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

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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

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RNA Based Strategies:

Facilitate exon skipping and re-code premature termination codon

Alter gene expression or RNA processing

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DNA Based Strategies:

Manipulate gene product to prevent or treat a disease

Gene Therapy1

Advantages:

Personalized therapy

Disadvantages:

Blood–brain barrier represents a challenge

Immune response

Cellular toxicity

Potential oncogenesis

Technological limitations

Ethical issues

Examples of Potential Disease Targets

Retinal dystrophy

Spinal muscular dystrophy

MLD

X-ALD

LI-CLN2

*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*

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

  1. Gambello MJ, Li H. J Genet Genomics 2018;45(2):61–70.
  2. NIH. What is gene therapy? Available at: https://ghr.nlm.nih.gov/primer/therapy/genetherapy. Accessed January 29, 2019.
  3. 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.
  4. Bavik C, et al. PLoS One 2015;10(5):e0124940.
  5. Nature Education. Gene-Based Therapeutic Approaches. Available at: https://www.nature.com/scitable/topicpage/gene-based-therapeutic-approaches-3881. Accessed November 15, 2018.
  6. Evers MM, et al. Adv Drug Delivery Rev 2015;87:90–103.
  7. 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.
  8. Schueren F, Thoms S. PLoS Genet 2016;12(8):e1006196.
  9. Wang D, Gao G. Discov Med 2014;18(97):151–161.
  10. NIH. What is gene therapy? Available at: https://ghr.nlm.nih.gov/primer/therapy/genetherapy. Accessed January 29, 2019.