Lysosomal storage diseases in North America: a comprehensive review of enzyme therapies and unmet needs

Abstract

This review explores enzyme replacement therapies (ERTs) for lysosomal storage diseases (LSDs), focusing on disease characteristics, mechanisms of action, clinical benefits, limitations, and implications for patient care and access. LSDs are a group of over 50 rare, inherited metabolic disorders caused by mutations affecting lysosomal enzymes, membrane proteins, or transporters. This leads to the accumulation of undegraded macromolecules in tissues such as the CNS (central nervous system), heart, and muscles, resulting in progressive dysfunction and possible death. ERTs, approved by FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency), have been the cornerstone of treatment since 1995, significantly improving the patient’s quality of life reducing organ damage and stabilizing cardiac and renal function. However, ERTs require lifelong intravenous infusions and have limited efficacy to treat CNS symptoms due to their inability to cross the BBB (blood–brain barrier). Some patients develop immune responses known as ADA (anti-drug antibody), which can compromise treatment effectiveness. Emerging research into nanotechnology and combination therapies may help overcome these limitations. Newer formulations such as pegunigalsidase (Elfabrio®) use for FD (Fabry disease), exhibit lower affinity for developing ADA compared to other ERTs, offer reduced immunogenicity and safety profiles enhancement. Cost remains a major barrier, with annual treatment expenses often exceeding hundreds of thousands of dollars. Access to ERT is uneven, particularly in underfunded healthcare systems. In North America, reimbursement varies by region and payer, potentially delaying treatment and impacting outcomes. This review draws from MEDLINE, Cochrane Reviews, and PubMed (1984–2025) using search terms such as LSDs, ERTs, rare diseases, Gaucher disease, Fabry disease, and others. Ongoing research and health policy reforms are essential to improve access, equity, and therapeutic outcomes for patients with LSDs.

Plain language summary

What Are Lysosomal Storage Diseases? Rare inherited disorders where the body cannot break down certain substances because a specific enzyme is missing or faulty. This causes harmful buildup in organs like the brain, heart, and muscles, leading to serious health problems.

What Is Enzyme Replacement Therapy (ERT)? Main treatment involving regular intravenous infusions of the missing enzyme. First used in 1995, ERT can slow organ damage, improve daily function, and extend life.

Limitations of ERT: Cannot reach the brain, so it does not help with nervous system symptoms; must be given for life; Some patients develop immune reactions that reduce their benefit.

Research to Improve ERT- Scientists are testing new drug designs, such as nanotechnology, small material technology, delivery systems, and combined approaches to help enzymes reach the brain and work more effectively.

Cost and Access ERT can cost hundreds of thousands to over a million US dollars per year. In many countries, limited healthcare funding makes access difficult, and delays can worsen outcomes.

Keywords

enzyme replacement therapy lysosomal storage disease lysosomes rare disease

Introduction

Lysosomal storage diseases (LSDs) are a diverse group of over 50 rare inherited metabolic disorders caused by mutations in lysosomal genes, which encode enzymes, membrane proteins, and transporters essential for lysosomes’ function. Lysosomes house more than 60 hydrolytic enzymes responsible for breaking down macromolecules such as proteins, lipids, and carbohydrates.^{1, ²} Genetic mutations or enzyme deficiencies result in toxic substrate accumulation, which affects organs like the CNS, skeletal muscles, and kidneys. In addition to their catabolic role, lysosomes act as nutrient sensors, regulating signal transduction, growth, and vesicle trafficking.^3,4

Lysosomal enzymes are synthesized in the cytoplasm, modified with mannose-6-phosphate (M6P) in the Golgi apparatus, and transported to lysosomes via M6P receptors through endocytosis or autophagy.^4,5 Lysosomes play an important role in maintaining cellular homeostasis and must respond quickly to change in various metabolic conditions or invasion of infectious agents to protect cells from death and damage.⁶ Lysosomes are involved in innate and adaptive immune functions, through recognition of foreign materials such as bacterial, parasites and viral, activation of immune signals such as antibody production, antigen processing and T cell homeostasis; therefore, dysfunction of lysosome directly cause broad spectrum of clinical manifestations.^{6, ⁷} Since lysosomes are housekeeping organelles, it is expected that dysfunctional lysosomes can cause multiple problems in peripheral organs and CNS.⁸

LSDs can be categorized into mucopolysaccharidosis (MPS) (mucopolysaccharidoses), mucolipidosis, and sphingolipidoses based on the accumulated substrates.^1,3 Though individually rare, their combined incidence is estimated at 1 in 4,000 live births globally. In North America, certain populations exhibit higher prevalence rates. For example, Gaucher disease (GD) has a carrier rate of approximately 8.9% among Ashkenazi Jewish individuals, with an incidence of 1 in 450 live births in this population. Additionally, MPS and Fabry disease also exhibit notable prevalence within specific ethnic groups, making early recognition essential for timely intervention.^1,3,9,10

Clinical manifestations of LSDs vary widely depending on the type of disease. MPS disorders, for instance, present with coarse facial features, hepatosplenomegaly, corneal clouding, skeletal abnormalities, and cognitive decline.¹⁰ Sphingolipidoses, on the other hand, are characterized by neurodegeneration, enlargement of the liver and spleen, and ataxia.¹¹

Currently, available treatments for LSDs include bone marrow transplantation, ERTs, SRTs (substrate reduction therapy), PCT (pharmacological chaperone therapy), GT (gene therapy), and lysosomal transplantation. ERT is the most used treatment for several LSDs. ERTs work using functional replacement enzymes in exchange for the deficient or absent of endogenous enzymes. Given by i.v. administration, they are typically given weekly or biweekly. SRTs are aiming to decrease the production of the substrate that accumulates due to the defective lysosomal enzyme. By reducing the synthesis of these substrates, the burden on the lysosome is lowered due to minimizing cellular damage.¹² The advantages of SRTs include small molecules, which allow the drug taken orally. It can potentially penetrate BBB, and the drug does not cause the formation of ADA.¹² However, not all patients respond well to SRTs due to SE (side effects) of severe gastrointestinal and neurological problems.¹² Another approach to treating LSDs is pharmacological chaperone therapy (PCT), which uses small molecules. PCT assists mutated enzymes to fold properly reaching the lysosomes, where they can function correctly. However, this treatment is effective only for specific misfolded mutations, and only a small subset of patients possesses such mutations.^13,14 GT works by delivering a functional copy to replace mutated genes using viral vectors such as lentivirus. The goal is to restore long-term expression of the missing or dysfunctional lysosomal enzyme, for permanent correction after a single treatment. The limitation includes immune compatibility, high cost, and challenges in delivery.^15,16 Lysosomal transplantation, also called cell-based therapy, is an emerging approach that involves transplanting healthy cells or lysosomes capable of producing the missing enzyme into the patients. The donor lysosomes or cells can supply enzymes to neighboring cells through cross-correction mechanisms. This method is still under investigation due to several challenges that still need to be addressed.¹⁷

These various therapies do not offer cure. They aim to improve symptoms, extend survival, and enhance the quality of life of the patients. Despite these breakthroughs, rare disease management faces persistent challenges. High costs of development, patients’ limited access to treatments, and ongoing safety concerns with ERTs present barriers to patients and healthcare providers. Additionally, SEs such as immune reactions (i.e. formation of ADA) and infusion-related complications remain significant considerations in clinical care.¹²

