Treatment Strategies of
Monogenic Diseases
Substrate-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 therapies1,9

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 itself10–14
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
Dietary Restriction1
Advantages:
Disadvantages:
Examples of Potential Disease Targets:
PKU, phenylketonuria.
GA-1, Glutaric aciduria type 1.
GSDs, Glycogen storage disorders.
LC-FAODs, Long chain fatty oxidation disorders.
People with PKU, who lack the enzyme that metabolises phenylalanine, should follow a phenylalanine-restricted (low-protein) diet that includes a supplemental formula providing the essential elements of protein without phenylalanine2,3
Toxin Removal1
Advantages:
Disadvantages:
Examples of Potential Disease Targets:
*Ammonul® is approved by the U.S. Food and Drug Administration.
ORNT1, mitochondrial ornithine transporter 1; UCD, urea cycle disorder.
The body’s ammonia detoxification pathway converts ammonia into urea. In UCDs, there are deficiencies in components of this pathway, resulting in accumulation of ammonia, which is neurotoxic. The use of ammonia-scavenging drugs – such as intravenous Ammonul®*, a mixture of sodium benzoate and sodium phenylacetate – has been used for the chronic management of UCDs1
Figure reproduced with permission from Urea Cycle Disorders Consortium. Urea Cycle Disorders. Available at: https://www.rarediseasesnetwork.org/cms/ucdc/Learn-More/Disorder-Definitions. Accessed January 29, 2019.
Substrate Reduction1
Advantages:
Disadvantages:
Examples of Potential Disease Targets:
Nitisinone is a substrate-reduction drug that has been in use for many years to treat hereditary tyrosinemia type I. Nitisinone blocks the catabolic pathway of tyrosine at an earlier stage, resulting in the milder phenotype associated with tyrosinemia type III6,7
Figure reproduced from the National Center for Biotechnology Information. PubChem Compound Database; CID 115355. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/115355. Accessed February 15, 2019.
References
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- Gambello MJ, Li H. J Genet Genomics 2018;45(2):61–70.
- New England Consortium of Metabolic Programs. PKU Primer for Adolescents and Adults. Available at: http://newenglandconsortium.org/for-families/phenylketonuria-pku/pku-primer-for-adolescents-and-adults/. Accessed January 29, 2019.
- PKU Clinic. University of Washington, Seattle. What is the diet for PKU? Available at: https://depts.washington.edu/pku/about/diet.html. Accessed January 29, 2019.
- Urea Cycle Disorders Consortium. Urea Cycle Disorders. Available at: https://www.rarediseasesnetwork.org/cms/ucdc/Learn-More/Disorder-Definitions. Accessed January 29, 2019.
- El-Gharbawy A, Vockley J. Nonmitochondrial metabolic cardioskeletal myopathies. In: Cardioskeletal Myopathies in Children and Young Adults. 2017;265–303.
- CenterWatch. Orfadin (nitisinone). Available at: https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/765/orfadin-nitisinone. Accessed November 15, 2018.
- ScienceDirect. Nitisinone. Available at: https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/nitisinone. Accessed January 3, 2019.
- National Center for Biotechnology Information. PubChem Compound Database; CID=115355. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/115355. Accessed February 15, 2019.
- 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.
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