Screening data from 19 patients with late-onset Pompe disease for a phase I clinical trial of AAV8 vector-mediated gene therapy

Abstract

Late-onset Pompe disease (LOPD) is a multisystem disorder with significant myopathy. The standard treatment is enzyme replacement therapy (ERT), a therapy that is lifesaving, yet with limitations. Clinical trials have emerged for other potential treatment options, including adeno-associated virus (AAV) gene therapy. We present clinical parameters and AAV antibody titers for 19 individuals with LOPD undergoing screening for a Phase I clinical trial with an AAV serotype 8 vector targeting hepatic transduction (AAV2/8-LSPhGAA). Reported clinical parameters included GAA genotype, assessments of muscle function, upright and supine spirometry, anti-recombinant human GAA antibody titers, and biomarkers. Variability in measured parameters and phenotypes of screened individuals was evident. Eligibility criteria required that all participants have six-minute walk test (6MWT) and upright forced vital capacity (FVC) below the expected range for normal individuals, and were stably treated with ERT for >2 years. All participants had Pompe disease diagnosed by enzyme deficiency, and all had the common c.-32-13T>G LOPD pathogenic variant. Screening identified 14 patients (74%) with no or minimal detectable neutralizing antibodies against AAV8 (titer ≤1:5). 6MWT distance varied significantly (percent of expected distance ranging from 24% to 91% with an average of 60 and standard deviation of 21). Upright FVC percent predicted ranged from 35% predicted to 91% predicted with an average of 66 and standard deviation of 18. None of the participants had significantly elevated alanine transaminase, which has been associated with LOPD and could complicate screening for hepatitis related to AAV gene therapy. We review the parameters considered in screening for eligibility for a clinical trial of AAV8 vector-mediated gene therapy.

Keywords: Pompe disease; adeno‐associated virus; gene therapy.

FIGURE 1

AAV2/8‐LSPhGAA gene therapy with transduction of hepatocytes. With hepatic expression of GAA, protein then will act in other tissues (heart, muscle, and, at high doses, the brain) following uptake into tissue and protein processing. Ultimately, processed GAA will function in the lysosome. A benefit of liver specific GAA expression is suppression of anti‐GAA antibodies that can limit efficacy of gene therapy.

FIGURE 2

Laboratory tests, 6MWT, and upright spirometry data of study participants. Horizontal bars depict the mean value. For laboratory tests, the reference interval is depicted by brackets. 6MWT, 6‐min walk test; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Cr, creatinine; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GGT, gamma‐glutamyl transferase; Glc4, glucose tetrasaccharide; L, liter; mol, moles; mmol, millimoles; U, unit.