Frontiers in Clinical Drug Research - CNS and Neurological Disorders: Volume 8 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Clinical Drug Research - CNS and Neurological Disorders
- Sprache: Englisch
Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a book series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of central nervous system (CNS) and other nerve disorders. The scope of the book series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of contemporary molecular targets involved in neurological and CNS disorders. Reviews presented in the series are mainly focused on clinical and therapeutic aspects of novel drugs intended for these targets. Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for developing clinical trials and devising research plans in the field of neurology.
The eighth volume of this series features reviews that cover the following topics related to the treatment of a variety of CNS disorders, related diseases and basic research:
- Emerging Innovative Therapies of Spinal Muscular Atrophy: Current Knowledge and Perspectives
- Obesity Induced by The Neurological Drugs
- Molecular Mechanism of Nervous System Disorders and Implications for New Therapeutic Targets
- Glioma Imaging and Novel Agents
- Screening Models for Neuroleptic Drug-Induced Hyperprolactinemia: A Mini-Review
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Seitenzahl: 312
Veröffentlichungsjahr: 2020
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PREFACE
Neurodegenerative disorders are some of the overwhelming challenges modern medicine is facing. To find efficacious treatments for these disorders, we still need to advance our understanding of the various events and cellular processes that lead to neurodegeneration. These include pathological protein aggregation and factors that cause the death of neuronal cells.
Volume 8 of our book series Frontiers in Clinical Drug Research - CNS and Neurological Disorders features a set of exciting and remarkable new research projects presented by an emerging and expert panel of researchers. They have reviewed innovative research studies that could lead to a richer interpretation of the essentials needed to understand the nerve cell functions and/or failures.
This book presents cutting-edge, and in-depth investigations that outline neurodegeneration at the cellular level. It discusses new trends in neurodegenerative research aimed to slow down the progression of neurological ailments, offering hope to people with these debilitating and at times incurable illness. Thus chapter 1 covers the current knowledge and perspectives surrounding the emerging innovative therapies of spinal muscular atrophy, as well as pin-pointing the molecules that offer potential new treatments for this debilitating condition. Chapter 2 highlights the obesity induced by the usage of neurological drugs such as antiepileptic, antipsychotic, and antidepressant drugs. Chapter 3 discusses the development of new therapeutic targets based on the understanding of the molecular mechanisms that lead to infectious, functional, structural, and degenerative disorders of the nervous system. Chapter 4 briefly reviews the screening models for neuroleptic drug-induced hyperprolactinemia. The last chapter 5 evaluates the glioma imaging modalities and the novel agents that are being implicated to image glioma.
In short, this book presents a scholarly collection of research articles from the budding as well as established scientists in the field. It is hoped that the presentations will lead to a better understanding by the neuroscience community of the underlying mechanisms of brain disorders, leading to more effective treatments.
We are grateful for the timely efforts made by the editorial personnel, especially Mr. Mahmood Alam (Director Publications), and Mrs. Salma Sarfaraz (Senior Manager Publications) at Bentham Science Publishers.
Atta-ur-Rahman, FRS Honorary Life Fellow Kings College University of Cambridge Cambridge UKList of Contributors
Emerging Innovative Therapies of Spinal Muscular Atrophy: Current Knowledge and Perspectives
Tai-Heng Chen1,2,3,*,Ching H. Wang4,5Abstract
Spinal muscular atrophy (SMA) is a rare neuromuscular disorder charac- terized by the degeneration of motor neurons (MNs) in the spinal cord resulting in progressive muscle atrophy and weakness. Due to its early onset and severity of symptoms, SMA is notable in the health care community as one of the most common causes of early infant death. SMA is caused by missing a functional survival motor neuron 1 (SMN1) gene in patients who produce deficient levels of survival motor neuron (SMN) protein from a copy gene (SMN2), but that could not sustain the survival of spinal cord MNs. Before the end of 2016, there was no cure for SMA, and management only consisted of supportive care. Since then, several therapeutic strategies to increase SMN protein have developed and are currently in various stages of clinical trials. The SMN2-directed antisense oligonucleotide (ASO) therapy was first approved by the FDA in December 2017. Subsequently, in May 2019, gene therapy using an adeno-associated viral vector to deliver the DNA sequence of SMN protein was also approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs, and thereby improve motor function and survival. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a single therapeutic modality may not be sufficient. Neither therapy currently available provides a complete cure. Several other treatment strategies are currently under investigation. These include: establishing an early diagnosis to enable early treatment, a combination of the different treatment regimens, and frequency, dosage, and route variations of drug delivery. Understanding the underlying mechanisms of these treatments is the other area of needed study.