Among available treatment modalities, ERTs have emerged as the gold standard for managing several LSDs. Imiglucerase for GD, approved by the FDA in 1995, marked a significant milestone as the first ERT to gain regulatory approval.¹⁸ Since then, various ERTs have been developed and approved for multiple LSDs, including FD (Fabry disease), PD (Pompe disease), LAL-D (lysosomal acid lipase deficiency), NCL (neuronal ceroid lipofuscinosis), and MPSs.^1,3 Despite its clinical benefits, ERTs have several limitations. These include the development of neutralizing antibodies or ADA, causing the patients’ immune system to react against the treatment, the inability of therapeutic enzymes to cross the BBB, and the high cost of treatment, which restricts access for patients.¹⁹ Additionally, due to the large molecular size of the enzymes, their delivery into the affected tissues is limited. To improve bioavailability, new generation ERTs using liposomes, nanoparticles or PEG (polyethylene glycol) have been tried in several studies.^20,21 Other challenges include variability in patient immune responses and the transient nature of therapeutic effects that require treatment for life.^22–24

ERTs are administered via i.v. infusion on schedules such as weekly or biweekly. Most are recombinant enzymes produced in stable cell lines like CHO (Chinese hamster ovary) cells or human fibroblasts, providing distinct glycosylation patterns. ERT compensates for deficient enzymes by delivering functional recombinant enzymes enriched with M6P groups, facilitating lysosomal uptake via M6P receptors.^1,25–27 Cost-effective production methods using plant or yeast cells are also employed, followed by enzyme purification and modification for better lysosomal targeting.

Addressing the unmet needs of rare disease patients requires ongoing research, innovative treatment strategies, and policy changes to facilitate access to effective therapies. The growing awareness of rare diseases such as LSDs underscores the importance of continued investment in research and patient advocacy across North America.

The rationale for this review lies in the need to synthesize and critically evaluate the current landscape of ERTs, particularly as newer therapies continue to emerge, and clinical experiences evolve. Despite their success, ERTs present challenges related to immune responses, limited tissue penetration, lifelong treatment burden, and cost. A comprehensive review is needed to guide clinicians, researchers, and policymakers in optimizing care and shaping future therapeutic development.

The aims of this review are threefold: (1) to provide an overview of the epidemiology, genetic basis, and clinical manifestations of key LSDs treated with ERTs; (2) to summarize and compare current ERT options, including dosing strategies, clinical efficacy, and limitations; and (3) to discuss emerging directions in treatment and the implications for clinical practice and patient outcomes.

Methods of review

A literature search was conducted using MEDLINE, Cochrane Reviews, and PubMed covering the period from January 1984 to February 2025. Search terms included combinations of “lysosomal storage disorders,” “rare diseases,” “orphan drugs,” and specific disorders such as “Gaucher disease,” “Fabry disease,” “Pompe disease,” “lysosomal acid lipase deficiency,” “neuronal ceroid lipofuscinosis,” and “mucopolysaccharidoses.” Only articles published in English were reviewed.

I focused on peer-reviewed original research articles, clinical trials, systematic reviews, and authoritative guidelines related to ERT for LSDs. Inclusion criteria were studies that (1) provided clinical data on ERT use in LSDs, (2) addressed ERT-related outcomes, mechanisms, or dosing strategies, or (3) offered relevant epidemiological or genetic insights. Exclusion criteria included non-English publications, case reports with fewer than five patients, preclinical animal studies, and conference abstracts without full-text availability.

PRISMA flow diagram

Initial database searches yielded approximately 500 articles

↓

Screening titles and abstracts for relevance, yield 250 articles. Others were excluded for being non-clinical, irrelevant, or duplicative

↓

Full texts of 200 articles were assessed

↓

The final selection of 150 articles was included based on ERT, disease mechanisms, treatment outcomes, and clinical implications for LSDs. Reference lists were also screened to identify additional relevant studies

Gaucher disease

GD (OMIM #230800) is a rare autosomal recessive LSD caused by mutations in the GBA gene, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase, also known as GBA1, EC.3.2.1.45). This enzyme breaks down glucocerebroside (GLC) into glucose and ceramide. GBA1 deficiency leads to GLC buildup in organs such as the spleen, liver, bone marrow, and CNS.^28,29 Table 1 summarizes available ERTs, affected enzymes, disease names, year of approval. Clinical symptoms include spleen and liver enlargement, bone destruction, lung abnormalities, anemia, thrombocytopenia, leukopenia, and seizures. The disease affects 1 in 50,000 to 100,000 live births, but its prevalence is much higher in Ashkenazi Jews, with an estimated carrier rate of 1 in 17 and an incidence of 1 in 800 live births.^29,30

Table 1.

Year approval of ERTs for LSDs.

Diseases	Affected enzyme	Available ERTs	Year
GD	β-Glucocerebrosidas	Imiglucerase (Cerezyme^®)	1994
		Velaglucerase α (VPRIV^®)	2010
		Taliglucerase α (Elelyso^®)	2012
FD	α-Galactosidase A	Agalsidase α (Replagal^®)*	2001
		Agalsidase β (Fabrazyme^®),*	2003
		Pegunigalsidase alfa-iwxj (Elfabrio®)	2023
PD	α-Glycosidase	Alglucosidase α (Lumizyme^®)**	2010
		Myozyme^®)*	2006
		Avaglucosidase alfa-ngpt (Nexviazyme^®)	2021
LAL-D	Lysosomal acid lipase	Sebelipase α (Kanuma^®)	2015
ASMD	Acid sphingomyelinase	Olipudase alfa-rpcp (Xenpozyme^®)	2022
NCL2	Tripeptidyl-peptidase I	Cerliponase α (Brineura^®)^#	2017
AM	α mannosidase	Velmanase α (Lamzede^®)*	2018
MPS I	α-L-Iduronidase	Laronidase (Aldurazyme^®)	2003
MPS II	Iduronate-2-sulfatase	Idursulfase (Elaprase^®)	2006
MPS IVA	N-AG6S ⁺	Elosulfase α (Vimizim^®)	2014
MPS VI	N-AG4S ⁺⁺	Galsulfase (Naglazyme^®)	2005
MPS VII	β-glucuronidase	Vestronidase α (Mepsevii^®)	2017

Europe, Canada.

USA.

Given as intraventricular infusion.

AM, α mannosidosis; ASMD, Acid sphingomyelinase disease; FD, Fabry disease; GD, Gaucher disease; LAL-D, Lysosomal acid lipase deficiency; MPS, mucopolysaccharidosis; N-AG4S⁺⁺, N-acetyl galactosamine 4-sulfatase; N-AG6S⁺, N-acetylgalactosamine-6-sulfatase; NCL, Neuronal ceroid lipofuscinosis; PD, Pompe disease.

GD is classified into three types:

Type 1 (GD1): Chronic, non-neuronopathic form without CNS involvement.

Type 2 (GD2): Acute, fatal neuronopathic form affecting infants or toddlers.

Type 3 (GD3): Subacute neuronopathic form affecting juveniles.

There are currently no treatments for GD2 or GD3 due to ERTs that cannot penetrate the BBB; therefore, they have no effect on the neurological aspects of GD2 or GD3.³¹ ERTs include imiglucerase (approved in 1994), velaglucerase (2010), and taliglucerase α (2012) are used for GD1. Table 2 summarizes the characteristics of these ERTs as previously published.³²

Table 2.

