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Enzyme replacement therapy
Enzyme replacement therapy
Enzyme replacement therapy
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Enzyme replacement therapy
Other namesERT

Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body.[1] Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.[1]

ERT is available for some lysosomal storage diseases: Gaucher disease, Fabry disease, MPS I, MPS II (Hunter syndrome), MPS VI and Pompe disease.[1] ERT does not correct the underlying genetic defect, but it increases the concentration of the enzyme that the patient is lacking.[1] ERT has also been used to treat patients with severe combined immunodeficiency (SCID) resulting from an adenosine deaminase deficiency (ADA-SCID).[2]

Other treatment options for patients with enzyme or protein deficiencies include substrate reduction therapy, gene therapy, and bone-marrow derived stem cell transplantation.[1][3][4]

History

[edit]

ERT was developed in 1964 by Christian de Duve and Roscoe Brady.[1][5] Leading work was done on this subject at the Department of Physiology at the University of Alberta by Mark J. Poznansky and Damyanti Bhardwaj, where a model for enzyme therapy was developed using rats.[6] ERT was not used in clinical practice until 1991, after the FDA gave orphan drug approval for the treatment of Gaucher disease with Alglucerase.[1] ERTs were initially manufactured by isolating the therapeutic enzyme from human placenta.[1] The FDA has approved ERTs that are derived from other human cells, animal cells (i.e. Chinese hamster ovary cells, or CHO cells), and plant cells.[1]

Medical uses

[edit]

Lysosomal storage diseases are a group of diseases and a main application of ERT. Lysosomes are cellular organelles that are responsible for the metabolism of many different macromolecules and proteins.[7] They use enzymes to break down macromolecules, which are recycled or disposed.[7] As of 2012, there are 50 lysosomal storage diseases, and more are still being discovered.[8][7] These disorders arise because of genetic mutations that prevent the production of certain enzymes used in the lysosomes.[7] The missing enzyme often leads to a build-up of the substrate within the body. This can result in a variety of symptoms, many of which are severe and can affect the skeleton, brain, skin, heart, and the central nervous system.[8] Increasing the concentration of the missing enzyme within the body has been shown to improve the body's normal cellular metabolic processes and reduce substrate concentration in the body.[2]

ERT has also been successful in treating severe combined immunodeficiency caused by an adenosine deaminase deficiency (ADA-SCID).[9] This is a fatal childhood disease that requires early medical intervention.[9] When the enzyme adenosine deaminase is deficient in the body, the result is a toxic build-up of metabolites that impair lymphocyte development and function.[9] Many ADA deficient children with SCID have been treated with the polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) enzyme. This is a form of ERT that has resulted in healthier, longer lives for patients with ADA-SCID.[9]

Diseases and corresponding enzyme therapies. Information in this table is from pivotal clinical trials.[1]
Disease Enzyme Administration
Fabry disease Agalsidase beta IV
Fabry disease Agalsidase alfa IV
Gaucher disease Imiglucerase IV
Gaucher disease Taliglucerase alfa IV
Gaucher disease Velaglucerase alfa IV
Gaucher disease type I Alglucerase IV
Lysosomal acid lipase deficiency (Wolman disease/CESD) Sebelipase alfa IV
MPS I Laronidase IV
MPS II Idursulfase IV
MPS IVA Elosulfase alfa IV
MPS VI Galsulfase IV
Pompe disease Alglucosidase alfa (160L bioreactor) IV
Pompe disease Alglucosidase alfa (4000L bioreactor) IV
Thrombotic thrombocytopenic purpura Apadamtase alfa IV

Administration

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ERT is administered by IV infusion.[1][9][10] Typically, infusions occur every week or every two weeks.[1] For some types of ERT, these infusions can occur as infrequently as every four weeks.[1]

Complications

[edit]

ERT is not a cure for lysosomal storage diseases, and it requires lifelong IV infusions of the therapeutic enzyme.[10] This procedure is expensive; in the United States, it may cost over $200,000 annually.[10] The distribution of the therapeutic enzyme in the body (biodistribution) after these IV infusions is not uniform.[10] The enzyme in less available to certain areas in the body, like the bones, lungs, brain. For this reason, many symptoms of lysosomal storage diseases remain untreated by ERT, especially neurological symptoms.[10] Additionally, the efficacy of ERT is often reduced due to an unwanted immune response against the enzyme, which prevents metabolic function.[10]

Other treatments for enzyme deficiencies

[edit]

Substrate reduction therapy is another method for treating lysosomal storage diseases.[10] In this treatment, the accumulated compounds are inhibited from forming in the body of a patient with a lysosomal storage disease.[10] The accumulated compounds are responsible for the symptoms of these disorders, and they form via a multi-step biological pathway.[10] Substrate reduction therapy uses a small molecule to interrupt this multi-step pathway and inhibit the biosynthesis of these compounds.[10] This type of treatment is taken orally.[10] It does not induce an unwanted immune response, and a single type of small molecule could be used to treat many lysosomal storage diseases.[10] Substrate reduction therapy is FDA approved and there is at least one treatment available on the market.[10]

Gene therapy aims to replace a missing protein in the body through the use of vectors, usually viral vectors.[11] In gene therapy, a gene encoding for a certain protein is inserted into a vector.[11] The vector containing the therapeutic gene is then injected into the patient.[11] Once inside the body the vector introduces the therapeutic gene into host cells, and the protein encoded by the newly inserted gene is then produced by the body's own cells.[11] This type of therapy can correct for the missing protein/enzyme in patients with lysosomal storage diseases.[1]

Hematopoietic stem cell (HSC) transplantation is another treatment for lysosomal storage diseases.[12] HSCs are derived from bone-marrow.[13] These cells have the ability to mature into the many cell types that comprise blood, including red blood cells, platelets, and white blood cells.[13] Patients with enzyme deficiencies often undergo HSC transplantations in which HSCs from a healthy donor are injected. This treatment introduces HSCs that regularly produce the deficient enzyme since they have normal metabolic function.[12] This treatment is often used to treat the central nervous system of patients with some lysosomal storage diseases.[12]