INTRODUCTION
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by the degeneration of alpha motor neurons (MNs) in the spinal cord leading to muscle atrophy and weakness. Although recognized as a rare disease with an estimated worldwide incidence of ~1/10,000 live births, SMA is the second most common autosomal recessive genetic disorder and the most common monogenic disease-causing early infant death [1, 2]. The carrier frequency varies from 1 in 38 to 1 in 72, among different ethnic groups with a pan-ethnic average of 1/54 [3].
SMA was firstly reported in two infant brothers by Guido Werdnig in 1891 and later seven additional patients by Johan Hoffmann from 1893 to 1900 [4]. In 1995, scientists discovered the genetic basis of SMA, which involved the missing of a functional survival motor neuron 1 (SMN1) gene [5]. About 95% of SMA cases are caused by mutations or deletions in the SMN1 gene in chromosome 5q11.2–q13.3.2, thus termed as 5q SMA. Deletion or mutation of the SMN1 gene results in lacking the production of survival motor neuron (SMN) protein, a vital protein that enables the survival of spinal cord MNs. The degeneration of MNs, in turn, causes widespread muscle atrophy and weakness, the primary symptoms of SMA [3, 6].
At the molecular level, SMN protein acts as a multifunctional protein ubiquitously expressed in almost all somatic cells. SMN is involved in many cellular functions, including mRNA editing, splicing, and axonal transport [7]. The most appreciated canonical role of SMN is to serve as an essential ribonucleoprotein (RNP) for mRNA splicing. SMN protein is embedded in a complex with seven Gemins and UNR-interacting protein (UNRIP) that shuttles Sm protein onto nascent uridine-rich noncoding RNAs (snRNAs) upon their export to the cytoplasm, thereby creating small nuclear RNPs (snRNPs) that form spliceosomes in the nucleus [8-10]. In addition to facilitating snRNP assembly, the SMN complex plays a role in assisting arginine methylation of specific splicing-related proteins that are involved in pre-mRNA splicing [11, 12]. All cells are dependent upon SMN, but the reduction in snRNPs assembly can be particularly critical for specific cell types, particularly in MNs. Studies on SMA animal models have revealed a direct correlation between the ability to assemble snRNPs and SMA severity, and delivery of mature snRNPs even without the SMN component is sufficient to rescue SMA phenotypes [13-15]. Such an outcome implies that SMN protein levels might affect the splicing of SMN pre-mRNA to include exon 7 through an autoregulatory loop, thereby influencing a general process of snRNP biogenesis [16]. Besides the canonical role of SMN in the splicing machinery, other studies have highlighted its multiple roles in cellular functions. For example, the recruitment of SMN protein is also involved in many other essential cellular pathways, including DNA repair and protein and mRNA transportation along axons of MNs [17-19]. Collectively, studies to date support that loss of SMN-RNP complex assembly and its activity results in a series of different cellular pathways that lead to SMA. However, it is still unclear how a deficiency in the ubiquitously expressed SMN protein can selectively cause the degeneration of MNs [7]. Increasing evidence suggests SMN playing a pivotal role beyond the MNs. The autoregulatory mechanism of SMN may explain the more detrimental effects of SMN deficiency that could result in the selective MN degeneration in SMA. Nevertheless, the multifaceted roles of SMN protein are still under investigation, and it is unclear how a deficiency in ubiquitously expressed SMN can selectively cause the dramatic MN degeneration. The cell autonomous effects related to deficient SMN are responsible for the MNs degeneration; however, it does not account for the full SMA phenotype, implicating not only dysfunction of neural networks but other non-neuronal cell types involved in the disease process [20, 21]. For example, recent studies point that the MN survival and functionality of SMA animal and cellular models are highly dependent on glial cells, which play an essential role in neuronal communication and neuroinflammation [22, 23]. These findings imply that SMA could also be a neuroinflammatory disease.
