Treatment Strategies of
Monogenic Diseases
DNA-Based Strategies
Different strategies are being utilized for the treatment of monogenic diseases. These include DNA and RNA-based approaches as well as protein and substrate-based therapies1,5

Substrate and protein-based therapies target the downstream consequence of gene mutations
DNA-based and some RNA-based strategies target the abnormality in the gene itself6–10
Protein Based Strategies:
Replace a deficient or abnormal protein
Enhance endogenous enzyme activity
Substrate Based Strategies:
Restrict consumption of offending substrate
Facilitate degradation or removal of toxic substrate
RNA Based Strategies:
Facilitate exon skipping and re-code premature termination codon
Alter gene expression or RNA processing
DNA Based Strategies:
Manipulate gene product to prevent or treat a disease
Gene Therapy1
Advantages:
Disadvantages:
Examples of Potential Disease Targets
*Voretigene neparvovec-rzyl is approved by the U.S. Food and Drug Administration.
cGMP, cyclic-GMP; LI-CLN2, late infantile neuronal ceroid lipofuscinosis; MLD, metachromatic leukodystrophy; PDE, phosphodiesterase; X-ALD, X-linked adrenal leukodystrophy.
Voretigene neparvovec-rzyl*, the first approved in vivo gene therapy product in the U.S., is indicated for the treatment of children and adult patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Mutations in RPE65 block the visual cycle and impair vision. Treatment results in delivery of a normal copy of the RPE65 gene directly to retinal cells3
Figure reproduced from Figure 1: Bavik C, et al. PLoS One 2015;10(5):e0124940.
References
- Gambello MJ, Li H. J Genet Genomics 2018;45(2):61–70.
- NIH. What is gene therapy? Available at: https://ghr.nlm.nih.gov/primer/therapy/genetherapy. Accessed January 29, 2019.
- FDA. News Release. December 19, 2017. FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. Available at: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm589467.htm. Accessed January 29, 2019.
- Bavik C, et al. PLoS One 2015;10(5):e0124940.
- Nature Education. Gene-Based Therapeutic Approaches. Available at: https://www.nature.com/scitable/topicpage/gene-based-therapeutic-approaches-3881. Accessed November 15, 2018.
- Evers MM, et al. Adv Drug Delivery Rev 2015;87:90–103.
- Muscular Dystrophy UK. What is exon skipping and how does it work? Available at: https://www.musculardystrophyuk.org/progress-in-research/background-information/what-is-exon-skipping-and-how-does-it-work/. Accessed January 29, 2019.
- Schueren F, Thoms S. PLoS Genet 2016;12(8):e1006196.
- Wang D, Gao G. Discov Med 2014;18(97):151–161.
- NIH. What is gene therapy? Available at: https://ghr.nlm.nih.gov/primer/therapy/genetherapy. Accessed January 29, 2019.