Comparison of ERTs for GD treatment.³²

Drug name company	Dosing, pharmacokinetics, pharmacodynamics	Patient type, side effects, other information
Imiglucerase (Cerezyme^®, Genzyme Corp.)	Dose: 2.5 u/kg tiw – 60 u/kg qowPlasma t _1/2: 3–11 mins,Vd: 0.09–0.15 L/kg,Plasma Cl: 0.6–1.22 L/hr/kg,Available: 200 u/ mL/vial or400 u/mL/vialAdministration: dilute with 0.9% sterile NaCl USP to a final volume of 100 mL (for 200 u/vial) or 200 mL (for 400 u/vial). Infuse 1–2 h with an in-line filter of low protein binding 0.2 µm.Pregnancy: C	Standard care for GD1, non-neuronopathic GD3, and severe GD. Patients treated with imiglucerase can switch to velaglucerase with the same dose, and vice versa.SEs: nausea, abdominal pain, vomiting, diarrhea, rash, headache, fever, dizziness, chills, backache, and tachycardia. See below ^a
Velaglucerase α (VPRIV^®,Shire Human Genetic Therapies, Inc.)	Dose:15 u/kg–60 u/kg qowPlasma t_1/2: 11–12 mins,Vd: 82–108 mL/kg,Plasma Cl: 6.72–7.56 ml/min/kg,Available: 400 u/mL/vialAdministration: reconstitute with sterile water to 100 units/mL (do not shake); further dilute with 100 mL 0.9% sterile NaCl USP. Infuse over 1 hr with an in-line filter of low protein binding 0.2 µm.Pregnancy: B	Pediatric (age 4–17 years) and adult GD1, severe GD.SEs (pediatrics): URTI, rash, prolonged aPTT, pyrexia.Other SEs: nausea, abdominal pain, joint pain, diarrhea, dizziness, and asthenia/fatigue. See below for additional information.^a
Taliglucerase α (Elelyso^®, Pfizer Inc).	Dose: 11 u/kg to 73 u/kg qowPlasma t _1/2: 19–28.7 mins,Vd: 7.3–11.7 L/kg,Plasma Cl: 20 -30 L/hr/kg,Available: 200 units/vialAdministration: dilute with 5.1 mL sterile water USP then with 0.9% NaCl to a final volume of 100–200 ml. Infuse at rate 1.3–2.3 mL/min with an in-line filter of low protein binding 0.2 µm.Pregnancy: B	GD1 on imiglucerase can switch to taliglucerase α at the same dose.ADRs: URTI, headache, arthralgia, influenza/flu, urinary tract infection/pyelonephritis. See below for additional information. ^a

Since all three ERTs are given as intravenous injections, common symptoms of infusion reactions are: chest pain or discomfort, asthenia, fatigue, urticaria, erythema, increased blood pressure, back /extremity pain, and flushing. If infusion reactions occur, decreasing the infusion rate, temporarily stopping the infusion, or administering antihistamines and/or antipyretics are recommended. If anaphylaxis reaction occurs, infusion needs to be discontinued and initiate appropriate treatment.

aPTT, activated partial thromboplastin time; Cl, clearance; qow, every other week; qw, every week; SEs, side effects; tiw, three times a wee; URTI, upper respiratory tract infection; Vd, volume of distribution.

Fabry disease

FD (OMIM #301500) is an X-linked LSD caused by mutations in the GLA gene, leading to a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A, EC.3.2.1.22).³³ This enzyme breaks down globotriaosylceramide (Gb3) into galactosylceramide. Gb3 or its metabolite, globotriaosylsphingosine (lyso-Gb3), accumulates and causes symptoms such as peripheral neuropathy, pain, gastrointestinal issues, hypertrophic cardiomyopathy, and renal failure.³⁴

Since FD is X-linked disorder, males (XY) are easier to diagnose due to more distinct symptoms, while females (XX) often present with variable manifestations. FD affects 1 in 3000–7000 live births globally and 1 in 28,000 in the USA.^35-36

FD divided into two phenotypes:

Classical: Typically affects young males with little to no α-Gal A activity.

Late-Onset: Occurs between ages 40 and 70, with milder symptoms due to partial α-Gal A activity. Plasma lyso-Gb3 levels can distinguish between the classical and late-onset forms.

α-Gal A is the standard treatment for FD. In Europe and Canada, the EMA has approved agalsidase α (Replagal^®, Shire) and agalsidase β (Fabrazyme^®, Sanofi Genzyme). Until 2023, only agalsidase β is approved in the USA.^37–40 ERT-treated patients often develop ADA, which can be caused by neutralizing of the enzyme and suppressing its catalytic function or non-neutralizing activity, promoting its elimination via Fc portion of immunoglobulin. ADA formation often reduces drug efficacy and is commonly observed in patients treated with ERTs.^39–41 Table 3 compares these two ERTs.

Table 3.

Comparison of agalsidase α and agalsidase β for FD.^37,38

Agalsidase α (Replagal^®)	Agalsidase β (Fabrazyme^®)
Approved by EMA in Europe and Canada (2001)	Approved by FDA in USA (2003); by EMA in Europe and Canada (2001)
Human fibroblast with promoter of α-GLA	Chinese hamster ovary cells (CHO)
Dose: 0.2 mg/kg iv, every 2 weeks, infuse in 40 min. 1 vial of 3.5 ml contains 3.5 mg drug. Reconstitute with 0.9% NaClNot for 0–6 years old, or > 65 years	Dose: 1 mg/kg iv, every 2 weeks. 35 mg or 5 mg vials. Reconstitute with sterile water, then with 0.9% NaCl. Infuse at 15 mg/h., increase by increment 3–5 mg/h: for < 35kg, max infusion at 15 mg/hr., for >35 kg, minimum infusion time 1.5 h.
Efficacy: decreased plasma Gb3 and lyso-Gb3, decreased GFR, improved exercise capacity, hearing loss, vestibular function, nerve sensitivity, gastrointestinal symptoms, pain, and quality of life	Efficacy: same as agalsidase α
SEs: infusion reaction* pyrexia, dyspnea, rash, peripheral edema, headache, flushing, rigors, tachycardia, pain, swelling.*Infusion reaction or pyrexia: premedicated with Benadryl, or steroids	SEs: URTI, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness, and rash.
Formation of ADA in 20% of patients	Formation of ADA in 91% of patients

ADA, anti-drug antibodies; SE, side effects; URTI, upper respiratory tract infection.