Fig. (1) illustrates the genetic basis and pathogenesis of SMA. It also explains the cause of phenotypic variations. Complete loss of SMN protein resulted from deletion/mutations of smn or SMN1 (in humans and bonobos only) leads to embryonic lethality to all species [24, 25]. In the genomes of higher primate species, including humans, there is a nearly identical copy of SMN1, called SMN2 [5]. SMN2 differs from SMN1 by a single nucleotide (C-to-T) substitution in the exon 7. This single base-pair variation leads to skipping of exon 7 during RNA splicing and produces an SMN2 transcript lacking exon 7, called SMN∆7. Unlike the SMN1 gene, only a small amount of full-length (FL) mRNA is produced by the SMN2 gene due to this skipping of exon 7 during RNA splicing [26]. In contrast to the FL-SMN protein, SMN generated by the SMN∆7 transcript cannot oligomerize efficiently, resulting in truncated morphology, which is degraded rapidly [7, 9]. In SMA patients, alternative splicing in the SMN2 gene allows it to produce only ~10% of FL-SMN transcripts and protein. This low amount of SMN protein is sufficient to prevent embryonic lethality, but cannot fully compensate for the missing SMN1. In the human genome, there are variable numbers of SMN2 gene copies, and the amount of SMN protein produced is directly correlated with the copy number of the SMN2 gene. Consequently, the SMA severity is inversely related to the number of the SMN2 gene copy; the higher the copy number, the less severe the SMA phenotype. However, this phenotype-genotype correlation can be affected by other factors. Recent studies showed that other cellular mechanisms, like positive or negative disease modifiers, may also involve in the modulation of SMA clinical severity. For example, rare SMN2 variants (c.859G>C), as well as independent modifiers such as plastin 3 or neurocalcin delta, can further influence the disease severity [27-29]. In brief, the loss of the SMN1 gene leads to SMA, whose severity is partially modified by various copies of SMN2.
Fig. (1)) Genetic basis of spinal muscular atrophy (SMA) [30]. In a healthy individual, full-length (FL) survival motor neuron (SMN) mRNA and protein arise from the SMN1 gene. Patients with SMA have homozygous deletion or mutation of SMN1 but retain at least one SMN2 (indicated with an asterisk in the solid-border box on the right). However, SMN2 can be dispensable in a healthy individual (indicated with an obelisk in the dotted-border box on the left). This single-nucleotide change in exon 7 (C-to-T) of SMN2 causes alternative splicing during transcription, resulting in most SMN2 mRNA lacking exon 7 (∆7 SMN). About 90% of ∆7 SMN transcripts produce unstable truncated SMN protein, but a minority include exon 7 and code for FL, which maintains a degree of MN survival.CLINICAL CHARACTERISTICS OF SMA
The most severe type of SMA presents in infancy. Correlated with the onset of symptoms, here is a rapid and catastrophic loss of connectivity between MNs and their innervated muscles with depletion of neuronal endplates [1, 3]. As a consequence of MN degeneration, progressive muscle wasting and weakness become the main feature of SMA. These clinical symptoms presented with a spectrum of severity ranging from extremely compromised neonates with immediate respiratory failure to late-onset, minimal limb weakness in adulthood. However, unlike the relentless decline of motor function observed in other motor neuron disease (MND) like amyotrophic lateral sclerosis, patients with intermediate and milder forms of SMA tend to maintain their level of motor function over many years [31-33]. Interestingly, cognitive function is generally intact in patients with SMA, and they often have higher than average intelligence [1].
