With the recent evolution of enzyme therapy for lysosomal storage diseases, patients with lysosomal acid lipase deficiency (LAL-D) or Pompe disease (PD) now have more therapeutic options for managing the disease and improving their quality of life. Many promising others are on the horizon.

However, current enzyme therapies have limitations, including short intracellular half-lives that fail to normalize enzymatic levels long-term. To overcome this issue, patients are required to have lifelong biweekly or weekly infusions.

In addition, part of the infused therapeutic enzyme is uptaken by the liver and spleen, thereby decreasing the amount delivered to target organs. Also, native recombinant enzyme therapies cannot penetrate the postnatal blood-brain barrier, which might be particularly concerning in LSDs causing neurodegeneration. Therefore, the scenario is far from optimal.

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“As the LSD field moves forward into the next decade, researchers and clinicians must develop a new paradigm for LSD drug development that builds upon the substantial progress that has already been made,” Schuchman et al recently wrote in the Orphanet Journal of Rare Diseases. “Such drug development must address the missing needs of the current therapies, such as targeting difficult-to-reach pathologic organs including the [central nervous system] and skeletal system.”

Beyond Enzyme Therapy in LSDs

The primary goal of LSD treatments is to correct the levels of altered substrates in major affected cells and tissues. However, many experts defend a multidimensional approach when treating LSDs.

“The complexities resulting from lysosomal disruption, as well as the general metabolic and proinflammatory state, necessitate adjunctive treatments in addition to correction of the enzyme and substrate abnormalities in the majority of LSDs,” Grabowski and Mistry argued in a review article published in Molecular Genetics and Metabolism.

Several strategies have been investigated in the context of LSDs, including pharmacologic chaperones, enzyme activators, and substrate synthesis inhibition therapy. These strategies offer several advantages when compared with enzyme-based approaches.

Pharmacological Chaperones: the Future of Pompe Disease Therapeutics?

For instance, they are chemically synthesized and can achieve broader distribution and tissue penetration than enzyme-based therapies, including in fibrotic areas. Moreover, they can have positive or negative off-target effects, while enzyme-based approaches have unique specificities for substrates, and are unlikely to generate anti-drug antibodies, which can occur with enzyme-based approaches.

Long-term enzyme therapy has also been associated with concerning manifestations due to the ineffective delivery of enzymes to several tissues, such as the CNS and bones. In infantile LAL-D, the use of enzyme therapy for several years may cause obstruction of lymphatic drainage, leading to severe mesenteric lymphadenopathy with severe malabsorption.

However, there are also some caveats to pharmacologic chaperones, enzyme activators, and substrate synthesis inhibition therapy. For instance, they may be altered by specific drug-metabolizing enzymes in the liver and, thus, may require dosing adjustments. Furthermore, they have specific requirements in terms of the activity and location of the target enzyme.

Combination Therapy: The Future in LSD Therapeutics?

Given the pros and cons of each therapeutic approach, Grabowski and Mistry anticipate potential synergistic positive benefits from the combination of enzyme-based therapy and pharmacologic chaperones, enzyme activators, or substrate synthesis inhibition therapy together with hematopoietic stem cell therapy, with or without corrective lentivirus integration.

Accordingly, previous studies have shown enhanced exposure, distribution, and cellular uptake of therapeutic enzymes when coadministered with active-site-directed pharmacologic chaperones. This combination seems to be particularly attractive in conditions characterized by a high half-life of the therapeutic enzyme, such as Pompe disease.

Also, new recommendations for infantile LAL-D treatment include combined enzyme therapy, hematopoietic stem cell transplantation, and dietary therapy.

Therapeutic Possibilities in Lysosomal Acid Lipase Deficiency

Despite the recent advances and promising findings regarding combination therapy in LSDs, there is a long road ahead.

“As a field, the treatment paradigms for LSD are in their early stages, and much is needed at basic, clinical, and translational levels to improve outcomes for affected people and their families,” Grabowski and Mistry noted. “To unravel these complex, multilayered diseases and develop more complete therapies will require cooperative multidisciplinary efforts.”


Grabowski GA, Mistry PK. Therapies for lysosomal storage diseases: principles, practice, and prospects for refinements based on evolving science. Mol Genet Metab. 2022;137(1):81-91. doi:10.1016/j.ymgme.2022.07.014

Schuchman EH, Ledesma MD, Simonaro CM. New paradigms for the treatment of lysosomal storage diseases: targeting the endocannabinoid system as a therapeutic strategy. Orphanet J Rare Dis. 2021;16(1):151. doi:10.1186/s13023-021-01779-4