Lentiviral Vector Development for Metachromatic Leukodystrophy
To benefit the lentiviral vector (LV) development for metachromatic leukodystrophy (MLD), scientists at Creative Biolabs employ an advanced self-inactivating design and a moderately active internal promoter of the LVs, which can efficiently limit the interference of integration-dependent genotoxicity. Our seasoned scientists are pleased to share expertise and experience with our global clients and facilitate their meaningful researches.
The Introduction of MLD
MLD is an autosomal recessive lysosomal lipid storage disorder, usually caused by the deficiency of lysosomal arylsulfatase A (ARSA) enzyme, or more rarely caused by the deficiency of its activator protein saposin B (SAP-B). ARSA gene is located on chromosome 22q13.33 and is alternatively spliced with 8-9 exons combining to produce 3 different mRNA species. It encodes two isoforms of the same protein, an arylsulfatase involved in the lysosomal degradation of sphingolipid cerebroside 3-sulfate (sulfatide). As a major component of the myelin membrane, sulfatides are essential to its structure and function. Excess sulfatide triggers an inflammatory response including microglial activation, astrogliosis, recruitment of peripheral macrophages and secretion of pro-inflammatory cytokines. To date, about 1.4-1.8/100,000 live births suffer from MLD. Age of MLD onset varies from 18 months to adulthood and in the majority of the cases, the prognosis is severe and leads to a vegetative stage or death within a few years after diagnosis. The most common symptoms of MLD involves muscle wasting, weakness, muscle rigidity, developmental delays, and progressive loss of vision, seizures, impaired swallowing, paralysis, and dementia.
Figure 1. MRI in juvenile metachromatic leukodystrophy. (A) The central white matter shows signal hyperintensity and a streaky pattern, while the subcortical U fibers are spared. (B) Involvement of corpus callosum and posterior limb of internal capsule. (Kohlschütter, 2011)
Therapeutic Approaches to MLD
Various therapeutic approaches to MLD have been tested in experimental animal models. Among these, there are 4 promising approaches with clinical translation potential, including: 1) enzyme-replacement therapy (ERT); 2) bone marrow transplants; 3) gene therapy by ex vivo transplantation of genetically modified hematopoietic stem cells (HSC); and 4) AAV-mediated gene therapy directly to the central nervous system. In recent years, LVs have turned to be a high-efficient method for gene therapy. High-efficiency gene transfer into hematopoietic stem and progenitor cells (HSPCs) and long-term overexpression of the ARSA gene can be achieved through LVs. Scientists have prevented the development of major disease manifestations in mice. However, high transgene expression relies on multiple vector integrations into HSPCs, which increases the risk of integration-dependent genotoxicity.
LV Development for MLD at Creative Biolabs
New treatments of MLD are urgently needed. Scientists at Creative Biolabs employ a new strategy, using an advanced self-inactivating design and a moderately active internal promoter of the LVs. This strategy provides safety features, which can limit the interference of integration-dependent genotoxicity. For long-term follow-up studies, we have never detected hematopoietic abnormalities suggestive of clonal outgrowth or underlying hematologic malignancy.
Key Advantages of Our Service:
- New strategy, using an advanced self-inactivating design and a moderately active internal promoter of the LVs
- High-efficiency gene transfer into HSPCs
- Long-term overexpression of the ARSA gene
- Highly professional Ph.D. level scientists
In terms of extensive experience in LV Development, Creative Biolabs is proud to offer our clients the best service of LV development for MLD. We offer turn-key or ala carte services customized to our client's needs. Please contact us for more information and a detailed quote.
Reference
- Kohlschütter, A.; Eichler, F. (2011). Childhood leukodystrophies: a clinical perspective. Expert Rev Neurother. 11(10):1485-96.