Phenotypes and Classifications of SMA
SMA presents with a broad range of clinical severity, such as the age of onset and rate of progression. There are variabilities between and within each phenotypic subtype that constitutes a clinical continuum [34, 35] In general, SMA is classified into three main phenotypes based on age at symptoms/signs onset, and highest motor function achieved [3, 29, 35]. However, some patients with SMA are outliers on either end of the phenotypic spectrum. Besides, subclassification has also been proposed in SMA types 1 and 3, and sometimes in type 2 phenotype Table 1.
At the most severe end of the spectrum, patients with type 0 SMA (categorized into type 1A by some authors) are usually associated with prenatal onset of signs, such as a history of decreased fetal movements [36]. These rare cases usually present with arthrogryposis multiplex congenital and have profound hypotonia and respiratory distress soon after birth [37]. Life expectancy is extremely short, and if untreated, most of them are unable to survive beyond one month of age [1, 38].
Type 1 SMA patients account for more than 50% of the total incidence of SMA. As a general rule, infants with SMN1 biallelic deletions and only two copies of SMN2 have a 97% risk of this most severe phenotype of SMA. These patients usually present with symptoms onset before six months and are described as non-sitters because they never achieve independent sitting, which is the beginning of all major motor milestones. Notably, congenital heart defect is a feature of severe SMA phenotype, especially in SMA types 0 and 1 [39]. Respiratory muscle dysfunction attributes to most cases of mortality within the first two years of life. Studies of SMA natural history showed the median age of death is 13.5 months and the need for permanent ventilation (>16 hours per day) at 10.5 months for patients with two copies of SMN2 [40, 41].
Patients with the intermediate severity of type 2 SMA (Dubowitz’s disease) usually develop weakness within 7–18 months of age. Failure to achieve the major developmental milestones of independent walking brought these patients to clinical attention. Patients usually exhibit areflexia and proximal weakness that is more severe in the lower extremities than upper extremities. Although these patients can maintain a sitting position unaided (thus named “sitters”) and some can even stand with leg braces, none can walk independently. Fine tremors with digit extension or hand grips are commonly observed. Due to the wide variation of symptom severities in this group of patients, further classification has been proposed to subdivide them into 2.1 to 2.9 subtypes within type 2 SMA based on their functional levels [38, 42]. Weak swallowing might deter weight gain. Kyphoscoliosis usually develops and can result in a restrictive lung disease if not intervened by surgical or orthotic procedures. Similar to patients with type 1 SMA, clearing of airway secretions and coughing becomes difficult because of poor bulbar function and weak intercostal muscles. The majority of patients with type 2 SMA can survive into adulthood, with 93% surviving to 25 years. However, these patients usually require aggressive supportive care due to compromised swallowing ability and respiratory issues when they enter the adolescent years [43].
Type 3 SMA is the mildest form of SMA (also called Kugelberg-Welander disease). Patients usually have symptoms onset around 1.5 years of age. They can stand unsupported and walk independently. However, these patients exhibit an extensive symptom heterogeneity and are sometimes misdiagnosed with myopathy or muscular dystrophy. These patients can be further divided into two subgroups according to their age of onset: patients with type 3A have an onset of symptoms between 18 months and three years, and patients with type 3B usually present after three years [32]. Their distribution of weakness is similar to that seen in patients with types 1 and 2 SMA, albeit of a much slower progression. Some patients may be ambulatory until their middle age [42]. In clinical trials, type 3 patients who lost their ability to walk independently in childhood are often grouped with the non-ambulatory patients, or sitters, because they can be assessed with the same outcome measures.
At the other mildest end of the spectrum is an adult-onset form, known as type 4 SMA, who presents onset symptoms, usually a weakness of lower extremities, after the second decade. Type 4 patients have a good prognosis with ambulation into adulthood and a mostly average life span [44].