The newest drug approved in 2023 by the FDA was pegunigalsidase alfa-iwxj (Elfabrio^®) after Phase III trials (BRIDGE, BRIGHT, BALANCE).^42,45 Pegunigalsidase α (PRX-102), a recombinant enzyme produced in tobacco-derived cells and PEGylated offers advantages over Replagal^® or Fabrazyme^®. It is developed and marketed by Protalix Biotherapeutics in collaboration with Chiesi Global Rare Diseases. These advantages include slower degradation, increased molecular stability, reduced ADA responses, and having an extended half-life (80 vs 2 hours), that at 1 mg/kg can be infused monthly. A therapeutic regimen of 1 mg/kg bimonthly are being tested in clinical trials. It is not the currently approved dosing frequency. In some patients, this dose range is being applied as off label.⁴⁶

Pompe disease

PD (OMIM #232300) is a rare recessive LSD caused by mutations in the GAA gene encoding for acid alpha-glucosidase (GAA, EC.3.2.1.20), responsible for glycogen degradation in lysosomes. Glycogen accumulation leads to progressive cardiac, skeletal muscle, and CNS deterioration. Also known as acid maltase deficiency (AMD) or glycogen storage disease type II (GSDII), PD is classified into infantile-onset (IOPD) and late-onset (LOPD).^47,48

IOPD manifests before age 1 with cardiomyopathy and severe GAA deficiency, while LOPD occurs after age 1 with <20% GAA activity that lack cardiomyopathy. IOPD presents with rapid disease progression, enlarged heart, muscle weakness, hepatomegaly, and respiratory failure, often leading to early death.^49–51

Prevalence is 1 in 138,000 among Caucasians, 1 in 50,000 among Chinese, and 1 in 14,000 among Africans. A global incidence of PD is up to 1 in 9000 live births.^52,53

FDA approved recombinant human GAA (rhGAA) alglucosidase α (Lumi zyme^® if use in the USA or Myozyme^®, if use outside the USA), manufactured by Sanofi Genzyme for IOPD in 2006 and LOPD in 2010. Lumizyme^® is dosed at 20 mg/kg over 4 hr infusion, given every other week. Common SEs are myalgia, abdominal pain, diarrhea, dizziness, swelling, allergic reaction, and infusion-related reactions fever, chills, flushing, vomiting, fatigue, headache, and pruritis.⁵⁴ Despite treatment, children continued to have trouble swallowing, speech impairments, and CNS dysfunction.^55,56 Immune-mediated reactions, including necrotizing skin lesions and type III systemic responses, have also been reported in LOPD patients. About 60% of IOPD patients either died prematurely or became ventilator-dependent, with half showing initial positive responses that later deteriorated. All IOPD patients developed CRIM (cross-reactive immunological material) -negative status, associated with worsening symptoms and death despite ongoing therapy.⁵⁷ CRIM is referred to as substances that share immunological properties, causing an antibody or immune cell to recognize and bind to an antigen that is not the original target, due to shared epitopes or structural similarities.⁵⁸ Protocols to prevent CRIM include rituximab, methotrexate, or bortezomib, with or without IV gamma globulins, have shown some outcome improvement.^59,60

In 2021, the FDA approved the second-generation ERT avaglucosidase alfa-ngpt (NeoGAAA, Nexviazyme^®) manufactured also by the Sanofi Genzyme after a pivotal 49-weeks phase III COMET trial, for LOPD and geriatric use, but not for IOPD.⁶¹ This glycoengineered enzyme binds 15 times more strongly to mannose-6-phosphate receptors on target cell surfaces compared to the first generation.^62–64 Patients showed improvement in 6-min walking test (6-MWT) and stabilization of their respiratory function compared to Lumizyme®. Tables 4 to 7 show calculation of the drug and recommended infusion rate at 20 mg/kg or 40 mg/kg.

Table 4.

Calculation of the drug and step of the infusion of Lumizyme^®.⁵⁴

Patient weight (kg)	Total infusion volume (mL)	Step 11 mg/kg/h (mL/h)	Step 23 mg/kg/h (mL/h)	Step 35 mg/kg/h (mL/h)	Step 47 mg/kg/h (mL/h)
1.25–2.5	25	1.25	3.75	6.25	6.6
2.6–10	50	3	8	13	18
10.1–20	100	5	15	25	35
20.1–30	150	8	23	38	53
30.1–35	200	10	30	50	70
35.1–50	250	13	38	63	88
50.1–60	300	15	45	75	105
60.1–100	500	25	75	125	175
100.1–120	600	30	90	150	210
120.1–140	700	35	105	175	245
140.1–160	800	40	120	200	280
160.1–180	900	45	135	225	315
180.1–200	1,000	50	150	250	350
30.1–35	200	10	30	50	70
35.1–50	250	13	38	63	88
50.1–60	300	15	45	75	105
60.1–100	500	25	75	125	175
100.1–120	600	30	90	150	210
120.1–140	700	35	105	175	245
140.1–160	800	40	120	200	280
160.1–180	900	45	135	225	315
180.1–200	1,000	50	150	250	350

Table 5.

Recommended infusion volumes and rates of Nexviazyme for PD.

Patient weight (kg)	Total infusion volume for 20 mg/kg	Total infusion volume for 40 mg/kg
5–9.9	N/A	100 mL
10–19.9	N/A	200 mL
20–29.9	N/A	300 mL
30–34.9	200 mL	N/A
45–49.9	250 mL	N/A
50–59.9	300 mL	N/A
60–99.9	500 mL	N/A
100–119.9	600 mL	N/A
120–140	700 mL	N/A

Table 6.

Recommended infusion rates at 20 mg/kg dose for Nexviazyme.

Step 1	Step 2	Step 3	Step 4	Step 5
1 mg/kg/h	3 mg/kg/h	5 mg/kg/h	7 mg/kg/h	Continue 7 mg/kg/h

Table 7.

Recommended infusion rate at 40 mg/kg dose for Nexviazyme.

	Step 1	Step	Step 3	Step 4	Step 5
Initial rate	1 mg/kg/h	3 mg/kg/h	5 mg/kg/h	7 mg/kg/h	Continue 7 mg/kg/h
Subsequent rate (optional)	1 mg/kg/h	3 mg/kg/h	6 mg/kg/h	8 mg/kg/h	Continue 10 mg/kg/h

Lysosomal acid lipase deficiency

LAL-D (OMIM #278000) is a rare autosomal LSD caused by mutations in the LIPA gene, resulting in lysosomal acid lipase (LAL, EC 3.1.1.13). LAL hydrolyzes cholesteryl esters (CE) and triglycerides (TG).⁶⁵

LAL-D divided into Wolman disease (WD) and cholesterol ester storage disease (CESD). WD affects infants with no LAL activity, leading to death within 6 months, with visible lipid droplet accumulation in the liver, spleen, intestine, and lymph nodes.⁶⁵ WD is more common in the Iranian-Jewish population occurring at 1 per 2200 births. CESD affects older patients with partial LAL activity (1%–12%) and is identified through abnormal lipid profiles, liver dysfunction, or gallstones, occurring at 2.5 per 100,000 births.^65,66

FDA and EMA approved Sebelipase α (Kanuma^®) in 2015 manufactured Alexion Pharmaceuticals, a subsidiary of AstraZeneca.⁶⁷ The starting dose is 1 mg/kg weekly, increasing to 5 mg/kg if necessary.^68,69 Common SEs are abdominal pain, diarrhea, nasal congestion, cough, elevated liver enzyme, and infusion-related reactions such as flushing, difficulty breathing, chest discomfort. This ERT has improved survival, growth, carotid stenosis and dyslipidemia.⁷⁰

Acid sphingomyelinase deficiency

ASMD (OMIM# 607608), formerly known as Niemann-Pick disease types A, A/B, and B, is a rare autosomal recessive LSD caused by mutations in the SMPD1 gene, leading to deficiency of the enzyme acid sphingomyelinase (ASM). This results in sphingomyelin accumulation in organs such as the spleen, liver, lungs, bone marrow, lymph nodes, and CNS.^71,72 NPD-A leads to severe neurological complications and infant death, while NPD-B presents with milder neurological symptoms. ASMD affects 1 in 250,000 live births, with a higher prevalence (1 in 40,000) among Ashkenazi Jews.^71,73

In 2022, the FDA approved olipudase alfa-rpcp (Xenpozyme®) for non-CNS ASMD in adults and children, following regulatory approval in Japan (March 2022, SAKIGAKE designation) and Europe (June 2022).⁷⁴ The drug received Breakthrough Therapy designation based on positive results from the ASCEND and ASCEND-Peds trials, showing improved lung function and reduced spleen and liver volumes over 52 weeks.^72–74 The most frequently reported SEs are headache, cough, diarrhea, hypotension, and ocular hyperemia, occurring in more than 10% of patients. SEs observed in over 20% of cases included pyrexia, rhinitis, abdominal pain, nausea, rash, arthralgia, pruritus, and pharyngitis (Table 8).

