant alleles in dominantly inherited diseases as well as genes known to contribute to the phenotype of more complex diseases.

This chapter illustrates the rationale and current status of nucleic acid-based strategies for the treatment of two neurodegenerative movement disorders, Huntington’s disease and Parkinson’s disease.

NUCLEIC ACID-BASED THERAPEUTICS

Several types of nucleic acid-based therapeutics have been proposed. All those therapeutics may be grouped into two main classes, i.e., protein coding nucleic acids (DNA molecules) and non-coding nucleic acids (DNA or RNA molecules) with regulatory function (regulatory nucleic acids).

Protein Coding Nucleic Acids

The use of protein coding nucleic acids (usually cDNAs, i.e., the double-stranded DNA copies derived from the gene mRNAs) is aimed at providing the relevant cells with a protein that either permits to rescue a missing function or supplies a new function able to counteract or alleviate the disease. Candidate therapeutic genes are obvious in the case of recessively inherited neurodegenerative diseases due to loss-of-function mutations, such as, for example, lysosomal storage diseases or recessively inherited forms of Parkinson’s disease. For these disorders, the strategy relies on the delivery of the wild-type copy of the disease gene in order to supply the missing or defective protein. On the other hand, the choice of candidate therapeutic genes for non-inherited as well as dominantly inherited monogenic neurodegenerative diseases relies on the available knowledge about pathogenetic mechanisms.

A strategy that widely applies to the treatment of neurodegenerative diseases is the delivery of genes coding for neurotrophic factors (NTFs) as neuroprotective/neurorestorative agents. NTFs are secreted proteins expressed in both developing and adult nervous system. They regulate the development, maintenance, function and plasticity of the nervous system, and exert their actions through binding and activating specific cell surface receptors. A single neuronal group can respond to several NTFs and a given NTF affects many neuronal types. Neurons can derive trophic support not only from innervated cells (retrograde transport), but also from afferent neurons (anterograde transport), or even themselves (autocrine mechanism). Therefore, the trophic requirement of a neuronal population is due to a complex interaction between different NTFs that contribute to the highly specific connectivity of the nervous system. Importantly, NTFs not only promote neuron survival (survival effect), but can also protect specific neuronal populations against different types of brain insults (neuroprotective effect), and repair already damaged neurons (neurorestorative effect). In consideration of these properties, NTFs have been considered ideal candidates as neuroprotective and neurorestorative agents.

A peculiar type of therapeutic genes are those coding for gene-engineered antibodies aimed at ablating the abnormal function of specific intracellular proteins [3, 4]. Natural antibodies can be genetically engineered to obtain the so-called “intrabodies” (iAbs), i.e., smaller molecules which are more suitable to be intracellularly expressed. Among intrabody formats, the first choice is the single chain variable fragment (scFv) which consists of the variable domains of the immunoglobulin heavy (VH) and light (VL) chains kept together by a flexible polypeptide linker. The resulting molecule is a monovalent antibody fragment which still retains the binding specificity of full-length antibody but is encoded by a single gene. Intrabodies for...