The Implication of Phenotypic Classification in SMA Clinical Trials
Previous investigations concentrated on the natural history of SMA, and the efforts to develop standardized tools of outcome measures have assisted in achieving clinical trial readiness in the field [45, 46]. Early clinical trials used SMN2 copy numbers as a criterion for patient enrollment [47]. However, studies showed that while patients with a higher number of SMN2 copies generally have a milder phenotype, this prediction is not always accurate [29]. Other prognostic factors, such as the age of onset of symptoms within each SMA subtypes, have been identified [38].
Although the assignment of trial groups according to SMA subtypes (i.e., types 1, 2, and 3) has some clinical advantages, it is not always the best way to stratify patients. Within each SMA subtype, there could be the heterogeneity of phenotypes due to different stages of disease progression (e.g., some type 3 patients are still ambulatory, and some have lost it). Therefore, using the current motor function level (such as ambulant status) may be more relevant to clinical trial design and outcome measures. Several clinical trials have been conducted by stratifying patients into non-sitter, sitter, and walker to achieve the uniformity of functional level and use of appropriate outcome measures [48]. This approach acknowledges the SMA phenotypes as a continuum and focuses on the current functional status and the therapy response.
Furthermore, pulmonary function assessment may better reflect disease state than muscle strength [49]. Nevertheless, repeat evaluations are imperative before assigning a patient to a specific SMA type. In particular of patients with SMA types 2 and 3, the onset, time course, and extent of MN loss has not been well established, yet are vital in determining whether there is a specific therapeutic window for these patients with milder phenotypes.
IMPACTS OF EVOLVING SUPPORTIVE CARE IN SMA THERA- PEUTIC ERA
The successful disease modification of the newly developed therapies have altered the SMA clinical landscape and raised the needs for new supportive care and treatment guidelines [48, 50]. The need for multidisciplinary care standard for SMA patients was evident for quite sometime before the establishment of the standard of care (SOC) recommendations. Clinical outcome of SMA patients varies greatly depending on their demographic locations and the care they received. In 2007 a Consensus Statement for Standard of Care in Spinal Muscular Atrophy was published by an international multidisciplinary team addressing the comprehensive care standard for patients with SMA [51]. With the advent of disease-modifying treatments, and updated two-part SOC document was published in 2018 [52, 53]. The multidisciplinary team, which includes medical specialists in neurology, pulmonology, acute care, nutrition support, gastroenterology, orthopedics, physical therapy/rehabilitation, and other medical subspecialties, should continue to provide comprehensive care as the patients undergo specific therapies Fig. (2). Implementation of comprehensive SOC also plays a vital role in drug development because it eliminates the variability of treatment outcomes due to variable care received. Therefore, standardized care must be implemented for all patients participating in clinical trials [35, 48]. As such, updated SOC guidelines for SMA will continue to be necessary as more therapeutic modalities become available, and the definition of care standard may be changed with time.
Fig. (2)) Paradigm of multidisciplinary care of SMA, incorporating disease-modifying therapies with supportive care [30]. Novel disease-modifying medications and evolving multidisciplinary supportive management need to occur concomitantly to achieve the best possible outcome for SMA patients.In the therapeutic era, we reasonably expect that type 1 SMA patients will likely transition into less severe types 3 and 4 once treated, giving them a more extended or average lifespan. It remains unclear whether persistent interventions will be required, and a complete long-term reversal of symptoms will be attained. Unfortunately, because there is a paucity of studies investigating the support and medical needs of type 4 SMA patients (and soon the treated patients), it is unknown whether such lifespan extension will reveal new, previously unknown, comorbidities that could arise with age in this new, modified SMA affected population. In parallel with pre-clinical advances, continued evolution in multidisciplinary care with technological advances should be pursued, particularly for those with milder phenotypes after disease-modifying therapy.