Table 8.

Xenpozyme^® dose escalation regimen for ASMD patients.*,⁷⁴

Week	Dosage (>18 years)	Dosage 0–17 years)
First dose (day 1/week 0)	0.1 mg/kg	0.03 mg/kg
Second dose (week 2)	0.3 mg/kg	0.1 mg/kg
Third dose (week 4)	0.3 mg/kg	0.3 mg/kg
Fourth dose (week 6)	0.6 mg/kg	0.3 mg/kg
Fifth dose (week 8)	0.6 mg/kg	0.6 mg/kg
Sixth dose (week 10)	1 mg/kg	0.6 mg/kg
Seventh dose (week 12)	2 mg/kg	1 mg/kg
Eighth dose (week 14)	3 mg/kg (recommended maintenance dose)	2 mg/kg
Ninth dose (week 16)		3 mg/height/kg (recommended maintenance dose)

Use actual body weight for patients with a BMI ⩽30. For patients with a BMI >30, calculate adjusted body weight (kg) = (actual height in m)² × 30.

Neuronal ceroid lipofuscinosis-type 2

NCL comprises 13 heterogeneous LSDs characterized by progressive cognitive and motor decline, retinopathy leading to blindness, and myoclonic seizures.^75,76 NCL-2 (Jansky-Bielschowsky, OMIM #204500) is the most common form, caused by mutations in the CLN2 gene encoding tripeptidyl peptidase (TPP1). TPP1 deficiency disrupts protein processing, leading to severe symptoms, including psychomotor retardation, refractory seizures, ataxia, and blindness, with death typically by ages 7–8 due to aspiration pneumonia.^76,77

The prevalence of all NCL 1 per 100,000 live births, with NCL-2 at 0.5 per 100,000.^77,78 NCLs remain incurable with one ERT is approved for NCL-2. FDA-approved treatment in 2017 with cerliponase alfa (Brineura^®, manufactured by BioMarin Pharmaceutical), a recombinant TPP1 administered via intraventricular infusion to slow disease progression in children.⁷⁹ SEs include infusion-related reaction, headache, fever, fatigue, and allergic reactions.⁸⁰

Alpha mannosidosis

Alpha mannosidosis (AM; OMIM #2485000) is a rare autosomal LSD caused by mutations in the MAN2B1 gene, which encodes lysosomal α-mannosidase (LAMAN, EC 3.3.1.24). Enzyme deficiency leads to mannose-rich oligosaccharide accumulation in skeletal and muscle cells, the CNS, and causes immunodeficiencies. Its global prevalence is 1–2 per 100,000 live births.⁸¹

In 2018, the EMA granted orphan drug status for Velmanase α (Lamzede^®, rhLAMAN, manufactured by Chiesi Farmaceutici, Italy) for long-term use in patients with mild to moderate AM. In February 2023, the FDA approved Lamzede® for AM patients without CNS involvement in the US.^82,83 Each vial contains 10 mg of the medication. For patients weighing 49 kg or less, the infusion should be administered over 60 minutes. For patients weighing more than 50 kg, the infusion rate should be set at 25 ml per hour once weekly.^82,83

Mucopolysaccharidosis

MPS is a group of chronic, progressive LSDs caused by enzyme deficiencies that prevent the breakdown of glycosaminoglycans (GAGs). GAG accumulation leads to irreversible multisystem symptoms, often diagnosed late. There are 11 types and subtypes of MPS, ERTs approved for MPS I, II, IVA, VI, and VII.⁸⁴

Mucopolysaccharidosis I

MPS I (Hurler and Hurler-Scheie disease, OMIM #252800) results from mutations in the IDUA gene, which encodes α-L-Iduronidase (EC 3.2.1.76). This enzyme, taken up by lysosomes via MP-6 receptors, facilitates the breakdown of glycosaminoglycans (GAGs). Enzyme deficiency leads to the accumulation of GAGs, dermatan sulfate (DS), and heparan sulfate (HS) in the brain, causing neurodegeneration and systemic complications.⁸⁴

Children with MPS I appear normal at birth but develop severe symptoms within the first year, including cardiac, respiratory, skeletal, and ocular disorders, facial deformities, organomegaly, hernias, and hearing loss.^84,85 Severe cases typically result in a life expectancy of 10 years due to cardiac and respiratory issues.

The global prevalence is approximately 1 in 144,000 live births.^84,85 Laronidase (Aldurazyme^®) was FDA-approved in 2003 and manufactured by Genzyme, Cambridge MA, is indicated for moderate to severe MPS I.⁸⁶ The drug is supplied as 2.9 mg/5 mL and dosed at 0.58 mg/kg weekly.

Common SEs include infusion reactions such as fever, chills, tachycardia, rash, and respiratory symptoms. For hypersensitivity or acute cardiorespiratory issues, infusion should be stopped or adjusted. Pretreatment with antihistamines and antipyretics is recommended to reduce infusion reactions.⁸⁶

Mucopolysaccharidosis II

MPS II (Hunter syndrome, OMIM #309900) is caused by mutations in the IDS gene, which encodes the enzyme iduronate-2-sulfatase (I2S). This enzyme is essential for degrading HS and DS by removing sulfate from the 2-position of iduronic acid. Without this function, GAGs accumulate in various organs, leading to symptoms such as recurrent respiratory infections, joint stiffness, otitis media, cardiomyopathies, hepatosplenomegaly, hydrocephalus, spinal cord compression, and hearing loss.⁸⁷

MPS II is X-linked recessive, affecting males more severely, while females may be carriers if they have one mutated X chromosome. The disorder is classified into two forms: MPS IIA (severe) and MPS IIB (attenuated). Symptoms usually appear between ages 2 and 4, with MPS IIB often diagnosed in the second decade of life, showing slow progression and minimal cognitive decline. MPS IIB patients may live into their 50s, but complications can cause premature death. The prevalence of MPS II in males is estimated at 0.6–1.3 per 100,000 live male births in Great Britain and British Columbia, and 1 in 36,000 in Israel.^87,88

The FDA-approved idursulfase (Elaprase^®) 2006 manufactured by Takeda Pharmaceuticals. It is indicated for patients aged 5 and older and is administered at 0.5 mg/kg over 3 h. Common SEs include headache, pruritus, urticaria, flushing, and pyrexia. Serious reactions like anaphylaxis can occur, so patients should receive premedication and slow infusion rates to reduce the risk of hypersensitivity reactions. The drug has not been studied in pregnant women or the elderly.⁸⁹