See also

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References

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Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Enzyme replacement therapy

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Enzyme replacement therapy (ERT) is a medical treatment designed to address congenital deficiencies, particularly in lysosomal storage disorders (LSDs), by administering purified recombinant enzymes intravenously to restore partial enzymatic function and alleviate associated symptoms. This approach compensates for the body's inability to produce sufficient functional enzymes, which leads to the accumulation of substrates in cells and tissues. ERT has become a cornerstone therapy for several rare genetic conditions, with over a dozen FDA-approved products for various LSDs as of 2025, improving through regular infusions, though it is not curative and requires lifelong administration. The mechanism of ERT relies on the uptake of infused enzymes by target cells, often facilitated by modifications such as mannose-6-phosphate tagging to direct them to lysosomes, where they catalyze the breakdown of accumulated macromolecules like glycosaminoglycans or . Treatments are typically delivered via weekly or biweekly intravenous infusions lasting 1–4 hours, dosed by body weight, and can be administered in clinical settings or at home under supervision. Enzymes are produced using technology in cell lines such as ovary cells or plant cells to ensure high purity and scalability. Historically, ERT's development began in the with plasma-derived enzymes for conditions like alpha-1-antitrypsin deficiency, but recombinant forms gained prominence in the 1990s, starting with imiglucerase for approved by the FDA in 1994. By the early 2000s, multiple FDA-approved products expanded its applications, marking a shift from supportive care—such as blood transfusions or surgeries—to disease-modifying interventions for LSDs. As of 2025, ongoing advancements include next-generation enzymes with enhanced stability and targeted delivery to overcome tissue barriers. ERT is primarily applied to LSDs, a group of over 50 disorders caused by lysosomal enzyme defects, including (treated with imiglucerase, velaglucerase alfa, or taliglucerase alfa), Pompe disease (alglucosidase alfa, avalglucosidase alfa, or cipaglucosidase alfa with miglustat), (agalsidase alfa or agalsidase beta), and such as MPS I (laronidase), MPS II (idursulfase), and MPS VI (galsulfase). These therapies target specific enzyme deficiencies to reduce organ enlargement, improve cardiac and pulmonary function, and enhance mobility in affected patients. Early initiation, ideally through , maximizes benefits by preventing irreversible damage. Clinical efficacy varies by disease but generally includes reductions in substrate accumulation, such as decreased urinary glycosaminoglycans in MPS patients, alongside improvements in endurance (e.g., via 6-minute walk test), joint , and overall . For instance, in , ERT significantly shrinks liver and spleen volumes and stabilizes bone health. Long-term studies, including those up to 2025, confirm sustained stability in motor function for conditions like MPS IVA when started in adulthood. Despite its successes, ERT faces limitations, including poor penetration into the due to the blood-brain barrier, rendering it less effective for cognitive aspects of severe LSDs like MPS I and II. Challenges also encompass infusion-associated reactions (affecting up to 50% of patients), potential development of neutralizing antibodies that diminish efficacy, and restricted access to hard-to-reach tissues like and . Emerging strategies, such as and induction, aim to address these issues in recent clinical trials.

Overview and Mechanism

Definition and Principles

Enzyme replacement (ERT) is a targeted medical intervention involving the exogenous administration of purified recombinant to compensate for deficient or dysfunctional endogenous , particularly in genetic disorders such as lysosomal storage diseases (LSDs). These recombinant are typically produced using biotechnological methods, such as expression in mammalian cell lines like cells, to ensure proper and functionality mimicking the natural human . The aims to restore enzymatic activity within affected cells, thereby addressing the root cause of substrate accumulation that leads to cellular and . The foundational principles of ERT revolve around substrate clearance and reduction of pathological accumulations through restored hydrolytic activity. In LSDs, deficient enzymes result in the buildup of undegraded macromolecules within lysosomes, causing progressive cellular damage; ERT supplies functional enzymes that are internalized by target cells via , primarily through the mannose-6-phosphate receptor, and directed to lysosomes where they catalyze the breakdown of these substrates. This process prevents further lysosomal distension and mitigates downstream effects like and tissue , promoting metabolic without altering the patient's . The efficacy depends on the enzyme's ability to access affected tissues and maintain sustained activity, highlighting the importance of periodic infusions to sustain therapeutic levels. ERT primarily targets lysosomal hydrolases, a class of enzymes critical for catabolizing complex biomolecules in metabolic pathways. These hydrolases, such as acid in or A in , function within the acidic lysosomal environment to hydrolyze glycosphingolipids, glycoproteins, and mucopolysaccharides, ensuring the recycling of cellular components. By replacing these deficient hydrolases, ERT facilitates the resumption of normal degradative processes, reducing the metabolic burden on cells. Candidacy for ERT requires confirmation of an deficiency through diagnostic methods, including enzyme activity assays on leukocytes, fibroblasts, or plasma, which measure residual hydrolytic function, and to identify pathogenic mutations via techniques like next-generation sequencing. of affected tissues may also be used to assess substrate accumulation and correlate it with enzyme levels, ensuring the therapy is appropriate for the underlying genetic defect. Early is essential, as irreversible damage limits therapeutic benefits.

