Concerns Regarding Therapeutic Implications of Very Low-Level Dystrophin.

De Feraudy et al present an elegant study correlating low levels of dystrophin in muscle biopsy with clinical symptoms in dystrophinopathy patients. They selected for subjects who have DMD gene mutations with a higher likelihood of showing leaky (non‐null) dystrophin protein. They found 48 of 90 subjects (53%) to show detectable (residual) dystrophin on muscle biopsy (34 Group B = >0% but <5% dystrophin; 14 Group C = ≥5% normal dystrophin levels); the remaining 42 subjects showed no detectable dystrophin (Group A). Clinical findings in Group A were consistent with extensive published studies of Duchenne muscular dystrophy (DMD), where undetectable levels of dystrophin are consistent with a typical DMD phenotype. Likewise, Group C findings were consistent with previous studies where dystrophin levels greater than 5% are associated with a milder DMD or Becker muscular dystrophy (BMD) phenotype.

The main focus of the authors was the 34 subjects in Group B with very low dystrophin levels (>0% but <5%). Of these 34, 28 (82%) showed splice site or pseudoexon mutations; these types of mutations are expected to result in residual levels of biochemically normal dystrophin protein.

The authors note that “Very low residual dystrophin protein quantity can cause a shift in disease phenotype from DMD toward BMD” (Abstract). The authors note that their data has implications for therapeutic approaches to dystrophin replacement, such as gene therapy, CRISPR gene editing, and exon skipping.

Unfortunately, there is a key limitation to this interpretation of their data that is not noted by the authors. Namely, the large majority of subjects studied (82%) were likely producing low levels of biochemically normal dystrophin (full‐length, 427kDa) from birth. In contrast, there are no current or envisioned therapeutic approaches to DMD that seek to introduce biochemically normal dystrophin. Instead, gene therapy, exon skipping, and envisioned CRISPR approaches aim to introduce biochemically abnormal, semifunctional dystrophin. Although very low levels of biochemically normal dystrophin, especially when present from birth, may mitigate clinical symptoms, this cannot be assumed for biochemically abnormal dystrophin introduced later in life. The study results, although interesting for a genotype–phenotype correlation, should not be extrapolated to being informative in a dystrophin‐restoring therapeutic context.

By not making the distinction of biochemically normal versus biochemically abnormal dystrophin, the authors may inadvertently heighten the expectations of patients, families, physicians, and regulatory agencies regarding anticipated clinical benefit from very low levels of semifunctional dystrophin.