Mucopolysaccharidosis IVA

MPS IV is divided into MPS IVA and IVB. MPS IVB results from mutations in the GLB1 gene, which encodes β-galactosidase, but there is no FDA-approved treatment for IVB, so the focus of this review is on MPS IVA.⁹⁰

MPS IVA (Morquio syndrome, OMIM #253000) is caused by mutations in the GALNS gene, leading to a deficiency in N-acetylgalactosamine-6-sulfatase, which results in the accumulation of GAGs like KS and C6S.⁹¹ Symptoms, typically detected between ages 1 and 3, include skeletal dysmorphia, growth retardation, cervical spine compression, joint hypermobility, respiratory issues, hearing loss, and sleep apnea with cognitive impairment that is usually mild.^92,93 The prevalence is approximately 0.14 per 100,000 live births.⁹⁴

FDA-approved Elosulfase α (Vimizim®, BioMarin, CA) was approved in 2014. Common SEs include pyrexia, vomiting, headache, and fatigue. Pre-treatment with antihistamines or antipyretics is recommended to decrease the SE of infusion.⁹⁰

Mucopolysaccharidosis VI

MPS VI (Maroteaux-Lamy syndrome, OMIM #253200) results from mutations in the ARSB gene, which encodes N-acetyl galactosamine 4-sulfatase (NAG4S or arylsulfatase B, EC 3.1.6.12). This enzyme catalyzes the removal of sulfate esters. Enzyme deficiency leads to the accumulation of GAGs, DS, and chondroitin 4-sulfate (CS) throughout the body.⁹⁵

Patients with MPS VI often have poor quality of life and a life expectancy of 20–30 years due to pulmonary infections, restrictive lung disease, and cardiac conditions. Skeletal complications include dystonia multiplex, scoliosis, joint stiffness, contractures, pectus carinatum, and spinal cord compression. Other features include coarse facial features, macroglossia, hirsutism, umbilical hernia, hepatomegaly, and corneal clouding. The incidence is approximately 0.04 per 100,000 live births.⁹⁵

Galsulfase (Naglazyme^®), approved by the FDA in 2005, manufactured by BioMarin Pharmaceutical Inc., CA is produced via recombinant DNA technology in Chinese hamster ovary cells.⁹⁶ It is administered at 1 mg/kg and supplied as a 5 mg/ml solution for dilution in 250 ml of 0.9% NaCl. Infusion begins at 6 ml/h for the first hour, up to 80 ml/h over the remaining 3 h if tolerated. To prevent infusion reactions, the duration can be extended to 20 h. Pretreatment with antihistamines, with or without antipyretics, is recommended to reduce hypersensitivity risks.⁹⁶ Infusions must be stopped immediately if severe reactions occur, such as anaphylaxis, shock, respiratory distress, bronchospasm, or type III immune complex-mediated events showing as pruritus or chills. Medical intervention should follow. SEs include rash, pain, urticaria, pyrexia, nausea, vomiting, dyspnea, and abdominal pain.^96,97 Patients should be monitored for spinal or cervical cord compression (SCC) symptoms, such as back pain, limb paralysis, or incontinence, which may require surgical decompression. Naglazyme^® is indicated for patients aged 5 and older but has not been studied in pregnant or patients over 29 years old.

Mucopolysaccharidosis VII

MPS VII (Sly syndrome, OMIM #253220) results from mutations in the GUSB gene, which encodes the enzyme β-glucuronidase (GUS, EC 3.2.1.31). Enzyme deficiency leads to the accumulation of HS, CS, DS, GM2, and GM3. Clinical features include cognitive impairment, hepatosplenomegaly, coarse facial features, cardiac valve disease, recurrent upper respiratory infections, short stature, and bone dysplasia.^98,99 Most patients do not survive into adulthood due to airway obstruction and heart disease complications. In rare cases, infants are born with hydrops fetalis, characterized by fluid accumulation in fetal compartments, often resulting in stillbirth or early death. The global incidence is approximately 0.027 per 100,000 live births.¹⁰⁰

In 2017, the FDA approved recombinant human GUS (rhGUS) vestronidase alfa-vjbk (Mepsevii^®, Ultragenyx Pharmaceutical Inc., Novato, CA) for pediatric and adult use. Premedication with non-sedating antihistamine, with or without an antipyretic, is recommended 30 to 60 minutes before infusion.¹⁰¹ In 2018, Mepsevii® received authorization in the European Union, United Kingdom, Brazil, Chile, and Mexico (Table 9).

Table 9.

Recommended i.v. rate schedule for Mepsevii ® at dose of 4 mg/kg, for MPS VII.¹⁰¹

Patient weight (kg)	Total MEPSEVII dose range (mg)	Total MEPSEVII (Volume (rounded mL)	Total infusion volume of drug and diluent (infuse over 4 h (mL)	Infusion rate for 1st hour (2.5%) mL/h	Infusion rate per hour for 3 h (97.5% (mL/h)
3.5–5.9	14–23.6	10	20	0.5	6.5
6–8.4	24–33.6	15	30	0.8	9.8
8.5-10.9	34–43.6	20	40	1	13
11–13.4	44–53.6	25	50	1.3	16.3
13.5–15.9	54–63.6	30	60	1.5	19.5
16–18.4	64–73.6	35	70	1.8	22.8
18.5–20.9	74–83.6	40	80	2	26
21–23.4	84–93.6	45	90	2.3	29.3
23.5–25.9	94–103.6	50	100	2.5	32.5
26–28.4	104–113.6	55	110	2.8	35.8
28.5–30.9	114–123.6	60	120	3	39
31–33.4	124–133.6	65	130	3.3	42.3
33.5–35.9	134–143.6	70	140	3.5	45.5
36–38.4	144–153.6	75	150	3.8	48.8
38.5–40.9	154–163.6	80	160	4	52
41–43.4	164–173.6	85	170	4.3	55.3
43.4–45.9	174–183.6	90	180	4.5	58.5
46–48.4	184–193.6	95	190	4.8	61.8
48.5–50.9	194–203.6	100	200	5	65
51–53.4	204–213.6	105	210	5.3	68.3
53.5–55.9	214–223.6	110	220	5.5	71.5
56–58.4	224–233.6	115	230	5.8	74.8
58.5–60.9	234–243.6	120	240	6	78
61–63.4	244–253.6	125	250	6.3	81.3
63.5–65.9	254–263.6	130	260	6.5	84.5
66–68.4	264–273.6	135	270	6.8	87.8
68.5–70.9	274–283.6	140	280	7	91

Advantages, limitations, future advancement of ERTs

Several advantages of ERTs include delaying disease progression, improving quality of life, reducing liver and spleen volume, stabilizing heart and renal functions, alleviating gastrointestinal symptoms, and decreasing neuropathic pain.^18,20 However, ERTs also have notable drawbacks. One significant limitation is their short half-life, necessitating frequent i.v. administration throughout a patient’s life. This short half-life often results in fluctuating therapeutic effects.¹⁸ Additionally, drug bioavailability varies due to differing expression levels of MP-6 receptors in various tissues. While the liver and spleen have high MP-6 receptor expression and sequester much of the administered dose, bones, cartilage, and eyes express fewer receptors, limiting ERT efficacy in these tissues.^1,20–23