Biochemical Mechanism

Enzyme replacement therapy (ERT) relies on the delivery of recombinant lysosomal enzymes that are engineered to mimic the natural mannose-6-phosphate (M6P) targeting signal found on endogenous lysosomal hydrolases. These enzymes are produced with high-mannose N-glycans modified by the addition of M6P residues in the Golgi apparatus, catalyzed by GlcNAc-1-phosphotransferase and an uncovering enzyme, which exposes the phosphate for recognition. This tagging enables the recombinant enzymes to bind to M6P receptors on the cell surface, primarily the cation-independent mannose-6-phosphate receptor (CI-MPR), facilitating uptake into target cells via clathrin-mediated endocytosis. Once internalized, the enzyme-receptor complex is transported within clathrin-coated vesicles to early endosomes, where the mildly acidic environment promotes dissociation of the from the receptor. The receptors recycle back to the trans-Golgi network or plasma membrane, while the unbound enzymes progress to late endosomes and subsequently fuse with through the action of vesicular trafficking proteins such as Rab7 and SNARE complexes. In the , the enzymes undergo proteolytic processing to their mature, active forms, restoring degradative capacity against accumulated substrates; for instance, in , recombinant enzymes like idursulfase facilitate the breakdown of glycosaminoglycans such as dermatan and heparan sulfates, preventing lysosomal distension and cellular dysfunction. Pharmacokinetically, infused recombinant enzymes exhibit short plasma half-lives, typically ranging from 26 minutes for galsulfase to 1.5–3.6 hours for laronidase, due to rapid binding to M6P receptors and subsequent cellular uptake. This leads to preferential distribution to highly vascularized tissues such as the liver and , where uptake can achieve significant enzyme activity restoration, while shows more modest accumulation owing to limited vascular access. The short circulation time necessitates frequent intravenous infusions to maintain therapeutic levels, with clearance primarily mediated by receptor-dependent rather than renal or hepatic . A key limitation of ERT is the poor penetration across the blood-brain barrier (BBB) in adults, as the tight endothelial junctions restrict access to the , resulting in negligible delivery to at conventional doses. This confines therapeutic effects to peripheral tissues and , leaving CNS manifestations of diseases like VII untreated unless high-dose regimens (e.g., 20 mg/kg) are employed, which can achieve 1–3% of wild-type activity in the but at the risk of systemic overload. Alternative strategies, such as , are explored to circumvent this barrier for CNS-involved lysosomal storage disorders.

Historical Development

Early Discoveries

The discovery of lysosomes in 1955 by provided the foundational understanding necessary for recognizing lysosomal storage disorders (LSDs) as conditions caused by enzyme deficiencies leading to substrate accumulation within cells. Building on this, researchers in the and identified specific enzyme deficiencies in various LSDs, such as beta-glucuronidase in VII (MPS VII), identified in 1973, and other hydrolases in related disorders. In 1964, de Duve proposed the concept of enzyme replacement therapy (ERT) as a potential treatment, suggesting that exogenous enzyme administration could restore lysosomal function and alleviate storage pathology. This idea marked the initial theoretical framework for ERT, emphasizing the need for enzymes capable of cellular uptake and targeting to lysosomes. In the early , preclinical experiments in animal models began to test the feasibility of ERT, focusing on intravenous to demonstrate substrate clearance and uptake. Initial studies in mice with induced or genetic deficiencies showed that infused lysosomal enzymes could be taken up by cells via , reducing accumulated substrates in tissues like liver and . For instance, experiments with beta-glucuronidase in feline MPS VII models, established in the late , illustrated partial clearance of glycosaminoglycans in affected organs, providing proof-of-concept for systemic delivery. These studies highlighted the potential of ERT to mitigate storage but also revealed limitations, such as short in circulation. By the , initial human applications emerged through case reports of ERT for non-lysosomal enzyme deficiencies, prefiguring broader use in LSDs. Notably, polyethylene glycol-modified (PEG-ADA) was administered to patients with (SCID) due to ADA deficiency, achieving partial immune restoration and metabolic correction in early trials starting around 1986. These efforts demonstrated clinical tolerability and efficacy in reducing toxic metabolites, though sustained benefits required repeated dosing. Early preclinical work consistently identified key challenges, including enzyme instability during circulation and inefficient targeting to affected tissues, particularly those protected by barriers like the blood-brain barrier. Researchers noted that unmodified enzymes were rapidly cleared by the liver without reaching lysosomes, prompting investigations into modifications for improved mannose-6-phosphate receptor recognition, a mechanism elucidated in the late 1970s and early 1980s. These hurdles underscored the need for optimized formulations to enhance delivery and longevity in vivo.

Key Milestones and Approvals

The landmark approval of enzyme replacement therapy (ERT) occurred in 1991 when the U.S. (FDA) granted approval to alglucerase (Ceredase), a placental-derived form of , for the treatment of type 1 . This therapy, produced by Genzyme Corporation, marked the first regulatory endorsement of ERT for a lysosomal storage disorder, demonstrating clinical benefits such as reduced spleen and liver volumes in patients. The approval was facilitated by the , which incentivized development for rare diseases, and relied on pivotal phase 3 trials showing sustained improvements in hematologic parameters. In the , a significant shift toward recombinant production revolutionized ERT manufacturing, addressing supply limitations of human-derived enzymes like Ceredase. This culminated in the FDA approval of imiglucerase (Cerezyme), a recombinant human expressed in ovary (CHO) cells, also for type 1 . The use of CHO cells enabled scalable, consistent production with human-like , improving safety and efficacy over placental sources, and Cerezyme quickly became the standard treatment, with over 8,000 patients enrolled in long-term safety studies by the early 2000s. The 2000s saw expansions into additional lysosomal storage disorders, broadening ERT's clinical scope. In 2003, the FDA approved agalsidase beta (Fabrazyme) for , a recombinant alpha-galactosidase A produced in CHO cells that reduced globotriaosylceramide accumulation in vascular , based on phase 3 data from 58 patients showing histologic improvements. That same year, laronidase (Aldurazyme) received approval for mucopolysaccharidosis type I (MPS I), including Hurler and Hurler-Scheie forms, as a recombinant alpha-L-iduronidase that improved forced in a placebo-controlled of 45 patients. These approvals highlighted ERT's versatility across enzyme deficiencies, with subsequent extensions to pediatric populations. More recent milestones include the 2017 FDA approval of vestronidase alfa (Mepsevii) for MPS VII (Sly syndrome), a recombinant beta-glucuronidase that addressed a previously untreatable rare disorder, supported by phase 3 evidence of reduced glycosaminoglycan levels in 12 patients. As of 2025, ongoing clinical trials are exploring CNS-targeted ERT variants, such as fusion proteins designed to cross the blood-brain barrier, including tividenofusp alfa for Hunter syndrome (MPS II), which received priority review by the FDA in July 2025 based on phase 2/3 data showing cognitive stabilization, although the review was extended in October 2025 to April 2026. Parallel production advancements have enhanced ERT efficacy through glycoengineering, particularly the addition of mannose-6-phosphate (M6P) glycans to facilitate lysosomal targeting via cation-independent mannose-6-phosphate receptor-mediated uptake. Techniques like enzymatic remodeling in cell-free systems or engineered phosphotransferase expression in producer cells have increased M6P content—up to 15-fold in some cases—improving cellular delivery and therapeutic outcomes, as seen in next-generation ERTs for Pompe disease. These innovations, building on recombinant platforms, continue to refine ERT for broader disease applications.

