Investigation of Individualised Antisense Oligonucleotides (ASOs) in People With Unique Genetic Variants Causing Severely Debilitating, Life Threatening (SDLT) Central Nervous System (CNS) Conditions

This phase 1/2 multicentre, open-label, within-participant dose escalation clinical trial is designed to evaluate individualised antisense oligonucleotides (ASOs) in participants aged 1 year or older with severely debilitating, life threatening (SDLT) central nervous system (CNS) conditions caused by unique genetic variants amenable to correction by an ASO. The trial consists of two parts: Part A: a 30-day Screening period and a minimum 4-week Run-in period followed by Part B: a 48-week Treatment period and Safety Follow-up. For each part, the investigator will determine if the participant is appropriate for participation based on disease stage, rate of disease progression, and likelihood of benefit from ASO treatment at the time that the ASO is available.

Inclusion criteria

• The first participant receiving the individualised ASO, must be between 1 and 17 years of age (inclusive) at the time they receive their first ASO dose.
• The CNS condition is severely debilitating and/or life threatening.
• The identified genetic variant is unique.
• The identified genetic variant is considered the underlying cause of disease.
• The identified genetic variant is amenable to correction by an ASO.
• In the opinion of the investigator, the disease is at a stage that, if halted or slowed by treatment with the individualised ASO, has a reasonable chance to improve the participant's overall disease burden/impact on quality of life.
• In the opinion of the investigator, participant, and/or the participant's legally authorised representative, existing therapies have not resulted in meaningful benefit.

Exclusion criteria

• Known history or presence of any clinically significant hepatic, renal/genitourinary, gastrointestinal, cardiovascular, cerebrovascular, pulmonary, endocrine, immunological, musculoskeletal, neurological, psychiatric, dermatological, or haematological disease or condition other than the primary disease for which the individualised ASO is being developed that in the opinion of the Investigator could affect patient safety or interfere with study outcomes.
• Any contraindication to brain MRI scans.
• Any contraindication to sedation or anaesthesia.
• Any contraindication to lumbar punctures or IT infusions.
• Treatment with another ASO within 24 weeks of Screening.
• Treatment with any gene replacement therapy at any time.