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


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


Quick manufacturing

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


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


Examples of Potential Disease Targets:

Amyotrophic lateral sclerosis

Spinal muscular atrophy

Huntington’s disease

Hereditary transthyretin-mediated (hATTR) amyloidosis*


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


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

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


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* 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


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


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

RNA Interference18-21


Safe method with acceptable gene knockdown efficacy

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


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


Transthyretin in hereditary transthyretin-mediated (hATTR) amyloidosis*


      1. Antisense therapy. Available at: Accessed January 31, 2019.
      2. Huntington’s Outreach Project for Education. Available at: 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: Accessed January 31, 2019.
      7. FDA. News Release. December 23, 2016. FDA approves first drug for spinal muscular atrophy. Available at: Accessed January 31, 2019.
      8. Spinraza® (nusinersen). Highlights of Prescribing Information. Cambridge, MA; Biogen; revised 10/2018. Available at: 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:
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: 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: 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: Accessed January 29, 2019.
      20. O’Keefe EP. Mater Methods 2013;3:197. Available at: 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:
      22. NCBI. RNA Interference (RNAi). Available at: Accessed January 29, 2019.
      23. Nature Education. Gene-Based Therapeutic Approaches. Available at: Accessed November 15, 2018.
      24. NIH. What is gene therapy. Available at: Accessed January 29, 2019.