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Lysosomal Storage Diseases

Lysosomal storage diseases (LSDs) comprise a family of more than 40 distinct diseases resulting from enzymatic deficiencies leading to accumulation of unwanted substances in lysosomes of various cell types. Lysosomes are the cellular recycling centers where materials are taken apart into their basic components for re-use in the cell. This process requires the sequential action of different enzymes specific for particular materials (substrates), and deficiency in one leads to accumulation of its substrate in lysosomes.

As a group, these are the most common type of childhood genetic disorders, with an estimated combined frequency of 1 in 7700 live births, and thus represent a significant worldwide health problem. These diseases are autosomal recessive, i.e. both parents carry a gene with mutations that reduce (>90-95%), or eliminate altogether, the activity of the respective enzyme. Typically, these diseases affect multiple organs or tissues and left untreated are invariably fatal.

Most enzyme-deficient cells throughout the body are capable of taking up normal enzymes and deliver them correctly to lysosomes where they degrade the stored materials. This mechanism is the basis for enzyme replacement therapy (ERT) where patients receive regular intravenous (iv) infusion of recombinant lysosomal enzymes produced by different pharmaceutical/biotech companies. Currently this approach is available for a subset of these diseases without neurological involvement, such asGaucher disease, Fabry disease, Pompe disease, Hurler syndrome (mucopolysaccharidosis type I), Maroteaux–Lamy syndrome (MPS type VI). However life-long enzyme replacement therapy carries a tremendous financial burden given the exceptional cost of these recombinant enzymes. Finally, the blood brain barrier (BBB) prevents iv infused recombinant lysosomal enzymes (and most other proteins and large molecules in blood) from entering the brain, and as such ERT is not available presently for lysosomal storage diseases affecting the nervous system.

A key aspect in industrial production of recombinant enzymes for ERT, and gene therapy is that cells genetically engineered to produce lysosomal enzymes at high-than-normal levels release them in massive quantities into the growth medium of cultured cells, or the extracellular environment in animals. Functional enzymes present in the extracellular space end up in the bloodstream and become available to most enzyme-deficient cells in the body outside of the nervous system. Thus, in principle, the goal of gene therapy for lysosomal storage diseases is simple: turn a subset of endogenous cells into microfactories to produce large quantities of normal enzyme that by virtue of being released from these cells become available to the vast majority of enzyme-deficient cells in the body. The main targets that are being explored for this purpose are liver, muscle, bone marrow stem cells, and different cell types in the nervous system.

Over the years many cell and gene therapy approaches have been tested in animal models of lysosomal storage diseases, and two main approaches have emerged as the most promising for translation into human clinical trials: In vivo gene transfer by direct infusion of viral vectors (AAV and lentivirus vectors) encoding normal enzymes; or modification of bone marrow stem cells in culture with viral vectors encoding normal enzymes (retrovirus and lentivirus vectors) followed by transplantation (this latter approach is often referred to as ex vivo gene therapy). For in vivo gene transfer, adeno-associated virus (AAV) and HIV-1-derived lentivirus vectors are the most effective gene delivery vehicles as they are devoid of any viral genes, are capable of infecting dividing and non-dividing cells with no apparent short- or long-term toxicity, and most importantly appear to be capable of directing life-long high-level expression of the recombinant enzymes (in the absence of immunological complications related to expression of normal enzymes in animals where the enzyme is absent entirely).

AAV-based in vivo gene therapy has been tested in scores of animal models of lysosomal storage diseases and consistently shown good to exceptional therapeutic efficacy, especially more recently with the use of more powerful versions of these AAV vectors. The first human clinical trials in lysosomal storage diseases were conducted in diseases affecting the nervous system because ERT is not available for any of them, and secondly because AAV vectors are exceptionally effective in infecting neurons and expressing new genes with no apparent toxicity or loss of expression over time. There is now evidence from long-term studies showing that gene expression remains stable > 8 years in monkeys, and > 96 weeks in humans. Infusion of AAV vectors directly into the brain has shown remarkable therapeutic effect in numerous animal models of lysosomal storage diseases with neurological involvement. Based on this efficacy there have been at least two clinical trials conducted to date in Canavan and Batten disease using AAV2 vectors injected directly into the brain. Both trials demonstrated that this approach is safe in humans, and in the Batten disease trial there was some evidence of either stabilization or slowing down of disease progression. Currently, there is a new trial for Batten disease using a new and more powerful AAV vector that has demonstrated considerably higher efficiency in mice and monkeys (ClinicalTrials.gov Identifier: NCT01161576). Many trials are in the planning phases for other lysosomal storage diseases with neurological involvement. Translation of AAV vector basedin vivo gene therapy for lysosomal storage diseases without neurological features using either intravascular (liver directed) or intramuscular injections has been slower due to potential immunological complications (seemingly absent from direct injections into the brain) associated with these delivery routes, and also the fact that ERT is available for some of these diseases. Currently there is an ongoing trial for Pompe disease investigating intramuscular infusion of an AAV vector encoding alpha-Glucosidase (ClinicalTrials.gov Identifier: NCT00976352).

Bone marrow transplantation with lentivirus-modified patient-derived hematopoietic stem cells (HSCs) has shown exceptional results in different mouse models of lysosomal storage diseases resulting in correction of pathologic findings throughout the CNS, and also peripheral organs. This approach relies on genetically modified HSC-derived cells (macrophages in the case of CNS) trafficking to the sites of disease and becoming an in situ source of recombinant enzyme. An ongoing clinical trial is testing the safety and efficacy of this approach in metachromatic leukodystrophy patients (http://mldfoundation.org/research-SanRaffaele.html). This trial is taking place at the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) in Milan, Italy.


For more information on lysosomal storage diseases, please visit the following websites:

Genetic and Rare Diseases Information Center (GARD)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)


Please consult your physician before making any medical decisions.