Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

Abstract

A rare disease is defined by its low prevalence in the general population. Although the fixed threshold slightly varies between different countries, a specific disorder is usually considered to be rare when it affects less than 50–60 in 100,000 individuals. [...]

Introductory Chapter: RNA Drugs Development and Commercialization

“…There are estimated 5000-8000 rare monogenic diseases that can be cured by gene therapies, including CRISPR-Cas [36]. Commercialization of CRISPR technology leads to several clinical trials that utilize CRISPR-Cas9 modalities to correct mutations that cause sickle cell anemia, β-thalassemia, cystic fibrosis, Duchenne muscular dystrophy, Huntington's chorea, and hereditary retinal degenerative diseases [24,37].…”

Is the world ready for human germline genetic editing using CRISPR/Cas9?

“…While polygenic diseases are influenced by multiple genes and may be difficult to edit, monogenic diseases can be eliminated from a human through editing at one target site through a CRISPR system. Over 4000 monogenic mutations account for more than 80% of all rare diseases, which are usually untreatable [58]. By utilizing GGE through CRISPR/Cas9, these normally untreatable diseases can be eliminated from an individual and future generations.…”

Discovery of novel compounds and target mechanisms using a high throughput, multiparametric phenotypic screen in a human neuronal model of Tuberous Sclerosis

“…Successful drug development for central nervous system (CNS) disorders remains a challenge, with clinical failures outpacing successes 1 . Rare genetic diseases with identified genetic causes represent a tractable near-term opportunity for therapeutic development, with ∼70% of the ≥6,000 identified genetically defined disorders having an impact on the CNS 2,3 . Severe neurodevelopmental and seizure disorders represent a disease area of significant unmet medical need, often affecting patients early in life 2,3,4,5 .…”

“…Rare genetic diseases with identified genetic causes represent a tractable near-term opportunity for therapeutic development, with ∼70% of the ≥6,000 identified genetically defined disorders having an impact on the CNS 2,3 . Severe neurodevelopmental and seizure disorders represent a disease area of significant unmet medical need, often affecting patients early in life 2,3,4,5 . When considering non-lesion pediatric epilepsy patients, ∼25-45% have a known genetic cause with identified gene targets spanning diverse cellular functions including ion channels, synaptic proteins, mTOR (mammalian target of rapamycin) pathway regulators and chromatin remodeling and transcription regulators 3,4,5 .…”

“…Severe neurodevelopmental and seizure disorders represent a disease area of significant unmet medical need, often affecting patients early in life 2,3,4,5 . When considering non-lesion pediatric epilepsy patients, ~25-45% have a known genetic cause with identified gene targets spanning diverse cellular functions including ion channels, synaptic proteins, mTOR (mammalian target of rapamycin) pathway regulators and chromatin remodeling and transcription regulators 3,4,5 . Despite our growing understanding of disease mechanisms in epilepsy, the current standard of care still relies on therapeutics seeking to address broad symptoms such as traditional anti-seizure medication (ASM) that globally suppress neuronal excitability through multiple mechanisms, including blocking of voltage-gated ion channels (e.g.…”