The Rare Responsibility: Signals and Circuits

Dear Impossible Readers,

Rare neurological diseases are a complex and diverse group of conditions that affect the brain, spinal cord, and peripheral nerves. They often occur in ways that impact movement, sensation, or cognitive function, disrupting daily life. These conditions can arise from genetic mutations, developmental issues, autoimmune responses, or degenerative processes, each type presenting unique challenges for diagnosis and treatment. Although individual cases are rare, they collectively highlight the vulnerability and complexity of the nervous system, emphasising why research into these disorders is urgent. Some manifest in infancy, while others develop in adulthood, but all share the challenges of being poorly understood, frequently underdiagnosed, and historically neglected by research. Progress may be slow, but consistent, and scientific advances in the past decade are beginning to make a difference. The examples below illustrate five out of eight hundred known rare neurological diseases. Currently, about 95% of rare diseases lack an approved treatment, leaving patients and families with only supportive or symptomatic care.

Conditions such as spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease (CMT), Huntington’s disease, Rett syndrome, and neuromyelitis optica spectrum disorder (NMOSD) illustrate this diversity. Onset varies from infancy, as in SMA, to early childhood with Rett, or adulthood in Huntington’s and NMOSD, reflecting different windows of nervous system vulnerability. They affect distinct neural systems: motor neurons in the spinal cord (SMA), peripheral nerves (CMT), specific brain regions involved in movement and cognition (Huntington’s), developing brain circuits (Rett), and the optic nerves and spinal cord (NMOSD). This diversity emphasises why treatments must be precisely tailored to the affected cell types, circuits, and underlying mechanisms.

Current research increasingly leverages detailed knowledge of each disease. In SMA, Spinraza® (nusinersen, Biogen) modifies SMN2 gene splicing to increase functional SMN protein levels, while Zolgensma® (onasemnogene abeparvovec, Novartis) delivers a healthy SMN1 gene via AAV9 viral vector for a potential one-time, long-lasting correction. In Huntington’s disease, tominersen (Roche/Ionis) uses antisense technology to target mutant huntingtin RNA, aiming to reduce toxic protein accumulation and slow neurodegeneration. In NMOSD, Soliris® (eculizumab, Alexion/AstraZeneca) blocks complement protein C5, preventing immune-mediated nerve injury, while Uplizna® (inebilizumab, Horizon Therapeutics) depletes B cells to reduce relapse frequency. For Rett syndrome, NGN-401 (Neurogene) delivers a functional MECP2 gene to neurons, aiming to restore normal synaptic function, with careful dosage to prevent overexpression toxicity. In CMT, experimental therapies like ELP-02 (Elpida Therapeutics) for CMT4J and the AAV9-SH3TC2 program from Project Foresee aim to correct Schwann cell gene defects, potentially restoring myelination and nerve conduction. These treatments are promising because they address the root causes (i.e., faulty genes, toxic proteins, or immune misfires) using modern platforms such as viral gene delivery, antisense oligonucleotides, and precision immune modulation.

Looking ahead, several innovative therapies show promise for rare neurological diseases because they aim to intervene at the fundamental level of disease biology. Gene therapy could restore proper protein function in neurons or Schwann cells, preserving muscle strength and nerve signalling, as seen in SMA and now in CMT trials. Gene editing could precisely correct harmful mutations, such as excising or repairing the CAG repeat expansion in Huntington’s, thus halting toxic protein production before irreversible neuronal damage occurs. Cell replacement therapies could repopulate damaged neural circuits with new, functional neurons or supportive glia, an approach particularly relevant in Rett syndrome and advanced neurodegeneration. Immune retraining could reset the immune system in disorders like NMOSD, preventing future attacks while sparing normal immune defence, building on insights from current targeted antibody therapies. Nerve regeneration drugs could repair myelin or promote axon growth, restoring connectivity in diseases like CMT, SMA, or NMOSD, especially when combined with neuroprotective agents to stabilise existing pathways. These strategies are not merely ideas. They are actively being tested, with CRISPR editing, engineered stem cells, and next-generation biologics, bringing long-term, disease-modifying outcomes within reach.

Although these biological breakthroughs are still in development, today’s assistive technologies already help close the gap. Innovations such as powered exoskeletons, advanced mobility aids, and smart neuroprosthetics can provide individuals with rare neurological diseases greater independence and quality of life, enabling them to walk, lift, or carry out daily tasks that might otherwise require constant support. These solutions are not cures, but they represent a future where assistive technology collaborates with medicine to reduce barriers and empower individuals now, while we continue striving for long-term treatments.

Looking forward to your vote,
Yours possibly

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