Clinical Applications

Targeted Diseases

Enzyme replacement therapy (ERT) primarily targets lysosomal storage diseases (LSDs), more than 70 inherited metabolic disorders caused by deficiencies in lysosomal , resulting in the progressive accumulation of undegraded substrates within cells. This accumulation disrupts lysosomal function and leads to cellular damage, inflammation, and multisystem organ dysfunction, including neurological impairment, skeletal abnormalities, and cardiopulmonary complications. ERT is particularly suitable for these conditions because it supplies the missing enzyme to degrade accumulated substrates, thereby alleviating substrate buildup and mitigating downstream organ pathology, though it is most effective for non-neurological manifestations due to limited blood-brain barrier penetration. Among LSDs, ERT has been developed for several subtypes of (MPS), including MPS I (Hurler and Scheie syndromes), MPS II (), MPS IVA (Morquio A syndrome), MPS VI (Maroteaux-Lamy syndrome), and MPS VII (Sly syndrome), as well as , , and Pompe disease. In , deficiency of leads to accumulation of glucosylceramide in macrophages, causing , bone lesions, and . Similarly, in Pompe disease, acid alpha-glucosidase deficiency results in buildup in lysosomes, particularly affecting skeletal and , leading to and . involves alpha-galactosidase A deficiency, with globotriaosylceramide accumulation in vascular , contributing to renal failure, strokes, and cardiac issues, while MPS disorders feature buildup, resulting in coarse facial features, joint stiffness, and corneal clouding. Eligibility for ERT in these LSDs emphasizes early intervention to prevent irreversible damage, often identified through programs that detect enzyme deficiencies via or fluorometric assays for conditions like Pompe and MPS I. Biomarkers such as elevated chitotriosidase levels in plasma, which reflect activation and disease burden in , further aid in and monitoring suitability for initiation. Beyond LSDs, similar replacement strategies are applied in other enzyme deficiencies, such as augmentation therapy with purified for to protect against lung by inhibiting neutrophil elastase; this FDA-approved therapy demonstrates biochemical efficacy and slowing of lung density loss, though clinical benefits continue to be evaluated in long-term studies.

Specific Enzyme Therapies

Imiglucerase for Gaucher Type 1 Imiglucerase, marketed as Cerezyme by Sanofi (Genzyme), is a recombinant form of the enzyme , approved for the treatment of type 1, a lysosomal storage disorder characterized by deficient enzyme activity leading to glucocerebroside accumulation in macrophages. In phase III clinical trials, imiglucerase treatment resulted in a significant reduction in spleen volume by 30-50% within the first year, with mean reductions of approximately 33% observed across adult patients receiving doses of 30-60 U/kg every two weeks. Long-term data from observational studies and registries indicate sustained improvements in bone health, including decreased incidence of bone crises, increased density, and resolution of in a majority of patients after 5-10 years of therapy. Additional recombinant options include velaglucerase alfa and taliglucerase alfa, which show comparable efficacy in reducing substrate accumulation and improving hematologic parameters. Agalsidase Beta for Fabry Disease Agalsidase beta, marketed as Fabrazyme by Sanofi (Genzyme), is a recombinant α-galactosidase A that targets by hydrolyzing globotriaosylceramide (GL-3) accumulated in vascular and other tissues. An alternative therapy is agalsidase alfa, marketed as Replagal by Takeda (Shire). Randomized controlled trials and long-term extensions have demonstrated stabilization of renal function, with estimated (eGFR) maintained in patients without baseline impairment over 4-5 years of treatment at 1 mg/kg every two weeks, contrasting with progressive decline in untreated cohorts. Cardiac benefits include reduction in left ventricular (LV) mass index, with meta-analyses of clinical studies showing greater LV mass regression in agalsidase beta-treated patients compared to or alternative therapies, particularly in males with classic after 1-2 years. Laronidase for Mucopolysaccharidosis Type I (MPS I) Laronidase, recombinant human α-L-iduronidase, addresses MPS I (Hurler and Scheie syndromes) by degrading glycosaminoglycans (GAGs) such as dermatan and heparan sulfate. Phase III randomized trials in patients aged 6-43 years showed enhancements in pulmonary function, with forced vital capacity (FVC) increasing by an average of 5-6% from baseline after 26 weeks compared to placebo, and sustained improvements over 3-4 years in open-label extensions. In children with attenuated MPS I, long-term treatment promotes growth, with height velocity increasing by 35-192% in those aged 8-12 years after one year, alongside reductions in urinary GAG levels by approximately 50-60% as a biomarker of substrate clearance. As of 2025, biosimilar versions of laronidase have been evaluated in phase III trials, showing equivalent efficacy in maintaining urinary GAG reductions. Alglucosidase Alfa for Pompe Disease Alglucosidase alfa, recombinant human acid α-glucosidase, treats Pompe disease by replenishing the deficient responsible for breakdown in lysosomes. In infantile-onset Pompe disease, clinical trials and extensions report improved ventilator-free survival, with approximately 83% of treated infants alive without invasive ventilation at 18 months versus 25% in historical controls, reflecting cardiac and respiratory benefits over 2-3 years. For late-onset cohorts, a randomized phase III trial demonstrated stabilization of pulmonary function and improved walking distance (6-minute walk test) after 18 months at 20 mg/kg every two weeks, with evidence of reduced muscle accumulation in responders. Newer formulations, such as avalglucosidase alfa approved in 2021, offer enhanced uptake and potentially better outcomes in both forms. Other Specific Therapies for MPS Disorders For MPS II (), idursulfase, marketed as Elaprase by Takeda (Shire), reduces urinary levels by 50-60% and improves joint mobility and growth in clinical trials. Galsulfase, marketed as Naglazyme by BioMarin Pharmaceutical, for MPS VI (Maroteaux-Lamy) similarly decreases accumulation, enhancing endurance as measured by 6-minute walk tests over 1-2 years. Elosulfase alfa, marketed as Vimizim by BioMarin Pharmaceutical, for MPS IVA (Morquio A) improves walking distance and pulmonary function in phase III studies, while vestronidase alfa for MPS VII (Sly) reduces levels and stabilizes disease progression. Comparative Efficacy Across Therapies Meta-analyses of enzyme replacement therapies for lysosomal storage diseases reveal variable success in substrate reduction and clinical outcomes, with urinary GAG or accumulated substrate levels decreasing by 60-80% in responsive conditions like MPS I and , though efficacy is lower in neuronopathic or late-stage presentations due to blood-brain barrier limitations. Overall, these therapies consistently demonstrate organ-specific benefits, such as visceral and skeletal improvements in and MPS I, renal and cardiac stabilization in Fabry, and respiratory gains in Pompe, but response rates differ by disease and patient age at initiation. As of 2025, ongoing research into next-generation ERT, including improved stability and delivery methods, continues to address limitations in tissue penetration and immune responses. Leading manufacturers in the enzyme replacement therapy market include Sanofi (Genzyme) with products such as Cerezyme and Fabrazyme, Takeda (Shire) with Replagal and Elaprase, and BioMarin Pharmaceutical with Vimizim and Naglazyme.

