Treatment Strategies
for Monogenic Diseases

Protein-Based Strategies

Different strategies are being used for the treatment of monogenic diseases. These include DNA and RNA-based approaches as well as protein and substrate-based therapies1,14

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Substrate-based and protein-based therapies target the downstream consequence of gene mutations

DNA-based and some RNA-based strategies target the abnormality in the gene itself15–19

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

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RNA Based Strategies:

Facilitate exon skipping and re-code premature termination codon

Alter gene expression or RNA processing

Learn more

DNA Based Strategies:

Manipulate gene product to prevent or treat a disease

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Enzyme Replacement Therapy1,2

Advantages:

Direct delivery of deficient enzyme

Disadvantages:

Weekly/biweekly IV infusion

Time burden

Costly

Usually does not cross blood–brain barrier

Immunogenic

Examples of Potential Disease Targets:

Gaucher disease

Fabry disease

Pompe disease

Mucopolysaccharidosis type I, II, IV-A, and VI

LALD

Hemophilia and other bleeding disorders

IV, intravenous; LALD, lysosomal acid lipase deficiency.

Concentrates of clotting factor VIII (for hemophilia A) or IX (for hemophilia B) are used as a replacement therapy for the reduced amount of the factor in the blood 3

Organ / Cell Transplantation1

Advantages:

Permanent supply of deficient enzyme

Occasional cure

Domino or carrier transplantation in certain conditions is life-saving with donor shortage

Disadvantages:

Narrow treatment window

Cannot restore irreversible damage

May not fully treat CNS disease

Surgical complications

GVHD

Immune suppression

Examples of Potential Disease Targets:

MLD

X-ALD

Mucopolysaccharidoses

Krabbe disease

UCDs

MSUD

MMA

PA

CNS, central nervous system; GVHD, graft-versus-host disease; MLD, metachromatic leukodystrophy; MMA, methylmalonic aciduria; 
MSUD, maple syrup urine disease; PA, propionic aciduria; UCD, urea cycle disorder; X-ALD, X-linked adrenal leukodystrophy.

In Krabbe disease, deficient levels of the galactocerebrosidase (GALC) enzyme lead to destruction of myelin on nerve cells and the conversion of microglia to toxic cells called globoid cells. Hematopoietic stem cell and bone marrow transplantation (HSCT/BMT) is successful for Krabbe disease if patients are treated before the onset of symptoms or if they have a milder form of disease. The donor stem cells can lead to production of healthy microglia to populate the nervous system and deliver GALC enzymes 1,5,6

Chaperone Therapy1

Advantages:

Oral

Broad bioavailablitity

Crosses blood-brain barrier

Non-immunogenic

Enhancement of endogenous enzyme activity

Acceptable safety profiles

Disadvantages:

Not all patients are suitable, depending on mutation

Examples of Potential Disease Targets:

Gaucher disease

Fabry disease

*Migalastat is approved by the U.S. Food and Drug Administration.

Fabry disease is caused by defects in the galactosidase alpha (GLA) gene, leading to a deficiency of this enzyme. Migalastat* is an oral pharmacologic chaperone of alpha-galactosidase A (alpha-Gal A) for the treatment of Fabry disease in adults who have amenable GLA variants8

 

 

Figure reproduced from Figure 5: Ishii S. Proc Jpn Acad Ser B Phys Biol Sci 2012;88(1):18–30.

Cofactor Replacement or Supplementation1

Advantages:

Enhancement of endogenous enzyme activity

Mostly oral administration

Disadvantages:

Some require intramuscular injection

Examples of Potential Disease Targets:

PKU

Biotinidase deficiency

Cobalamin disorders

PAH, phenylalanine hydroxylase; PKU, phenylketonuria.

Tetrahydrobiopterin (BH4) is the natural cofactor of PAH, the defective enzyme in most cases of PKU. Pharmacologic BH4 supplementation is effective in almost half of patients with PKU and selectively used for BH4-responsive patients with PKU in clinical practice1,11

 

 

Figure reproduced from National Center for Biotechnology Information. Genes and Disease, 1998. Available at: https://www.ncbi.nlm.nih.gov/books/NBK22253/. Accessed February 15, 2019.

Product Supplementation1

Advantages:

Dietary supplement only

Disadvantages:

Compliance

Examples of Potential Disease Targets:

PKU

UCDs

Biotinidase deficiency

PKU, phenylketonuria; UCD, urea cycle disorder.

Biotinidase is an enzyme that produces free biotin during turnover of biotinylated proteins. Administration of pharmacologic doses of the vitamin biotin can ameliorate or prevent clinical symptoms in patients with biotinidase deficiency12

 

 

 

 

 

 

 

 

 

 

 

 

 

References

      1. Gambello MJ, Li H. J Genet Genomics 2018;45(2):61–70.
      2. NIH. Enzyme Replacement Therapy. Available at: https://livertox.nih.gov/EnzymeReplacementTherapy.htm. Accessed January 29, 2019.
      3. NIH. Hemophilia. Available at: https://www.nhlbi.nih.gov/health-topics/haemophilia. Accessed January 29, 2019.
      4. Organ and tissue transplantation. Available at: https://www.betterhealth.vic.gov.au/health/ConditionsAndTreatments/organ-and-tissue-transplantation.
      5. Mayo Clinic. Krabbe disease – diagnosis & treatment. Available at: https://www.mayoclinic.org/diseases-conditions/krabbe-disease/diagnosis-treatment/drc-20374183.
      6. Mayo Clinic. Krabbe disease – symptoms & causes. Available at: https://www.mayoclinic.org/diseases-conditions/krabbe-disease/symptoms-causes/syc-20374178.
      7. News Medical Life Sciences. What are chaperone proteins? Available at: https://www.news-medical.net/life-sciences/What-are-Chaperone-Proteins.aspx. Accessed December 4, 2018.
      8. GlobeNewswire, Inc. FDA Approves Galafold™ (migalastat) for the Treatment of Certain Adult Patients with Fabry Disease. Available at: https://globenewswire.com/news-release/2018/08/10/1550472/0/en/FDA-Approves-Galafold-migalastat-for-the-Treatment-of-Certain-Adult-Patients-with-Fabry-Disease.html. Accessed November 15, 2018.
      9. Ishii S. Proc Jpn Acad Ser B Phys Biol Sci 2012;88(1):18–30.
      10. Differences between cofactor and coenzyme. Available at: http://www.differencebetween.net/science/biology-science/differences-between-cofactor-and-coenzyme/. Accessed January 29, 2019.
      11. National Center for Biotechnology Information. Genes and Disease, 1998. Available at: https://www.ncbi.nlm.nih.gov/books/NBK22253/. Accessed February 15, 2019.
      12. Strovel ET, et al. Genet Med 2017;19(10):1079.
      13. National Center for Biotechnology Information. PubChem Compound Database; CID=171548. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/171548. Accessed February 15, 2019.
      14. Nature Education. Gene-Based Therapeutic Approaches. Available at: https://www.nature.com/scitable/topicpage/gene-based-therapeutic-approaches-3881. Accessed November 15, 2018.
      15. Evers MM, et al. Adv Drug Delivery Rev 2015;87:90–103.
      16. 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.
      17. Schueren F, Thoms S. PLoS Genet 2016;12(8):e1006196.
      18. Wang D, Gao G. Discov Med 2014;18(97):151–161.
      19. NIH. What is gene therapy? Available at: https://ghr.nlm.nih.gov/primer/therapy/genetherapy. Accessed January 29, 2019.