Objective: Describe results of an antisense oligonucleotide (ASO) treatment trial in a patient with ataxia-telangiectasia (AT).

Background: AT is a neurodegenerative, incurable disease of children caused by biallelic variants in the ATM gene. Affected individuals exhibit cerebellar degeneration, immunodeficiency and susceptibility to cancer. The treated subject harbors biallelic pathogenic variants on ATM (NM_000051.3: c.8585-13_8598del and c.7865C>T; p.Ala2622Val) and was referred by ATCP, a family advocacy foundation. The c.7865C>T variant creates a novel splice donor site, truncating the reading frame. Atipeksen, an allele-specific ASO, restores normal splicing in cells with c.7865C>T variant.

Method: Protocol design and dosing were conceived based on an ASO with similar chemistry (nusinersen) accumulated experience. The primary clinical endpoint was the AT-NEST scale. Secondary outcomes included structured global impression of change, physical, occupational therapy and neuropsychological scales. Biomarkers included serum and cerebrospinal fluid neurofilament light chain (NfL), serum alfafetoprotein (AFP), MR imaging with volumetric assessments and digital wearable sensors.

Results: Investigational treatment started at 2 years and 10 months old. ASO was administered intrathecally with escalation, loading and maintenance phases and has been ongoing for 5 years. No serious adverse events were encountered during the trial. Safety-related findings included elevated CSF opening pressure measurements and contrast enhancement of cranial and spinal nerves, both without clear correlation to clinical symptoms. The subject has steady gains in motor development.  She outperforms cohorts of age-matched and genotype-matched individuals with classic  AT (FIGURES 1 AND 2).  NfL were stable and AFP did not rise, as usually observed in AT (FIGURE 3). Digital wearables are comparable to mildly affected individuals  (FIGURE 4). There were no volumetric changes in cerebellar volume compared to untreated AT children.

Conclusion: Results demonstrate encouraging signs of efficacy, in clinical and biomarker endpoints.  A limitation of this work is that intrathecal ASO treatment is not expected to impact systemic manifestations of AT.  Nevertheless, our results provide hope that variant-specific, splice-switching ASOs may be a treatment option to mitigate neurological decline in individuals with candidate variants in ATM.

Figure 1

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Figure 4

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