Overcoming Challenges in 
Gene Therapy Development

While several gene therapy treatments have received regulatory approval and many more are in late-stage development, challenges remain that need to be addressed before gene therapy can achieve its full potential. This section will review primary challenges to successful gene therapy and some of the strategies developed to overcome them.

COMPLEX-DISEASES

Gene Delivery

Limited tissue specificity

Challenge:

Ideally, therapies would selectively target a particular type of cell or tissue with minimal unwanted deleterious off-target expression1,2

 

Advances:

  • Use of tissue-specific promoters (eg, 
in AAV vectors) that naturally drive the expression of a particular gene in the tissue(s) of interest3,2,4
  • Use of microRNA-mediated suppression of transgene expression. MicroRNAs regulate gene transcription by binding to target sequences on the 3’ untranslated region (UTR) of mRNA. Placing microRNA target sites into the 3’UTR of the transgene expression cassette can prevent off-target transgene expression1,5

Examples

Hemophilia B

Sustained therapeutic expression of factor IX has been achieved in men with hemophilia B (n=10) infused with an AAV vector engineered with a liver-specific promoter and factor IX transgene6

Suppress Heptotoxicity

MicroRNA-mediated suppression has been used to suppress hepatotoxicity driven by adenovirus E4 expression7

Retinal Dystrophy

(voretigene neparvovec-rzyl)*

LUXTURNA™ (voretigene neparvovec-rzyl)* uses the AAV2 vector to carry a functional copy of the RPE65 gene into the retinal pigment epithelial (RPE) cells to compensate for the biallelic RPE65 mutation-associated retinal dystrophy. 8

*LUXTURNA™, by Spark Therapeutics, received approval by the U.S. Food and Drug Administration on December 19, 2017 for the treatment of patients with biallelic RPE65 mutation-associated retinal dystrophy.9
AAV, adeno-associated virus.

Transgene Persistence or Durability

Loss of transgene expression and vector retention

Challenge:

Persistence of transgene expression is particularly important for long-term treatments1,10

ADVANCES:

  • Lifelong expression can be achieved by vector re-administration or increased vector doses3,11
  • Episomal vectors can potentially persist for life if delivered into relatively quiescent tissues and/or cells (e.g. liver, brain, heart, motor neurons, or muscle)1,12
  • Vector persistence can be significantly improved by the introduction of DNA homology sequences into the transgene, which promotes a higher frequency of vector integration into the host genome11,13
  • Minicircle DNAs provide more persistent expression than routinely used plasmids, for reasons still not completely understood1
  • Episomal vectors are engineered to enhance their extrachromosomal transgene retention14

Examples

Chimeric Antigen Receptor (CAR) T-cell–based Approaches

Chimeric antigen receptor (CAR) T-cell–based approaches, such as KYMRIAH® (tisagenlecleucel)*, benefit from signaling T cells to grow and divide while killing tumor cells15,16. The CAR of KYMRIAH® contains a 
4-1BB costimulatory domain that is responsible for expansion and persistence of KYMRIAH®17

Minicircle DNA

Enhanced and prolonged transgene expression of minicircle DNA in lungs of mice has been successfully demonstrated using a non-viral delivery formulation10

Maintaining physiologic levels of gene expression

CHALLENGE:

Transgene expression should be at physiologic levels to enable therapeutic outcomes without toxic effects18,19

ADVANCES:

  • Systems have been developed that allow the control of the expression of the gene at physiologic levels
    Exogenously regulated systems rely on an external factor (e.g. administration of a drug) to turn the gene on and off18
  • Endogenously controlled gene regulation systems rely on physiologic stimuli to control transgene expression – physiologically responsive gene expression/regulatory elements incorporate negative feedback loops where the recombinant protein shuts off its own production in response to the presence or absence of a physiologic signal18,19

Examples

AAV Vectors Using the Tetracycline-Off System

AAV vectors coupled with the tetracycline-off system (using tetracycline to deactivate the expression) have been used as a exogenously controlled gene regulation system for in vivo CNS applications18

Hypoxia-Regulated Glial Cell-Specific AAV Vectors

Hypoxia-regulated glial cell-specific AAV vectors exploit hypoxia as a physiologic trigger for gene expression as an anti-angiogenic strategy directed at arresting neovascularization in the eye20

