Lysosomal Storage Diseases

Lysosomal storage diseases (LSDs) are 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, and deficiency in one leads to accumulation of its 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, so they’re present when 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.
In principle, the goal of gene therapy for lysosomal storage diseases is simple: turn a subset of native 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.

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 nondividing 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. 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.

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 ( Identifier: NCT01161576). 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 ( 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:

Please consult your physician before making any medical decisions.

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