RECENT ADVANCES IN INNOVATIVE THERAPEUTICS IN SMA: FOCUSING ON SMN AND BEYOND
In general, the therapeutic strategies in SMA can be divided into those targeting SMN protein and those independent of SMN. The latter can be further divided into eight different therapeutic approaches Fig. (3). The fact that SMN2 copies can produce a variable amount of SMN protein to compensate for the lack of a functioning SMN1 in SMA provided an initial therapeutic target for attempting to augment the SMN2 function to increase SMN protein [54]. This approach was successful by the initial proof-of-concept studies [55, 56]. Meanwhile, increasing evidence has shown that SMN deficiency produced pathology beyond MNs and involved cells both within and outside the CNS. Pathological changes have been identified in several peripheral organs, such as the cardiovascular system, gastrointestinal tract, immune system, and kidneys, both in pre-clinical animal models and in SMA patients [20, 50, 57-60].
Fig. (3)) Therapeutic approaches for SMA [30].We summary the updated information of pre-clinical and clinical trials for potential therapeutic agents in Table 2. Understanding the precise underlying mechanisms of whether the therapy relies on SMN-dependent or SMN-independent pathways remains an essential aspect of therapeutic development for SMA [61]. Among these therapeutic approaches, upregulating SMN protein production by modulating SMN2 splicing or replacing an exogenous SMN1 gene has proven the most successful [62, 63]. These two forms of therapeutics have been introduced into commercial use after approved by the FDA over the past two years. Parallel to these SMN-dependent approaches, several SMN-independent therapeutics such as neuroprotective agents, myostatin inhibitors, skeletal muscle troponin activator, and stem cell therapy are being developed as possible adjunctive therapies [64, 65]. Importantly, the recent breakthrough of novel therapies for SMA may also inspire similar approaches for other genetic MND. For example, spinal muscular atrophy with respiratory distress type 1 (SMARD1) caused by IGHMBP2 gene mutation is a non-5q SMA, which accounts for the second most common MND of infancy following SMA [66].
In the following sections, we will describe the therapeutic development of several SMN-dependent compounds and the status of several SMN-independent targeting treatments aiming at both CNS and-non-CNS tissues.
The therapeutic approaches for SMA are generally categorized into SMN-dependent and SMN-independent therapies, which can be further divided into four branches of development, respectively. The yellow circle color of SMN1 gene replacement therapy of SMN-dependent pathway indicates its difference from other three therapies in the SMN-dependent category which mainly target SMN2. The dash lines of outer rims connecting the SMN-dependent and SMN-independent approaches imply the potential for combinatory effect as a “cocktail therapy” for SMA.
SMN-DEPENDENT THERAPIES FOR SMA
SMA has been regarded as a unique model disease for translational research due to its well understood molecular pathogenesis and a clear therapeutic target of SMN2 gene retained in all SMA patients. As a proof-of-concept, the initial approach was to modify SMN2 gene expression in order to increase the FL-SMN transcripts to replace the function of the missing SMN1 gene [1, 3, 29, 50]. As shown in Table 2, this idea prompted investigations into the upregulation of SMN2 transcription by activating promoter of the gene, enhancing exon 7 inclusion during splicing, modulating SMN protein translation, and preventing SMN protein degradation. Another way of replacing the SMN1 gene function would be to introduce an exogenous SMN1 gene via a viral vector directly.
Previous SMN-Targeted Clinical Trials with Equivocal Outcomes
Early studies investigating the therapeutic potential of histone deacetylase inhibitors (HDACIs) and demonstrated their ability to increase SMN2 transcription through modification of chromatin structure in vitro and in SMA animal models [56, 67]. Histones are core proteins of chromatin that play a role in epigenetic regulation of gene expression via their acetylation status. Several potential HDACIs were initially proposed to benefit SMA, including valproic acid, phenylbutyrate, and trichostatin A, which activated the SMN2 promotor and increased the FL-SMN production [65, 68].