Delivery and Administration

Routes and Methods

Enzyme replacement therapy (ERT) is predominantly administered via intravenous (IV) infusion, which serves as the standard route for delivering recombinant enzymes to target tissues throughout the body. This method involves a slow drip over 1 to 4 hours to reduce the risk of infusion-related reactions, with infusion durations typically around 3 hours for many formulations. Infusions can be performed in clinical settings or at home, where home administration has been shown to be safe and effective for conditions like and , potentially easing the lifelong treatment burden. ERT enzymes are commonly supplied as lyophilized powders in single-dose , which are reconstituted prior to administration. Reconstitution typically involves adding sterile to the , followed by dilution in 0.9% (normal saline) to achieve the desired concentration for . Stabilizers such as , , and citrate salts are included in these formulations to maintain enzyme stability during storage and preparation, with often used at concentrations around 340 mg per to prevent degradation. Alternative routes are under investigation to address limitations of IV delivery, particularly for (CNS) involvement. , involving direct injection into the , is experimental for CNS diseases like MPS III ( type D), where it has shown potential to drive uptake across the blood-brain barrier in preclinical models. Subcutaneous routes are also being piloted for select s, offering advantages like self-administration, though they remain non-standard due to challenges in and are primarily explored for proteins like C1-esterase inhibitor in related replacement therapies. Patient preparation for ERT infusions includes with antihistamines, such as diphenhydramine, administered 1 to 24 hours prior to reduce risks. For patients requiring frequent dosing, venous access is often facilitated by implanted ports (port-a-caths), which support long-term IV administration in lysosomal storage disorders by minimizing vein damage from repeated punctures.

Dosing and Monitoring

Enzyme replacement therapy (ERT) dosing is typically weight-based and administered intravenously at regular intervals, with most regimens occurring every 1 to 2 weeks to maintain therapeutic enzyme levels. For type 1 , imiglucerase is dosed at 60 units per kilogram of body weight every 2 weeks, while velaglucerase alfa and taliglucerase alfa follow similar 60 units/kg every-other-week schedules. In Pompe disease, alglucosidase alfa is given at 20 mg/kg every 2 weeks over approximately 4 hours. For (MPS), laronidase for MPS I is 0.58 mg/kg weekly, idursulfase for MPS II is 0.5 mg/kg weekly, and galsulfase for MPS VI is 1 mg/kg weekly. These standard doses are often individualized based on disease severity and patient response, with initial infusion rates adjusted gradually to minimize reactions. Dose adjustments in ERT involve guided by clinical outcomes and biomarkers, differing slightly between pediatric and adult patients due to body weight scaling and growth considerations. In MPS disorders, doses may be increased if urinary (GAG) levels remain elevated, targeting a reduction of at least 50% from baseline. For , adjustments are made based on chitotriosidase or glucosylsphingosine (lyso-Gb1) levels, with pediatric dosing scaled by weight to achieve similar exposure as adults. In Pompe disease, higher doses (up to 40 mg/kg every 2 weeks) have been explored for non-responders, particularly in infants, to improve muscle and respiratory function. Anti-drug antibodies, which develop in up to 20-30% of patients across ERTs, can neutralize activity and necessitate dose escalation or switching products to restore efficacy. Monitoring ERT effectiveness relies on a combination of biochemical assays, clinical assessments, and to evaluate stabilization or . Enzyme activity is assessed via trough levels in plasma, ensuring sustained pharmacodynamic effects between infusions, particularly in Pompe disease where glucose tetrasaccharide (Glc4) serves as a key for clearance. In , biomarkers like lyso-Gb1 and chitotriosidase are tracked quarterly, alongside levels and platelet counts, to confirm reductions in substrate accumulation. For MPS, urinary levels and 6-minute walk test (6MWT) distances are primary metrics, with MRI used to measure liver and volumes for progression. Quality-of-life scales, such as the , and respiratory function tests (e.g., forced ) are incorporated to assess broader functional impacts, with evaluations typically every 3-6 months.