Another major challenge is the inability of ERTs to cross the BBB. Many LSDs affect CNS, leading to neurodegeneration. Because ERTs cannot reach the CNS, patients often experience disease progression despite long-term therapy.^22–24

Immune responses are another concern. Patients on ERTs may develop ADA, which can be either neutralizing, directly inhibiting enzyme activity, or non-neutralizing, accelerating enzyme clearance through Fc receptors on immune cells. Complete neutralization of ERTs has been observed in CRIM-negative patients, who often exhibit strong immune responses. Allergic reactions involving IgE antibodies have also been reported.⁵⁷

ERTs rely on active transport to enter cells and reach lysosomes, but this rate-limiting step significantly reduces their therapeutic efficacy.¹⁰² Despite large infusion volumes, only a small fraction of the administered enzyme reaches its target. To overcome these limitations, next-generation ERTs have been developed to enhance stability and efficacy.¹⁰³ These strategies include encapsulating recombinant enzymes in liposomes or nanoparticles to extend half-life and reduce immune responses. Various nanoparticles—such as polystyrene, polyelectrolyte capsules, liposomes, and extracellular vesicles—are being tested.¹⁰³

One promising advancement is Pegunigalsidase α (PRX-102), a recombinant enzyme produced in tobacco-derived cells that bound to PEG (polyethylene glycol) moieties. Following three Phase III clinical trials—BRIDGE, BRIGHT, and BALANC, FDA approved pegunigalsidase alfa-iwxj (Elfabrio^®) in 2023 for FD, administered every 2 weeks at a dose of 1 mg/kg.^42–46

Different strategies have been evaluated to improve the biodistribution of the lysosome enzymes, such as direct administration of nanoparticles enzyme to the affected tissue using intrathecal or intraventricular techniques. Other method is using protein modification that fused into peptides/proteins allowing a receptor-mediated internalization in the target cells.⁹⁵ The latest strategy recalls the Trojan Horse scheme, which leads to crossing biological barriers. Receptor- and cellular-based Trojan Horses have been evaluated as novel alternatives for treating LSDs by enhancing receptor targeting through novel functional groups, developing safer and more effective intrathecal or intracerebroventricular delivery methods, exploring chimeric enzyme formulations for better BBB penetration, and investigating combination therapies or nanocarriers to improve the distribution and therapeutic outcomes of ERTs.^104,105

Relevance to patient care and clinical practice

LSDs are rare and often underdiagnosed in the USA, but they are more frequently recognized among Jewish descendants and populations in European and Asian countries due to higher prevalence. Recent newborn screening (NBS) pilot studies in various U.S. states have enhanced understanding of LSD epidemiology and diagnosis. NBS aims to improve public health outcomes by enabling early detection and treatment, supported by parental education, clinical follow-ups, and available therapies.^106,107 The Recommended Uniform Screening Panel offers guidelines for state-based programs, detailed in Table 10.

Table 10.

Available and unavailable newborn screening for LSDs.¹⁰⁷

Disease type	Age of onset	Presenting symptoms	IL	KY	MO	NY	OH	PA
GD
Type 2	Infant	N, L, S, R	Yes	No	Yes	No	No	Yes
Type 3	<2-year-old	N, l, S
KD
Infant	<6 months	N, M	No	Yes	Yes	Yes		Yes
Late infant	6–12 months	N
Late onset	>12 months	O, M
PD
Classical	1 month	L, S, M, R, C	Yes	Yes	Yes	Yes	No	Yes
Non-classical	12 months	M, R, C
FD
Classical	4–8-year-old	G, P, R, C	Yes	No	Yes	No	No	Yes
ASMD
Type A	3 months	N, L, S, O	Yes	No	No	No	No	Yes
Type B	Teen	L, S, R, M
MPS I
Severe	6–12 months	N, L, S, R, C,	Yes	Yes	Yes	No	No	Yes
Attenuated	3–10-year-old	milder
MPS II
Severe	18months- 4-years old	N, L, S, C, O	No	No	No	No	No	No
Attenuated	>10-year-old	milder

<, less than; ASMS, Acid sphingomyelinase disease; C, cardiac; FD, Fabry Disease; GD, Gaucher disease; H, hematologic; KD, Krabbe disease; KY, Kentucky; L, liver; M, muscular; MO, Missouri; MPII, mucopolysaccharidosis type II; MPS, Mucopolysaccharidosis type I; N, neurologic; NY, New York; O, ophthalmic; OH, Ohio; P, pain; PA, Pennsylvania; PD, Pompe disease; R, respiratory; S, spleen.

Although ERTs alleviate symptoms, additional treatments for complications like psychosis, cardiac dysfunction, and depression often require multidisciplinary care. Since LSDs typically manifest in childhood, regular monitoring through lab tests, imaging, and clinical assessments is crucial for early detection and intervention.

Due to their rarity, LSDs are often poorly understood by physicians in Northern America regarding their physical characteristics and clinical manifestations. Many have infantile forms where early detection and treatment with ERTs can significantly improve survival and treatment outcomes. Effective management typically requires a multidisciplinary team of physicians, scientists, pharmacists, and other healthcare providers to develop tailored therapeutic protocols addressing the complex, multisystem challenges faced by LSD patients.¹⁰⁸

Global equity care accessibility of ERTs

There is a growing concern globally about the equity of care for individuals with LSDs, particularly when it comes to access to ERTs. Patients from lower socioeconomic backgrounds or rural areas may face significant challenges in obtaining the necessary care. Health disparities can arise due to variations in insurance coverage, availability of healthcare providers, and geographic limitations on where treatments are available.¹⁰⁹

In some areas, access to specialized clinics and multidisciplinary teams necessary to properly manage LSDs can be limited, leaving patients with inadequate treatment options. For example, in China, due to the high cost of ERTs, most adults with late-onset Pompei disease received medication with insufficient doses. Patients experience progression of the disease faster than if the drug is given at correct dosing.¹¹⁰ Ethnic and racial disparities also persist in access to care. Minority populations may be more likely to experience delays in diagnosis or receive suboptimal care due to systemic inequities within healthcare systems.

In Canada, while the publicly funded healthcare system provides some support for ERTs, the lack of a national policy on the reimbursement of orphan drugs leads to inconsistencies between provinces. Some provinces may approve funding for ERT for certain LSDs, while others may not, leaving patients without access to life-saving treatments. This patchwork system can create inequities in care, particularly for those in provinces with less generous coverage or bureaucratic delays.^111,112 Patients’ access to appropriate healthcare and social services is subject to significant delays and lacks coordination. Patients residing in rural or remote areas face significant challenges in accessing specialized healthcare services. These include limited availability of specialists, long travel distances for treatments, and lack of coordinated care, leading to increased financial and emotional burdens. Participants reported experiencing stigma and discrimination within the healthcare system. This includes medical professionals’ limited knowledge about rare diseases, difficulties in obtaining accurate diagnoses, and a lack of patient engagement in healthcare decisions. Such systemic issues contribute to delayed treatments and psychological distress. Patients and caregivers often encounter convoluted application procedures, unclear eligibility criteria, and a lack of formal appeal processes for negative reimbursement decisions. Furthermore, physicians’ reluctance to submit drug applications further exacerbates these challenges.^111–113

