QurAlis Licenses Novel Mechanism for Fragile X Syndrome Treatment

Fragile X syndrome (FXS) is a genetic disorder that causes intellectual disability, behavioral challenges, and various physical characteristics. Research in the past three years has highlighted several key unmet needs and target populations for intervention:

1. Lack of Curative Therapies:

Despite advances in understanding the neurobiology of FXS, there are still no approved curative therapies. Clinical management primarily focuses on addressing specific symptoms and behavioral issues. This represents a significant unmet need, and research continues to explore potential treatments targeting the underlying genetic cause and downstream pathways affected by the lack of fragile X mental retardation protein (FMRP).

2. Focus on Symptomatic Treatment:

Current treatments for FXS primarily target co-occurring conditions such as anxiety, hyperactivity, and seizures. While these interventions can improve quality of life, they do not address the core deficits associated with FXS. There is a need for more research on interventions that target the core symptoms of FXS, such as intellectual disability, language deficits, and social communication challenges.

3. Improving Supportive Care:

Given the lack of curative treatments, improving supportive care for individuals with FXS and their families is crucial. This includes access to appropriate educational and therapeutic services, as well as support for caregivers. Research is needed to identify best practices for supportive care and to develop interventions that address the specific needs of individuals with FXS across the lifespan.

4. Clinical Research Accessibility for Families:

Participating in clinical research can be challenging for families of individuals with FXS, particularly those living in rural areas or with limited resources. Efforts are underway to make clinical research more accessible to these families, such as through the development of decentralized trial designs and the use of telehealth technologies.

5. Collaborative Research on Natural History and Outcome Measures:

To develop effective treatments, a better understanding of the natural history of FXS and the long-term outcomes for individuals with the disorder is needed. Collaborative research efforts are focused on collecting longitudinal data on individuals with FXS to track their development and identify factors that influence their outcomes.

6. Clinical Trial Consortia and Novel Trial Designs:

The rarity of FXS makes it challenging to conduct large-scale clinical trials. To overcome this challenge, clinical trial consortia are being formed to pool resources and expertise. Novel trial designs, such as adaptive trials and platform trials, are also being explored to accelerate the development of new treatments.

7. Addressing the Molecular and Neuronal Mechanisms of Disease:

FXS is a monogenic disorder, meaning it is caused by a single gene mutation. This makes it an attractive target for therapies that aim to correct the underlying genetic defect. Research is ongoing to identify the molecular and neuronal mechanisms of disease, which will inform the development of new targeted treatments.

8. Translating Basic Science Findings to Humans:

One of the challenges in FXS research has been translating findings from basic science and animal models to humans. Efforts are underway to bridge this gap, such as through the development of human-based cellular models and the use of induced pluripotent stem cells.

Target Populations:

Research in FXS focuses on several key target populations:

• Infants and young children: Early intervention is critical for maximizing developmental outcomes in FXS. Research is needed to identify effective early intervention strategies and to develop tools for early diagnosis.

• Adolescents and young adults: This is a period of significant transition for individuals with FXS, and research is needed to address the specific challenges they face, such as social and vocational integration.

• Adults: Research is needed to understand the long-term health and social outcomes for adults with FXS and to develop interventions that promote their well-being.

• Females with FXS: Females with FXS often have milder symptoms than males, but they can still experience significant challenges. Research is needed to better understand the specific needs of females with FXS and to develop tailored interventions.

By focusing on these unmet needs and target populations, researchers hope to improve the lives of individuals with FXS and their families.

FMR1-217 is a little-known RNA isoform of the FMR1 gene, comprised of exon 1 and a pseudo-exon in intron 1. It is generated through mis-splicing of the FMR1 RNA, particularly in individuals with Fragile X syndrome (FXS). While ASO treatment targeting FMR1-217 shows promise for FXS, the provided text does not mention any other indications for which FMR1-217-targeting ASOs are being trialled.

However, the provided text mentions ASO therapies targeting other genes and conditions. These include:

• Tau: In FXS, Tau protein levels are increased. Tau-targeting ASOs have been shown to alleviate autism-like phenotypes in Fmr1 knockout mice, a model of FXS. The intervention model involved treating Fmr1 KO male mice with Tau-targeting ASO and subjecting them to behavioral tests and biochemical analysis.
• FXTAS (Fragile X-associated tremor/ataxia syndrome): Short ASO steric blockers targeting rCGG (RNA containing expanded CGG repeats) have shown therapeutic potential in FXTAS. In FXTAS cells, ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing. In the cytoplasm, ASOs decrease FMRpolyG biosynthesis and accumulation. Delivery of ASO into the brain of an FXTAS mouse model reduced inclusion formation, improved motor behavior, and corrected gene expression.
• ALGS (Alagille syndrome): Reducing Poglut1 levels in postnatal livers of ALGS mouse models using ASOs improved bile duct development and biliary tree formation, preventing liver damage. Cell-based signaling assays indicated that reducing POGLUT1 or mutating POGLUT1 modification sites on JAG1 increases JAG1 protein and signaling.
• Various neurological disorders: ASOs are being used to treat various neurological disorders by modifying gene expression and mRNA splicing. Examples include nusinersen for spinal muscular atrophy, milasen for Batten's disease, STK-001 for increasing SCN1A expression, and an ASO that reduces SCN8A mRNA abundance in developmental and epileptic encephalopathy.
• Other diseases: ASOs are being developed for a wide range of diseases, including cancer, viral infections, and hereditary impairments. Examples include BP1001 for hematologic malignancies and solid tumors, ASOs targeting EZH2 for FXS, and ASOs for spinocerebellar ataxias, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, and Parkinson disease.
• PCSK9: A chemically modified PCSK9 ASO with potential for oral delivery has been developed. Oral dosing in dogs resulted in 7% bioavailability in the liver. Target engagement was confirmed by PCSK9 and LDL cholesterol lowering in cynomolgus monkeys.
• CMT1A (Charcot-Marie-Tooth disease type 1A): ASOs effectively suppress PMP22 mRNA in affected nerves of CMT1A mouse models. Treatment after disease onset restored myelination, MNCV, and CMAP.
• Calmodulinopathies: ASO-mediated depletion of an affected calmodulin gene ameliorated disease manifestations in human iPSC-derived cardiomyocytes and mouse models.
• MDS (MECP2 duplication syndrome): ASO therapy reduced MeCP2 protein in an MDS mouse model and reversed disease features. In a humanized MDS model, ASO mitigated behavioral deficits and restored gene expression.
• Timothy syndrome: ASOs decreased exon 8A inclusion in human cells in vitro and in vivo, rescuing defects in patient-derived cortical organoids and migration in forebrain assembloids.
• SCN8A encephalopathy: ASO targeting Scn2a mRNA reduced seizures and extended lifespan in a mouse model.
• DUX4 (Facioscapulohumeral muscular dystrophy): Systemically delivered ASO targeting DUX4 repressed the transcript, protein, and target gene expression in mice, alleviating muscle pathology.

It is important to note that these are examples of ASO therapies targeting different genes and conditions, and not specifically FMR1-217.