Background of Gene Therapy for Lysosomal Storage Diseases
Lysosomal storage disorders (LSDs) are a heterogeneous group of genetic disorders caused by defects in proteins essential for lysosomal function, such as lysosomal hydrolases, as well as transporter proteins, integral membrane proteins, cofactors and enzyme modifiers or activators. Specific therapies aimed at correcting metabolic defects have been developed for many LSDs, including hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT), drug chaperone therapy (PCT), and substrate reduction therapy (SRT). LSDs are ideal candidates for gene therapy approaches for several reasons:
(Ⅰ) LSDs are single-gene disorders, and the disease can theoretically be corrected by correcting the genetic defect.
(Ⅱ) If lysosomal enzymes are secreted from a small number of transduced cells, they can be taken up by adjacent affected cells via the mannose 6-phosphate receptor. The advantage is that a small number of transduced cells can have a therapeutic effect, resulting in benefits to multiple organs.
(Ⅲ) Even a slight increase in enzyme activity (up to 10%) may be sufficient to obtain clinical benefit and partial phenotype correction.
Fig. 1. In vivo and ex vivo gene therapy. (Penati R, et al., 2017)
Solutions
At the time of treatment with LSDs, intravenous ERT controls damage to internal organs but does not prevent neurological damage. Depending on the type of disease, HSCT has important limitations when performed on early variants unless treatment is administered before the onset of disease. Therefore, our team of experts develops gene therapies to try to overcome these problems. Our gene therapeutic solutions aim to increase or restore the activity of defective enzymes in the cells of patients with LSDs. This is not obtained by providing the missing enzyme protein, but by using viral or non-viral derived vectors to deliver a functional copy of the defective gene. We develop different viral vectors to accomplish gene transfer, including:
❖ Herpes viruses.
❖ Retroviruses.
❖ Lentiviruses.
❖ Adeno-associated viruses (AAV).
❖ Adenovirus (Ads).
❖ Other viruses.
Working closely with geneticists, we identify defective genes in LSDs and develop animal models that allow preclinical testing. Based on improved knowledge of the molecular basis of LSDs combined with technological advances in therapeutic agent optimization and preparation, CD BioSciences offers different gene therapy strategies for LSDs using in vivo or ex vivo procedures to achieve gene transfer.
- Ex Vivo Gene Therapeutic Solutions for LSDs
- In Vivo Gene Therapeutic Solutions for LSDs
- Genome Editing Solutions for LSDs
What Viral Vectors We Offer for Gene Transfer?
- Have the ability to effectively infect cells using viruses
- Expression of viral genes that can lead to replication and subsequent virulence
- Genes encoding replication and capsid or envelope functions are removed from the viral genome and made available in trans during vector production.
- Viral genes are replaced by expression cassette sequences encoding transgenes of interest, selected promoters and other regulatory elements.
Advantages of Our Gene Therapeutic Solutions for LSDs
- Long-term expression of therapeutic proteins.
- Indicated for patients with rare conditions.
- Methods for completely and consistently correcting enzyme defects.
- Improved viral vector technology.
- Engineered vectors and expression cassettes for improved transduction efficiency and penetration into specific tissues.
CD BioSciences' mission is to provide preclinical gene therapy strategies for lysosomal storage diseases that provide new ideas for drug discovery. We look forward to collaborating with you in the discovery of innovative LSD therapeutic strategies. If you are interested in our solutions, please feel free to contact us.
Reference
- Penati R, et al. (2017) Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I. J Inherit Metab Dis. 40(4):543-554.