Hematopoietic Cell Therapy for Metabolic Disease

The lysosome, an intracellular organelle responsible for the intracellular sorting, recycling, and digestion of organic molecules, was first described 50 years ago by Christian de Duve.¹ All known lysosomal storage diseases (LSD) are single gene defects and with few exceptions are autosomal recessive in inheritance. Loss of functional activity of lysosomal enzymes results in accumulation of substrates, such as glycoproteins or mucopolysaccharides (MPS).² The clinical manifestations of LSD vary depending on the specific enzymatic deficiency, level of residual activity, and site of substrate accumulation (Table I, Table II). Variability in disease severity is observed in patients with the same disorder, because small differences in enzyme activity may result in marked differences in clinical disease.

Table I. Storage diseases treated with blood and marrow transplantation

	Lysosomal SD		Sphingolipidoses
	MPS I	MPS VI	GLD	MLD
Syndrome	Hurler	Maroteaux-lamy	Krabbe
Incidence⁎	1:100,000	1;235,000	1:141,000	1:92,000
Deficiency	α-l-iduronidase	Arylsulfatase B	Galactocerebrosidase	Arylsulfatase a
			I: infantile form	I: late infantile
			II: juvenile form	II: juvenile
			III: adult form	III: adult
Phenotype	Hepatosplenomegaly	Hepatomegaly
Visceral	Upper airway complications		Severe vomiting
	Respiratory infections
	Valvular dysfunction	Valvular dysfunction
	Hernias	Hernias
Skeletal	Dysostosis multiplex	Dysostosis multiplex
Neurologic	Mental retardation	None	Seizures, hypertonia,	Hypotonia, seizures
	Hydrocephalus		Ataxia, spasticity	Irritability, ataxia
Other	Corneal clouding	Corneal clouding	Vision loss	Blindness
Treatment
ERT	In clinical trials	In clinical trials
HCT	3y OS ∼70% for HLA	Visceral	Neurologic	Neurologic
	Matched related and unrelated transplants	Improvement	Improvement	Deterioration or improvement
Problems	Reports of high graft failure	Orthopedic problems	Symptomatic infants are unlikely to benefit from HCT	Persistence of peripheral neuropathy
	Poor correction of skeletal and heart disease	Progress
Animal models	Mouse, dog, cat	Cat, rat, dog, mouse	Mouse, sheep, dog, monkey	Mouse

OS, overall survival; HCT, hematopoietic stem cell transplantation; ERT, enzyme replacement therapy.

Table II. Storage diseases treated with blood and marrow transplantation

	Oligosaccharidosis Mannosidosis	Enzyme localization deficit Mucolipidosis II	Peroxisomal SD adrenoleukodystrophy
Syndrome		I cell disease
Incidence*	1:500,000	1:325,000	1:42,000
Deficiency	α-Mannosidase	Phosphotransferase	ABCD1 gene product
	I: early, severe
	II: late, mild
Phenotype	Hepatosplenomegaly	Hepatosplenomegaly	Adrenocortical
Visceral	Vomiting	Gingival hypertrophy	Deficiency may occur
		Respiratory infections
	Immune deficiency	Valvular dysfunction
	Tall stature
Skeletal	Dysostosis multiplex	Dysostosis multiplex
Neurologic	Mental retardation	Rapid psychomotor	Deficits in cognition, gait
		Deterioration	Vision, hearing, swallowing
Other	Ocular clouding
Treatment
ERT
HCT	Improvement in CNS and skeletal problems	Limited neurologic stabilization	Improvement in early disease
		Limited visceral improvement
Problems			Peripheral nerve demyelinization
			Not known to be effective for AMN
Animal models	Mouse, cat, cattle, guinea pig	Cat

SD, Storage disease; VLCacylCoA, very long chain acyl coenzyme A; OS, overall survival; MR; matched related; UCB, umbilical cord transplant; D, disorder; ERT, enzyme replacement therapy; AMN, adrenomyeloneuropathy; HCT, hematopoietic stem cell transplantation.

ALD, Adrenoleukodystrophy, CNS, Central nervous system, ERT, Enzyme replacement therapy, GLD, Globoid cell leukodystrophy, HCT, Hematopoietic stem cell transplantation, LSD, Lysosomal storage disease, M6P, Mannose 6-phosphate, MAPC, Multipotent adult progenitor cell, MLD, Metachromatic leukodystrophy, MPS, Mucopolysaccharidosis, mucopolysaccharide, MRI, Magnetic resonance imaging, MSC, Mesenchymal stem cell