ERT can be administered in hospitals, infusion centers, or at home under medical supervision. While home-based treatment reduces hospital-related costs and improves convenience, it still requires trained healthcare professionals for drug administration. A study conducted in Germany highlighted the financial burden associated with home-based ERT, estimating an annual cost of approximately €369,047 (~$400,000 USD) per patient.¹¹⁴ While this figure may seem high, it reflects the total cost of care and logistics associated with providing ERT outside of traditional clinical environments. Despite the expense, transitioning ERT to home-based administration has the potential to reduce indirect costs related to travel, time off work, and the need for hospital resources.¹¹⁴

The motivation behind studying and expanding home-based ERT options is rooted in the goal of improving accessibility and patient quality of life. Patients and caregivers have reported greater satisfaction, enhanced autonomy, and reduced emotional and logistical strain when therapy is administered at home.¹¹⁵ Moreover, home-based care models may facilitate adherence to therapy and better disease management outcomes. Importantly, decentralizing ERT can address disparities in access, particularly for rural populations who may face geographic or transportation barriers to specialized centers. By making treatment more available in community settings or through home infusion programs, healthcare systems can support equity in rare disease care.^114–116 Therefore, the study and implementation of home-based ERT are not only about cost containment but also about delivering patient-centered care and ensuring broader access to life-saving therapies.

Equity of care accessibility in North America

While North America has some of the most advanced healthcare systems globally, access to medication, including ERT, remains an issue for certain populations. In the USA, the accessibility of treatments is significantly influenced by insurance status. Those with employer-sponsored insurance or private insurance plans may have relatively easier access to treatments, though they still face high out-of-pocket costs. Conversely, individuals without insurance or those relying on public insurance may experience difficulties in accessing the care they need due to limitations in coverage.^117,118

The cost of ERT varies significantly depending on the specific disorder, required dosage based on body weight), and geographic region.¹¹¹ In North America, the annual cost per patient typically ranges from $100,000 to over $500,000. Below are estimated annual costs for selected conditions:

Gaucher disease (Type 1): $98,000–$175,000

Fabry disease: Over $300,000

Pompe disease: Typically exceeds $500,000

Mucopolysaccharidoses (MPS) disorders: $200,000–$600,000

Private insurance and government programs (Medicaid, Medicare) may cover ERT, but policies often require high costs or prior authorization. Additionally, ERT pricing is influenced by market conditions and regulatory policies. In North America, higher costs stem from pharmaceutical pricing models, market exclusivity, and limited competition.^119,120

Securing financial assistance can be a prolonged and stressful process, requiring detailed documentation of medical need and potential outcomes. Public programs like Medicaid, which serves low-income individuals, may offer more comprehensive coverage, but even then, access to specialized care and therapies like ERT can be limited by administrative hurdles.

Furthermore, in both Canada and the USA, patients may face long waiting times for specialized treatment centers or be required to travel long distances to access ERT. The logistical and financial burdens of accessing care may result in some patients opting out of treatment, even when it is medically necessary.

Practical reflection from practitioner/pharmacist view

As the landscape of rare disease treatment continues to evolve, practitioners and pharmacists are uniquely positioned to play a transformative role in advancing the effective use of ERTs. Beyond clinical administration, their expertise is critical in optimizing dosing regimens, managing infusion-related reactions, monitoring therapeutic outcomes, and supporting adherence—particularly given the lifelong and resource-intensive nature of ERT.

From a pharmacist’s standpoint, understanding and interpreting biomarkers is integral to guiding ERTs and ensuring optimal outcomes. To illustrate this, Table 11 presents findings based on selected publication from 2022 to 2025—covering inflammatory markers, anti-drug antibody status, and novel biomarkers summarized as a practical reference to support monitoring and optimization of ERTs.

Table 11.

Selected inflammatory markers, ADAs, and novel biomarkers in LSDs.

Category	Disease(s)/context	Markers/biomarkers	Response to ERT	Key reference(s)
Inflammation markers	FD, GD, PD	CRP, TNF-α, IL 12, IL 17, IL21, CCL2, CCL3, CCL 8, PARC/CCL18, CH13L1, CXCL13, CXCL1, CXCL9, others	Reduced, but often not fully normalized—suggests residual inflammation/fibrosis	121,122
ADAs	PD (CRIM-negative), FD	Binding IgG, neutralizing antibodies	High/neutralizing ADAs can impair biochemical and clinical response; ADA kinetics vary (transient plateau), can cause death, worsening symptoms	123, 124
ADA	MPS II	Increase urinary GAG	Sustained ADA inhibit uptake of drugs	125
Immune tolerance/management	PD	High ADA, need immunomodulation protocols (rituximab, methotrexate, IVIG)	Some success with early immune-tolerance induction; outcomes variable	126
Disease-specific substrate biomarkers	GDFD	C1qa, Clec 4n,Gb/Lyso-Gb3, sICAM-1, SVCAM-1 (FD)	Sensitive to therapy; robust fall in substrate levels; plateauing observed especially with ADAs present	122, 127
Emerging novel biomarkers	KD, neurologic LSDs, GD3general meta/proteomic	Psychosine, Nfl, proteomic/metabolomic panels	Still investigational; some promising early trends but need longitudinal validation	128, 129
Complement activation	FD	ADA negative, C3a, c5a, Il-6, IL-10, TGF b1	Chronic inflammation caused kidney damage	130

ADA, Anti- drug antibodies; CRIM, cross reactive immunological material; CRP, C-reactive protein; FD, Fabry disease; GAG, glycosaminoglycan; GD, Gaucher disease; IL, interleukin; KD, Krabbe disease; MPS, mucopolysaccharidosis; Nfl, neurofilament light; PD, Pompe disease, TGF, Transforming growth factor; TNF, Tumor necrosis factor alpha.

Pharmacists are instrumental in ensuring safe and efficient drug preparation, navigating supply chain logistics, and facilitating patient education on home infusion protocols or side effects management. Moreover, pharmacists and clinicians can contribute to therapeutic optimization through pharmacovigilance efforts, real-world evidence, and collaboration with multidisciplinary care practitioners.

Looking ahead, pharmacists can help advance treatment by participating in research efforts, adopting pharmacogenomic tools to personalize therapy, and embracing digital health innovations that support remote monitoring and patient engagement. Pharmacists can advocate for formulary inclusion, equitable access policies, and orphan drug funding at institutional and national levels.

Advancing rare disease treatment requires more than scientific innovation—it calls for coordinated, patient-centered care driven by informed, empowered healthcare professionals. By integrating clinical expertise with system-level advocacy, practitioners and pharmacists can bridge gaps in treatment access, improve health outcomes, and ensure that therapeutic advancements translate into meaningful improvements in patients’ lives.

Conclusion

ERTs have become a cornerstone in the treatment of many LSDs, with numerous recombinant enzymes approved in recent decades and more in advanced clinical trials. Despite these advancements, significant challenges remain. Research continues to focus on enhancing ERT delivery across the BBB, increasing enzyme stability for prolonged activity, and minimizing adverse drug reactions. Additionally, combination approaches such as addition of SRT or PCT hold promise for overcoming resistance and achieving better clinical outcomes. Continued innovation is essential to meet the complex needs of LSD patients and improve their quality of life.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Lunawati L. Bennett

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