Risks and Complications

Adverse Effects

Enzyme replacement therapy (ERT) commonly elicits infusion-related reactions, which are typically mild and occur in varying incidences depending on the disease, reported from approximately 10% up to over 50% of patients during the initial infusions. These reactions often include fever, chills, and , resulting from release triggered by the exogenous activating immune cells and inflammatory pathways. Such symptoms usually manifest within minutes to hours of and are more frequent in the early treatment phase, affecting up to 53% of patients in certain lysosomal storage disorders like . Organ-specific adverse effects of ERT can include transient elevations in liver enzymes in certain therapies, such as for Niemann-Pick disease, indicative of mild in hepatic tissue, alongside general symptoms such as and gastrointestinal disturbances like , , , and . These liver enzyme increases are generally self-limited and resolve without intervention, with no evidence of progression to severe . In patients with , long-term ERT may initially exacerbate bone pain flares due to substrate mobilization and inflammatory responses in affected skeletal sites, though overall skeletal manifestations improve over time. Rare severe reactions, such as , have been reported in post-marketing surveillance, occurring in less than 1% of cases. Management of these non-immune adverse effects focuses on symptom-directed interventions, such as administering acetaminophen or other antipyretics for fever and chills, slowing the rate, or temporarily halting therapy. with antipyretics and antihistamines prior to infusions can prevent recurrence in susceptible patients, with incidence rates derived from clinical trials and post-marketing data guiding individualized adjustments. Monitoring during the first several infusions is essential to mitigate risks, ensuring most patients tolerate ERT long-term with minimal disruption.

Immune Response Challenges

One major challenge in enzyme replacement therapy (ERT) is the development of anti-drug (ADAs), which occur in a significant proportion of patients. In infantile-onset Pompe disease, approximately 90% of patients treated with alglucosidase alfa develop IgG against the recombinant enzyme, with a subset progressing to high sustained antibody titers (HSAT) that neutralize activity. IgE can also form, contributing to allergic responses, though IgG predominates in impairing therapeutic delivery. Similar is observed in other lysosomal storage disorders, such as , where up to 50% of male patients develop neutralizing ADAs during ERT with agalsidase beta. As of 2025, studies continue to explore ADA formation in patients on ERT, highlighting predictors like baseline biomarkers. The primary mechanism driving ADA formation involves the immune system's recognition of recombinant enzymes as foreign antigens, particularly due to differences in post-translational modifications like . Recombinant enzymes, often produced in non-human cell lines such as ovary (CHO) cells, exhibit glycosylation patterns—such as high-mannose structures or altered sialylation—that deviate from human endogenous forms, triggering B-cell activation and production. These foreign glycans facilitate to T-helper cells, amplifying humoral responses and leading to sustained ADA secretion that binds and inactivates the infused . ADAs significantly compromise ERT efficacy by accelerating enzyme clearance, thereby reducing its and tissue uptake. In patients with high-titer ADAs, this can result in attenuated clinical responses, such as diminished improvements in cardiac function or motor outcomes in Pompe disease, with some studies reporting up to 50% less reduction in accumulation compared to low-titer patients. Additionally, ADAs exacerbate infusion-associated reactions, increasing their frequency and severity through immune complex formation and complement activation. To mitigate these immune challenges, induction (ITI) protocols have been developed, often involving immunosuppressive agents like rituximab (anti-CD20 ) combined with to deplete B cells and suppress T-cell help, achieving ADA titer reductions in 68-100% of cross-reactive immunologic material (CRIM)-negative Pompe patients in reported cohorts. Enzyme switching represents another strategy; for instance, in , transitioning from imiglucerase (CHO-derived) to velaglucerase alfa (human cell line-derived) has shown lower ADA incidence (0% vs. 23.5% in comparative trials), owing to more native-like that evades immune detection. Ongoing monitoring of ADA titers guides these interventions to restore therapeutic .

Alternative and Complementary Approaches

Other Therapies for Enzyme Deficiencies

In addition to enzyme replacement therapy (ERT), several established non-ERT approaches address deficiencies, particularly in lysosomal storage disorders (LSDs), by targeting substrate accumulation, providing donor-derived enzymes, or stabilizing proteins. These therapies offer distinct mechanisms and outcomes, often complementing or serving as alternatives to ERT depending on disease stage, patient age, and organ involvement. For instance, while ERT delivers exogenous enzymes intravenously, other options like oral agents or one-time procedures aim to mitigate lifelong infusion needs or improve (CNS) penetration. Substrate reduction therapy (SRT) employs small-molecule inhibitors to decrease the synthesis of substrates that accumulate due to enzyme deficiency, thereby reducing lysosomal overload upstream of the enzymatic block. In type 1, oral agents such as inhibit glucosylceramide synthase, leading to a 12% reduction in liver volume and 19% in volume after 12 months of treatment, with non-inferiority to ERT in maintaining organ volumes over 24 months. Eliglustat, a newer SRT, achieves similar , with 77% of patients meeting composite clinical outcomes (including 17% liver volume reduction) after one year and 85% stability comparable to ERT in switch trials. SRT provides an oral alternative for ERT-intolerant patients but is associated with higher gastrointestinal side effects, such as diarrhea in 79% of users, limiting its use in severe or pediatric cases. Hematopoietic stem cell transplantation (HSCT) offers a potentially curative option by engrafting donor stem cells that produce functional enzymes, which are secreted and taken up by recipient tissues via cross-correction, including macrophages providing sustained enzyme supply. For type I (MPS I, ), HSCT in patients under 2.5 years old stabilizes psychomotor development, improves cognitive function, and achieves 62% 10-year survival, with superior metabolic correction compared to ERT. Unlike ERT, HSCT penetrates the blood-brain barrier, addressing CNS manifestations, and is more cost-effective long-term (approximately $70,000–$205,000 total versus $218,000 annually for ERT). However, it carries risks including and up to 10% mortality with modern protocols, making it suitable primarily for young, pre-symptomatic patients. Pharmacological chaperones represent another targeted strategy, using small molecules to bind and stabilize misfolded mutant enzymes, facilitating their proper trafficking to lysosomes and enhancing residual activity. In , is approved for patients with amenable mutations (affecting 35–50% of cases), reducing globotriaosylceramide (GL-3) inclusions and lyso-Gb3 levels while maintaining renal function and decreasing cardiac mass more effectively than ERT over 18–24 months. This oral avoids intravenous administration but is limited to specific genetic variants confirmed by assays. Supportive care focuses on symptomatic management of complications arising from enzyme deficiencies, employing multidisciplinary interventions to alleviate , improve mobility, and prevent secondary issues without directly addressing the underlying defect. For example, in , chronic is controlled with analgesics or anticonvulsants, while in or MPS disorders, orthopedic surgeries correct skeletal deformities like bone lesions or joint contractures. These measures enhance but do not alter disease progression, often serving as adjuncts to disease-modifying therapies. Comparatively, ERT requires lifelong biweekly infusions and excels in peripheral symptom control but falters in CNS and bone penetration, whereas HSCT provides a one-time potential cure with broader organ benefits at the cost of procedural risks. SRT and pharmacological chaperones offer convenient oral dosing with efficacy akin to ERT for in select LSDs like Gaucher and Fabry, though they may cause more tolerability issues and are less suitable for advanced disease. Combination approaches, such as SRT following ERT stabilization (e.g., ) or chaperones with ERT, demonstrate synergistic effects in enhancing enzyme activity and tissue substrate reduction, improving outcomes in crossover studies.

