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 genes to prevent or treat a disease

Dietary Restriction1


Directly restricts the offending substrate(s)

Ability to modify to supplement deficient product

Very effective

Disease-specific newer medical foods available


Compliance (high demands)


Lack of medical food availability

Insurance coverage

Close monitoring for nutritional deficiencies

Examples of Potential Disease Targets:

Aminoacidopathies (e.g. PKU)

Organic acidemias (e.g. GA-I)

Carbohydrate diseases (GSDs, galactosemia)



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


Effective in both the acute and chronic setting


Intravenous infusion required for acute cases of ammonia intoxication in patients with UCDs


Examples of Potential Disease Targets:



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

Substrate Reduction1


Small molecule

Oral administration


Usually crosses the 
blood–brain barrier


Long-term consequences are unknown

Applicable to limited diseases

Examples of Potential Disease Targets:

Tyrosinemia type I

Gaucher disease

Niemann–Pick C


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


      1. Gambello MJ, Li H. J Genet Genomics 2018;45(2):61–70.
      2. New England Consortium of Metabolic Programs. PKU Primer for Adolescents and Adults. Available at: Accessed January 29, 2019.
      3. PKU Clinic. University of Washington, Seattle. What is the diet for PKU. Available at: Accessed January 29, 2019.
      4. Urea Cycle Disorders Consortium. Urea Cycle Disorders. Available at: Accessed January 29, 2019.
      5. El-Gharbawy A, Vockley J. Nonmitochondrial metabolic cardioskeletal myopathies. In: Cardioskeletal Myopathies in Children and Young Adults. 2017;265–303.
      6. CenterWatch. Orfadin (nitisinone). Available at: Accessed November 15, 2018.
      7. ScienceDirect. Nitisinone. Available at: Accessed January 3, 2019.
      8. National Center for Biotechnology Information. PubChem Compound Database; CID=115355. Available at: Accessed February 15, 2019.
      9. Nature Education. Gene-Based Therapeutic Approaches. Available at: Accessed November 15, 2018.
      10. Evers MM, et al. Adv Drug Delivery Rev 2015;87:90–103.
      11. Muscular Dystrophy UK. What is exon skipping and how does it work? Available at: Accessed January 29, 2019.
      12. Schueren F, Thoms S. PLoS Genet 2016;12(8):e1006196.
      13. Wang D, Gao G. Discov Med 2014;18(97):151–161.
      14. NIH. What is gene therapy. Available at: Accessed January 29, 2019.