Recent Advances in RNA Therapy and Its Carriers to Treat the Single-Gene Neurological Disorders

The development of new sequencing technologies in the post-genomic era has accelerated the identification of causative mutations of several single gene disorders. Advances in cell and animal models provide insights into the underlining pathogenesis, which facilitates the development and maturation of new treatment strategies. The progress in biochemistry and molecular biology has established a new class of therapeutics—the short RNAs and expressible long RNAs. The sequences of therapeutic RNAs can be optimized to enhance their stability and translatability with reduced immunogenicity. The chemically-modified RNAs can also increase their stability during intracellular trafficking. In addition, the development of safe and high efficiency carriers that preserves the integrity of therapeutic RNA molecules also accelerates the transition of RNA therapeutics into the clinic. For example, for diseases that are caused by genetic defects in a specific protein, an effective approach termed “protein replacement therapy” can provide treatment through the delivery of modified translatable mRNAs. Short interference RNAs can also be used to treat diseases caused by gain of function mutations or restore the splicing aberration defects. Here we review the applications of newly developed RNA-based therapeutics and its delivery and discuss the clinical evidence supporting the potential of RNA-based therapy in single-gene neurological disorders.

Monogenic Causes of Strokes

Strokes are the main cause of death and long-term disability worldwide. A stroke is a heterogeneous multi-factorial condition, caused by a combination of environmental and genetic factors. Monogenic disorders account for about 1% to 5% of all stroke cases. The most common single-gene diseases connected with strokes are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Fabry disease, mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS) and a lot of single-gene diseases associated particularly with cerebral small-vessel disease, such as COL4A1 syndrome, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). In this article the clinical phenotype for the most important single-gene disorders associated with strokes are presented. The monogenic causes of a stroke are rare, but early diagnosis is important in order to provide appropriate therapy when available.

Patterns of Inheritance in Neurogenetic Disease

The human genome consists of approximately 22,000 genes that are encoded within the nuclear DNA and embedded in the chromosome. Mitochondria are the only cytoplasmic organelles that have their own DNA. Nuclear gene disorders and mitochondrial inheritance are discussed in this chapter. Nuclear gene disorders follow the patterns of inheritance originally described by Gregor Mendel. They often are referred to as single-gene disorders because 1 or more alleles of only 1 locus are the major determinants of phenotype.

AllelePred: A Simple Allele Frequencies Ensemble Predictor for Different Single Nucleotide Variants

Genomic medicine stands to be revolutionized through the understanding of single nucleotide variants (SNVs) and their expression in single-gene disorders (mendelian diseases). Computational tools can play a vital role in the exploration of such variations and their pathogenicity. Consequently, we developed the ensemble prediction tool AllelePred to identify deleterious SNVs and disease causative genes. In comparison to other tools, our classifier achieves higher accuracy, precision, F1 score, and coverage for different types of coding variants. Furthermore, this research analyzes and structures 168,945 broad spectrum genetic variants from the genomes of the Saudi population to denote the accuracy of the model. When compared, AllelePred was able to structure the unlabeled Saudi genetic variants of the dataset to mimic the data characteristics of the known labeled data. On this basis, we accumulated a list of highly probable deleterious variants that we recommend for further experimental validation prior to medical diagnostic usage.<br>

AllelePred: A Simple Allele Frequencies Ensemble Predictor for Different Single Nucleotide Variants

Genomic medicine stands to be revolutionized through the understanding of single nucleotide variants (SNVs) and their expression in single-gene disorders (mendelian diseases). Computational tools can play a vital role in the exploration of such variations and their pathogenicity. Consequently, we developed the ensemble prediction tool AllelePred to identify deleterious SNVs and disease causative genes. In comparison to other tools, our classifier achieves higher accuracy, precision, F1 score, and coverage for different types of coding variants. Furthermore, this research analyzes and structures 168,945 broad spectrum genetic variants from the genomes of the Saudi population to denote the accuracy of the model. When compared, AllelePred was able to structure the unlabeled Saudi genetic variants of the dataset to mimic the data characteristics of the known labeled data. On this basis, we accumulated a list of highly probable deleterious variants that we recommend for further experimental validation prior to medical diagnostic usage.<br>

Reactivation of a developmentally silenced embryonic globin gene

The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.

Prenatal Versus Postnatal Diagnosis of Meckel–Gruber and Joubert Syndrome in Patients with TMEM67 Mutations

Renal cystic diseases are characterized by genetic and phenotypic heterogeneity. Congenital renal cysts can be classified as developmental disorders and are commonly diagnosed prenatally using ultrasonography and magnetic resonance imaging. Progress in molecular diagnostics and availability of exome sequencing procedures allows diagnosis of single-gene disorders in the prenatal period. Two patients with a prenatal diagnosis of polycystic kidney disease are presented in this article. TMEM67 mutations were identified in both fetuses using a whole-exome sequencing (WES) study. In one of them, the phenotypic syndrome diagnosed prenatally was different from that diagnosed in the postnatal period.