Emerging Research Directions

Recent advancements in enzyme replacement therapy (ERT) are focusing on overcoming limitations in (CNS) penetration, particularly for lysosomal storage disorders (LSDs) like type III (MPS III), where neurological symptoms predominate. Intrathecal infusions have emerged as a promising route for direct CNS delivery, with clinical studies demonstrating improved activity and reduced substrate accumulation in the without significant systemic exposure. For instance, trials in MPS IIIA patients using intrathecal recombinant human N-sulfoglucosamine sulfohydrolase have shown tolerability and preliminary efficacy in stabilizing cognitive decline. Complementing these efforts, blood-brain barrier (BBB) shuttles and hybrid approaches with (AAV) vectors are under investigation to enhance systemic ERT's CNS access; preclinical models of MPS III have reported up to 50% restoration of activity in brain tissues following AAV-mediated delivery combined with ERT infusions. Efforts to develop next-generation enzymes aim to mitigate and extend therapeutic duration. Deimmunized variants, engineered to remove immunogenic epitopes, and plant-produced enzymes, such as those expressed in cells, have shown reduced antibody formation in preclinical and phase I/II trials for , with up to 80% lower anti-drug incidence compared to mammalian cell-derived counterparts. , the covalent attachment of chains, further prolongs plasma half-life—extending it from hours to days in formulations like pegunigalsidase alfa, which achieves stable over 24 months in clinical use and improves tissue uptake in the heart and kidneys. These modifications collectively lower dosing and enhance efficacy while minimizing infusion-related reactions. Integrating gene editing technologies like / with ERT represents a hybrid strategy for achieving both immediate symptom relief and long-term correction of enzyme deficiencies. In preclinical models of MPS I, CRISPR-assisted editing of hematopoietic stem cells has been combined with ERT infusions to enable cross-correction via enzyme secretion from edited cells, resulting in sustained lysosomal function restoration without repeated dosing. This tandem approach addresses ERT's transient effects by providing a one-time genetic fix alongside ongoing enzymatic support, with early trials demonstrating up to 40% editing efficiency in patient-derived cells for LSDs. Combination therapies pairing ERT with are advancing through clinical pilots, particularly for Pompe disease, where muscle weakness limits standard ERT's reach. Phase I/II trials of AAV-mediated GAA gene transfer as an adjunct to ERT have reported dose-dependent increases in clearance and respiratory function, with one-year follow-up showing 20-30% improvement in six-minute walk distance in late-onset patients. Similarly, personalized dosing models leveraging (AI) are being explored to optimize ERT regimens; in , AI-driven algorithms analyzing biomarkers and patient responses have enabled tailored infusions, maintaining stable disease control while reducing annual dosing volume by up to 25% in a phase II . Looking ahead, challenges persist in broadening access, especially for rare LSDs in low-resource settings, where high costs—often exceeding $300,000 annually per —restrict availability despite programs. As of 2025, regulatory expansions for compassionate use of next-gen ERTs in ultra-rare LSDs, such as those presented at international congresses, signal progress, but equitable global distribution remains a priority through initiatives like subsidized manufacturing and to developing regions. Overall, these directions hold potential to transform ERT into a more durable, accessible paradigm for deficiencies.

