Treatment Strategies of
Monogenic Diseases

RNA-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 therapies1,23

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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 itself3,11,13,18,24

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

Antisense Oligonucleotides1-6

Advantages:

Quick manufacturing

Can be controlled, measured, and re-directed as necessary without harming healthy cells

Disadvantages:

Difficult to deliver using intravenous injection or pill delivery

Unexpected toxic effects (e.g. hepatotoxicity) due to regulation of both normal and mutant alleles (off-target effects)5

Complex

Examples of Potential Disease Targets:

Amyotrophic lateral sclerosis

Spinal muscular atrophy

Huntington’s disease

Hereditary transthyretin-mediated (hATTR) amyloidosis*

Nusinersen

Nusinersen is an antisense oligonucleotide indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. It acts to increase exon 7 inclusion in SMN2 mRNA transcripts and production of full-length survival motor neuron (SMN) protein7,8†

Exon Skipping10,11

Advantages:

It restores the correct reading frame, rather than replacing the entire gene.

The resulting (partially or fully) functional protein can significantly reduce disease severity

Disadvantages:

Current exon-skipping approaches are not effective for a larger population of patients with different mutations

(i.e. depending on the size and location of the mutation, different exons need to be skipped)

Examples of Potential Disease Targets:

Duchenne muscular dystrophy

Eteplirsen

Eteplirsen* injection is indicated in patients with Duchenne muscular dystrophy who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping12

Translational Read Through13-15

Advantages:

Can restore the synthesis of full-length proteins or give rise to new protein isoforms with biological functions distinct from that of the original protein

Disadvantages:

Still unclear (high toxicity observed in long-term use, and requirement of intramuscular and intravenous delivery has been described)

Examples of Potential Disease Targets:

Duchenne muscular dystrophy

Hereditary retinal dystrophies

Ataluren

Ataluren* is an investigational medicine intended to treat nonsense mutation dystrophinopathies in Duchenne muscular dystrophy16

RNA Interference18-21

Advantages:

Safe method with acceptable gene knockdown efficacy

Viral vector-based delivery of shRNA allows for increased control in delivery

Disadvantages:

Can impair the normal function of the gene due to indiscriminate reduction of both the toxic mutant and the normal counterpart protein

Off-target effects

Technological limitations

Examples of Potential Disease Targets:

Superoxide dismutase I in amyotrophic lateral sclerosis

Cancer

Transthyretin in hereditary transthyretin-mediated (hATTR) amyloidosis*

References

      1. Antisense therapy. Available at: https://antisensetherapyassignment.weebly.com/pros-and-cons-of-antisense-therapy.html. Accessed January 31, 2019.
      2. Huntington’s Outreach Project for Education. Available at: http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/antisense-gene-therapy/. Accessed January 31, 2019.
      3. Evers MM, et al. Adv Drug Deliv Rev 2015;87:90–103.
      4. Rinaldi C, Wood MJA. Nat Rev Neurol 2018;14(1):9–14.
      5. Hagedorn PH, et al. Nucleic Acids Res 2018;46(11):5366–5380.
      6. Drug Development. Tegsedi for the treatment of polyneuropathy. Available at: https://www.drugdevelopment-technology.com/projects/tegsedi-inotersen-for-the-treatment-of-hattr/. Accessed January 31, 2019.
      7. FDA. News Release. December 23, 2016. FDA approves first drug for spinal muscular atrophy. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm534611.htm. Accessed January 31, 2019.
      8. Spinraza® (nusinersen). Highlights of Prescribing Information. Cambridge, MA; Biogen; revised 10/2018. Available at: https://www.spinraza.com/PI. Accessed January 31, 2019.
      9. Shafeghati Y, et al. Arch Iranian Med 2004;47:52.
      10. Aartsma-Rus A, et al. Nucleic Acid Ther 2017;27(5):251–259.
      11. 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.
      12. FDA. News Release. September 19, 2016. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263. Accessed January 29, 2019.
      13. Schueren F, Thoms S. PLoS Genet 2016;12(8):e1006196.
      14. Schwarz N, et al. Hum Mol Genet 2015;24(4):972–986.
      15. Hofhuis J, et al. Open Biol 2016;6(11). pii: 160246.
      16. Managed Care. FDA Won’t Approve Ataluren; PTC Therapeutics to Appeal. October 26, 2017. Available at: https://www.managedcaremag.com/news/fda-won-t-approve-ataluren-ptc-therapeutics-appeal. Accessed January 28, 2019.
      17. Siddiqui N, Sonenberg N. Proc Natl Acad Sci U S A 2016;113(44):12353–12355.
      18. Wang D, Gao G. Discov Med 2014;18(97):151–161.
      19. RNA Therapeutic Institute. How RNAi works. Available at: https://www.umassmed.edu/rti/biology/how-rnai-works/. Accessed January 29, 2019.
      20. O’Keefe EP. Mater Methods 2013;3:197. Available at: https://www.labome.com/method/siRNAs-and-shRNAs-Tools-for-Protein-Knockdown-by-Gene-Silencing.html. Accessed January 29, 2019.
      21. FDA. News Release. August 10, 2018. FDA approved first-of-its kind targeted RNA-based therapy to treat a rare disease. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM616518.htm?utm_campaign=08102018_PR_FDA%20approves%20new%20drug%20for%20rare%20disease%2C%20hATTR&utm_medium=
email&utm_source=Eloqua.
      22. NCBI. RNA Interference (RNAi). Available at: https://www.ncbi.nlm.nih.gov/probe/docs/techrnai/. Accessed January 29, 2019.
      23. Nature Education. Gene-Based Therapeutic Approaches. Available at: https://www.nature.com/scitable/topicpage/gene-based-therapeutic-approaches-3881. Accessed November 15, 2018.
      24. NIH. What is gene therapy. Available at: https://ghr.nlm.nih.gov/primer/therapy/genetherapy. Accessed January 29, 2019.