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Challenges of Enzyme Replacement Therapy: Poor Tissue Distribution in Lysosomal Diseases Using Pompe Disease as a Model

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Biobetters

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 19))

Abstract

Enzyme replacement therapy (ERT) has revolutionized treatment for patients with LSDs, currently available for Mucopolysaccharidosis I (MPS I), MPS II, MPS IV, MPS VI, Gaucher disease, Fabry disease, and Pompe disease. The therapeutic enzyme replacement effectively lowers substrate accumulation and has dramatically improved lifespan, increased overall quality of life, and diminished the extent of organ involvement in these conditions. Despite this progress, therapeutic deficiencies are evidenced in the different LSDs due to various factors: minimal or no enzyme delivery to all necessary target sites; delayed diagnosis resulting in irreversible substrate buildup and clinical consequences prior to starting ERT; inability of the therapeutic enzyme to reach certain sanctuary sites, nor pass blood–brain barrier; and immune responses abrogating treatment effectiveness. Present efforts towards bridging the gap between currently available therapies and a cure for LSDs are best viewed through the lens of our collective experience with Pompe disease. While ERT dramatically improved the prognosis in both infantile and later onset forms of Pompe disease, several limitations exist: the inefficiency of ERT distribution and uptake in the target muscular system, the inability of ERT to cross the blood-brain barrier, the presence of pathological preconditions or the degree of muscular and lysosomal damage, the presence of defective cellular machinery or autophagy, and the development of anti-rhGAA IgG antibodies against ERT. Dosage is also an issue as cases of clinical plateau and decline have been documented on standard doses followed by subsequent improvements with higher doses. The shortcomings and adverse effects of current therapies emphasize the need for therapeutic enhancements in addition to or in place of ERT such as immunomodulation, adjunctive therapies, reduction of defective autophagy, small molecule chaperone therapy, second generation (biobetter) ERT, and gene therapy to supplant current methods.

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Authors and Affiliations

  1. Department of Pediatrics—Medical Genetics, Duke University Medical Center, DUMC 103856, 595 Lasalle Street, GSRB 1, 4th Floor, Room 4010, Durham, NC, 27710, USA

    Priya S. Kishnani M.D.

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  1. Priya S. Kishnani M.D.
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Correspondence to Priya S. Kishnani M.D. .

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Editors and Affiliations

  1. Centre for Drug Evaluation and Research, Food and Drug Administration, Division of Biotechnology Review and Research III, Office of Biotechnology Products, Silver Spring, Maryland, USA

    Amy Rosenberg

  2. Genentech, Inc., South San Francisco, California, USA

    Barthélemy Demeule

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Kishnani, P.S. (2015). Challenges of Enzyme Replacement Therapy: Poor Tissue Distribution in Lysosomal Diseases Using Pompe Disease as a Model. In: Rosenberg, A., Demeule, B. (eds) Biobetters. AAPS Advances in the Pharmaceutical Sciences Series, vol 19. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2543-8_2

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