Background of in Vivo Gene Therapy for LSDs
Lysosomal storage disorders (LSDs) due to defects in soluble lysosomal enzymes are often considered good candidates for gene therapy. Gene therapy for LSDs is based on the delivery of a normal copy of the defective gene, which will direct the recipient cell to synthesize the normal enzyme. Genetic modifications can be performed ex vivo or in vivo. One strategy that is being extensively tested is based on direct in vivo gene therapy. It involves the direct delivery of a gene into an organ such as the liver or lung so that the gene product (enzyme) will not only correct the local cells but will also be secreted at high levels and subsequently recaptured by other target cells via the mannose-6-phosphate receptor. Notably, with major advances in vector technology and production, in vivo gene transfer has become a safe and effective technique for targeting the nervous system.
With years of experience in developing gene therapy strategies for LSDs, CD BioSciences is committed to providing clients worldwide with in vivo gene therapy strategies for LSDs by injecting gene transfer vectors directly into tissues or the circulatory system.
Gene Therapeutic Solutions for Lysosomal Storage Diseases In Vivo
The in vivo gene therapy strategy for LSDs is the direct injection of a viral vector encoding the gene of interest. We develop recombinant adeno-associated viruses (AAVs) as vectors to enable delivery of therapeutic lysosomal proteins to peripheral organs, including liver, lung, and muscle. These viral vectors are subject to adaptive immune responses during in vivo gene transfer, and we develop the following potentially synergistic strategies to reduce gene therapy-induced vector immunity in animal models of LSDs:
❖ Development of liver-directed gene therapy.
❖ Development of serotypes that are among the least abundant AAVs in nature, such as AAV8, AAV9 and AVV10.
❖ Development of AAVs with chimeric capsids.
❖ Use of immunosuppressive drugs to control antibody production against the virus prior to vector administration.
❖ Introduction of viral vectors into the brain via intranasal delivery.
What attracts customers to this strategy is the difficulty in controlling transgenic insertion sites in the genome, and our expert team develops site-specific genome editing to provide long-term, stable therapeutic expression of lysosomal enzymes.
Currently over 50% of LSDs have neurological involvement. We attempt to apply in vivo gene therapy to neurological LSDs. Most viral vectors do not cross the fully mature blood-brain barrier after intravenous administration. We offer customized protocols for effective gene delivery to the central nervous system.
(1) We attempt to develop polycationic polypeptides that compound and compress plasmid DNA.
(2) The compressed DNA package is bound and initially internalized by targeting specific cellular ligands to the plasma membrane.
(3) Endocytic DNA packages are designed to bypass the endosome/lysosome system.
(4) The nuclear localization signal in these packages will ensure effective nuclear localization.
Advantages of the In Vivo Gene Therapy Solutions
- Liver-directed gene therapy is capable of producing large amounts of LSDs enzymes systemically.
- In vivo gene therapy offers a safe and potentially therapeutic option for neurological LSDs.
- Advanced non-viral DNA complex delivery system.
- Allowing for the establishment of a continuous source of therapeutic enzymes in vivo for metabolic correction.
We are very innovative in the development phase to achieve each client's individual goals. We are ready to explore the value of in vivo gene therapy to meet the requirements of novel LSDs treatment strategies. For more information, please feel free to contact us.
Reference
- Rastall D P, Amalfitano A. (2015) Recent advances in gene therapy for lysosomal storage disorders[J]. The application of clinical genetics. 8: 157.