Engineering α-glucosidase to improve protein stability and cellular uptake for the potential treatment of Pompe disease

Botham, Rachel C.; Hallows, William C.; Reddy, C. Madhava; Dellas, Nikki; Homan, David; Lao, Jessica P.; Zhu, Cynthia; Chng, Chinping; Sero, Antoinette; Miller, M.T.; Choi, Su Jin; Sun, Baodong; McCluskie, Kerryn; Huisman, Gjalt W.; Silverman, Adam P.

doi:10.1016/j.ymgme.2020.12.028

Cited by 1 publication

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“…The use of protein engineering strategies has also shown promise in generating more stable GAA proteins, an application that would complement both ERT and gene therapy efforts. Using directed evolution and high-throughput screening methods, Dellas et al and Botham et al demonstrated that modified GAA amino acid sequences, containing up to 30 amino acid changes from the reference sequence, could drastically help increase protein stability at neutral and low pH ranges, increase expression and increase cellular uptake in Pompe disease fibroblasts and myoblasts [ 157 , 158 ]. These results will need to be corroborated in an in vivo setting to prove meaningful efficacy and safety of substituting a substantial number of amino acids; however, this strategy highlights another interesting avenue in which innovation could help leverage existing treatment modalities.…”

Section: Gene Therapy For Pompe Diseasementioning

confidence: 99%

Gene Therapy Developments for Pompe Disease

et al. 2022

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Pompe disease is an inherited neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The most severe form is infantile-onset Pompe disease, presenting shortly after birth with symptoms of cardiomyopathy, respiratory failure and skeletal muscle weakness. Late-onset Pompe disease is characterized by a slower disease progression, primarily affecting skeletal muscles. Despite recent advancements in enzyme replacement therapy management several limitations remain using this therapeutic approach, including risks of immunogenicity complications, inability to penetrate CNS tissue, and the need for life-long therapy. The next wave of promising single therapy interventions involves gene therapies, which are entering into a clinical translational stage. Both adeno-associated virus (AAV) vectors and lentiviral vector (LV)-mediated hematopoietic stem and progenitor (HSPC) gene therapy have the potential to provide effective therapy for this multisystemic disorder. Optimization of viral vector designs, providing tissue-specific expression and GAA protein modifications to enhance secretion and uptake has resulted in improved preclinical efficacy and safety data. In this review, we highlight gene therapy developments, in particular, AAV and LV HSPC-mediated gene therapy technologies, to potentially address all components of the neuromuscular associated Pompe disease pathology.

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Section: Gene Therapy For Pompe Diseasementioning

confidence: 99%