State‐of‐the‐art therapies for Rett syndrome

Abstract

Rett syndrome (RTT, Mendelian Inheritance in Man [MIM] 312750) is a rare genetic disorder leading to severe and progressive intellectual disability, almost exclusively affecting female children with an incidence of approximately 1 in 15 000 live births. It was first characterized in 1966 by Andreas Rett, a psychiatrist from Austria who specialized in neurodevelopmental disorders. 1 However, it was not until two decades later that RTT became officially recognized after a Swedish neurologist, Bengt Hagberg, observed patients with similar symptoms and decided, with French and Portuguese colleagues, to publish an article describing the syndrome. 2 RTT alone accounts for 10% of cases of profound intellectual disability of genetic origin in females. 3 RTT is a severe developmental disorder. 4,5 Females with RTT begin life apparently 'healthy'. However, from 6 to 18 months of age they undergo regression of early milestones, with deterioration of motor skills, eye contact, speech, and motor control; they then develop a range of neurological symptoms, including anxiety, respiratory dysrhythmias, and seizures. 5 Since most cases are sporadic, identifying a causative locus has been fraught with difficulties. Initially RTT was considered a purely nervous system pathology including neurons and astrocytes but in recent years it has emerged that RTT is also a neurometabolic pathology involving cholesterol abnormalities. 6,7

"Treatment for Anxiety and Future Treatments in Rett Syndrome"

“…are being developed to circumvent the immune-mediated toxicities associated with AAV. The innate and adaptive immune response against AAVs, highlighting the challenges and potential strategies to mitigate these responses, thereby enhancing the therapeutic potential of AAV gene therapy will be possible in the near future [30,31]. Actually, Aysha gene Therapies has announced the initiation of clinical development of gene therapy with T TSHA-102 in adult women with RTT in Canada.…”

Inhibitory Synaptic Influences on Developmental Motor Disorders

“…Males that are affected develop the syndrome extremely rapidly (within a few days postpartum) and die within 2 years [ 206 , 213 ]. Recently, there have been major advancements in the amelioration of Rett syndrome via growth factors (IGF1), MECP2 gene transfer, genetic corrections and approaches focusing on downstream targets in rodent models and human trials [ 207 , 214 , 215 , 216 , 217 , 218 , 219 ]. Despite these promising advances targeting MECP2 and its related downstream protein, there remains an influence on Rett syndrome symptoms of altered inhibitory neurotransmission on the motor phenotypes and altered chloride homeostasis [ 220 ].…”

Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders—Implications for Individuals with Rett Syndrome: A Systematic Review

“…In other instances, where some cell types might be refractory to current AAV gene delivery methods, AAV can be modified with novel capsids with preferential tropism to specific cell lineages, for example, targeting oligodendrocytes in white matter disease [113]. The literature regarding AAV9 and gene replacement methods in animal models of RTT is extensive and has been reviewed recently [13]; however, there are some additional important points to consider. In 2017, AAV capsids were developed that could increase their transduction efficiency within the Autonomic Nervous System (ANS) when delivered systemically [114], and this approach was used to increase the transduction efficiency of a transgene cassette in a mouse model of RTT [115].…”

“…This suggests that molecular therapies could potentially restore neuronal defects and, depending on the molecular therapy used, may offer symptom improvement across the lifespan of the disorder. The feasibility of gene therapies in neurodevelopmental disorders has been described previously [12], and the potential for transformative therapies focusing on RTT has also been discussed in literature [13][14][15][16][17]. Gene therapy is complicated in RTT due to the functional mosaic expression of MeCP2 in the brain cells.…”

“…The evidence synthesis covers gene therapy and other gene editing approaches such as CRISPR/Cas9. However, X-chromosome reactivation and RNA editing methods could also be viable options for treating individuals with RTT [13,61,127]. Recently, RNA editing of MeCP2 expression levels in the brainstem has been shown to alleviate symptoms in a mouse model of RTT [128] and epigenome editing was used to reactivate silenced MECP2 on the inactive X chromosome in RTT-derived stem cells and neurons [129].…”