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK548796/
  2. https://www.ncbi.nlm.nih.gov/books/NBK117221/
  3. https://ijponline.biomedcentral.com/articles/10.1186/s13052-018-0562-1
  4. https://pubmed.ncbi.nlm.nih.gov/40237692/
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC12419020/
  6. https://pubmed.ncbi.nlm.nih.gov/40288367/
  7. https://pmc.ncbi.nlm.nih.gov/articles/PMC12574230/
  8. https://pubmed.ncbi.nlm.nih.gov/39986311/
  9. https://www.annualreviews.org/doi/10.1146/annurev-genom-090711-163739
  10. https://www.ncbi.nlm.nih.gov/books/NBK563270/
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC5828774/
  12. https://www.tandfonline.com/doi/full/10.1080/19768354.2022.2079719
  13. https://www.mdpi.com/2077-0383/8/12/2190
  14. https://www.sciencedirect.com/science/article/abs/pii/S1096719211006524
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC6238252/
  16. https://link.springer.com/article/10.1007/s40262-014-0173-y
  17. https://www.pnas.org/doi/10.1073/pnas.0506892102
  18. https://www.sciencedirect.com/science/article/pii/S1525001622006736
  19. https://www.nature.com/articles/s41573-019-0036-1
  20. https://checkrare.com/mucopolysaccharidosis-type-vii-sly-syndrome/
  21. https://pubmed.ncbi.nlm.nih.gov/22970722/
  22. https://www.ncbi.nlm.nih.gov/books/NBK11588/
  23. https://pubmed.ncbi.nlm.nih.gov/10366443/
  24. https://www.nature.com/articles/pr199396.pdf
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC9512634/
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC8431097/
  27. https://www.oaepublish.com/articles/rdodj.2022.09
  28. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=5585
  29. https://www.nytimes.com/1991/04/09/business/company-news-fda-approves-genzyme-s-drug.html
  30. https://www.gaucherdisease.org/blog/25th-anniversary-fda-approval-ert/
  31. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=62491
  32. https://purplebooksearch.fda.gov/productdetails?query=020367
  33. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=15286
  34. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=106097
  35. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761047Orig1s000Approv.pdf
  36. https://www.neurologyadvisor.com/news/tividenofusp-alfa-gets-priority-review-for-hunter-syndrome/
  37. https://www.biospace.com/press-releases/denali-therapeutics-announces-fda-review-extension-of-bla-for-tividenofusp-alfa-for-the-treatment-of-mps-ii-hunter-syndrome
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC9246025/
  39. https://www.nature.com/articles/s41572-018-0025-4
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC8698519/
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC4345406/
  42. https://pmc.ncbi.nlm.nih.gov/articles/PMC7849573/
  43. https://pmc.ncbi.nlm.nih.gov/articles/PMC6373587/
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC5072572/
  45. https://pmc.ncbi.nlm.nih.gov/articles/PMC2440418/
  46. https://pubmed.ncbi.nlm.nih.gov/17409312/
  47. https://jmg.bmj.com/content/55/5/351
  48. https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.62910
  49. https://www.nature.com/articles/s41598-025-16351-4
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC3129995/
  51. https://www.nejm.org/doi/full/10.1056/NEJMoa0909859
  52. https://pmc.ncbi.nlm.nih.gov/articles/PMC12049060/
  53. https://www.mordorintelligence.com/industry-reports/enzyme-replacement-therapy
  54. https://pubmed.ncbi.nlm.nih.gov/20040319/
  55. https://pubmed.ncbi.nlm.nih.gov/17879143/
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC5484973/
  57. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020367s121lbl.pdf
  58. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103979s5309lbl.pdf
  59. https://pmc.ncbi.nlm.nih.gov/articles/PMC8362844/
  60. https://pmc.ncbi.nlm.nih.gov/articles/PMC3009387/
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC6182494/
  62. https://pmc.ncbi.nlm.nih.gov/articles/PMC4755045/
  63. https://www.ncbi.nlm.nih.gov/books/NBK11617/
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC5651539/
  65. https://www.ncbi.nlm.nih.gov/books/NBK117223/
  66. https://pubmed.ncbi.nlm.nih.gov/36499264/
  67. https://pmc.ncbi.nlm.nih.gov/articles/PMC10719471/
  68. https://pmc.ncbi.nlm.nih.gov/articles/PMC6115664/
  69. https://pubmed.ncbi.nlm.nih.gov/15886040/
  70. https://pmc.ncbi.nlm.nih.gov/articles/PMC5159621/
  71. https://pmc.ncbi.nlm.nih.gov/articles/PMC3298103/
  72. https://ojrd.biomedcentral.com/articles/10.1186/s13023-025-03844-8
  73. https://www.sciencedirect.com/science/article/pii/S2214426923000034
  74. https://pubmed.ncbi.nlm.nih.gov/17309642/
  75. https://www.ncbi.nlm.nih.gov/sites/books/NBK117223/table/findings.t5/?report=objectonly
  76. https://pmc.ncbi.nlm.nih.gov/articles/PMC8898438/
  77. https://www.mdpi.com/1422-0067/21/16/5784
  78. https://pubmed.ncbi.nlm.nih.gov/40420145/
  79. https://pmc.ncbi.nlm.nih.gov/articles/PMC4942633/
  80. https://pmc.ncbi.nlm.nih.gov/articles/PMC12107848/
  81. https://www.nature.com/articles/gim201670
  82. https://pmc.ncbi.nlm.nih.gov/articles/PMC11074017/
  83. https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.23382
  84. https://pmc.ncbi.nlm.nih.gov/articles/PMC4981103/
  85. https://pmc.ncbi.nlm.nih.gov/articles/PMC6615945/
  86. https://pmc.ncbi.nlm.nih.gov/articles/PMC6647464/
  87. https://ufhealth.org/conditions-and-treatments/lysosomal-storage-disease
  88. https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/s12987-022-00373-5
  89. https://curesanfilippofoundation.org/2019/09/facilitating-and-enhancing-cns-entry-of-systemically-delivered-aav-vectors-for-mps-iiia-iiib-in-mice/
  90. https://pubmed.ncbi.nlm.nih.gov/38680424/
  91. https://onlinelibrary.wiley.com/doi/full/10.1002/jimd.12080
  92. https://ojrd.biomedcentral.com/articles/10.1186/s13023-025-03705-4
  93. https://www.sciencedirect.com/science/article/pii/S2405580824001353
  94. https://www.mdpi.com/2073-4409/14/15/1147
  95. https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016%2823%2900077-1
  96. https://pmc.ncbi.nlm.nih.gov/articles/PMC10911405/
  97. https://www.researchgate.net/publication/381209671_A_Feasibility_Open-Labeled_Clinical_Trial_Using_a_Second-Generation_Artificial-Intelligence-Based_Therapeutic_Regimen_in_Patients_with_Gaucher_Disease_Treated_with_Enzyme_Replacement_Therapy
  98. https://straitsresearch.com/report/enzyme-replacement-therapy-market
  99. https://chiesirarediseases.com/media/20250909-chiesi-global-rare-diseases-highlights-continued-commitment-to-rare-disease-community-at-the-international-congress-of
  100. https://www.globenewswire.com/news-release/2025/11/11/3185542/0/en/Lysosomal-Storage-Disease-Treatment-Market-Analysis-Report-2025-Rising-Prevalence-of-Lysosomal-Storage-Disorders-and-Rise-of-Gene-Therapy-and-RNA-Based-Treatments-Global-Forecast-t.html
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