Single Administration of AAV

Single administration of AAV vectors of serotype 1 (AAV1) encoding the insulin (Ins) and glucokinase (Gck) genes has been shown to enhance glucose uptake without causing hypoglycemia in diabetic dogs after a follow-up period of 8 years21

Minimization of Immune Responses

Avoiding host immune response1,22

CHALLENGE:

Therapies need to be developed with strategies to avoid triggering host immune responses, as the immune responses can limit the viability of the transduced cells, limit expression of the transgene product, and/or cause local and/or systemic toxicity

ADVANCES:

  • Hide vector from immune system23
  • Use of lowest effective doses24
  • Modifications of the viral vector capsid (eg, altering the capsid to remove identified epitopes, use of empty capsid)24,25,26
  • Delivery of the engineered viruses to cells outside of the patient’s body3,24
  • Direct delivery to the target site (eg, injection into the liver, brain, eye)23
  • Hide immune system from vector23
  • By immune suppression (eg, transient immune suppression of signaling required for lymphocyte activation or inactivation of antibodies); or
  • By modulating the immune response away from immunity and toward tolerance (eg, direct expression away from antigen-presenting cells)

Examples

Hemophilia B

Results from a trial in patients with hemophilia B suggest that lower vector doses may not trigger T-cell responses to the capsid. Hemophilia B patients receiving up to 6×1011 vg/kg liver-directed AAV8 did not experience an increase in liver enzymes or loss of transgene expression; at the same time, levels of factor IX transgene were just above the threshold for therapeutic efficacy25

Duchenne Muscular Dystrophy

Use of a combination of immunosuppressants in a canine model of Duchenne muscular dystrophy demonstrated long-term expression of the therapeutic transgene, showing the utility of immune suppression in highly inflamed tissues where immune responses are expected to be more robust than in normal tissues23

Persistent neutralizing antibodies

CHALLENGE:

Humoral, anti-AAV antibody-mediated immunity is a major challenge to AAV gene therapy. It can result from childhood exposure to one or more serotypes or 
from prior administration of AAV vectors27

ADVANCES:

  • The capsid of AAV vectors can be engineered to evade anti-AAV neutralizing antibodies, which results in widespread transgene transduction of the entire brain and spinal cord via direct injection into the cerebrospinal fluid28,29

Examples

Transduction via the Cerebrospinal Fluid

Broad transduction of AAV9 and AAV2.5 into the brain and spinal cord parenchyma via cerebrospinal fluid has been achieved in non-human primates without increasing vector doses (~2×1012 vg per 3–6 kg animal)30

Safety Concerns

Insertional mutagenesis can occur 
by disruption of nearby genes1

Challenge:

(e.g. cancer genes – cases have been described of children developing leukemia after treatment with retrovirus-based gene therapies aimed at treating severe combined immunodeficiency)31

ADVANCES:

  • Development of ways to introduce genes to specific “safe” places in the genome31
  • For ex vivo applications, the gene integration site can be assessed for safety issues before the cells are introduced back into the host patient31
  • Use of non-integrating viral vectors in which the genetic material persists in the cell nucleus predominantly as extrachromosomal episomes (eg, AAV)32
  • HIV type 1 (HIV-1)-based lentiviral vectors are very effective vectors that have evolved to infect and express their genes in human helper T cells and other macrophages – strategies in pre-integration steps minimize and possibly prevent insertional mutagenesis33,34

Examples

CAR-T Therapy: Yescarta®

YESCARTA®* (axicabtagene ciloleucel), use integrated viral vectors (typically retroviral or lentiviral) to introduce the therapeutic gene ex vivo into an autologous stem cell35,36

Episome Strategy: Luxturna®

AAV-based treatments such as LUXTURNA™ † (voretigene neparvovec-rzyl) use an episome strategy where the virus enters the nucleus without integrating into the DNA37. AAV2 is used in the direct delivery of LUXTURNA™ into retinal pigment epithelial cells, resulting in a non-pathogenic and low inflammatory response8

Practicalities of Gene Therapy

Manufacturing

Challenge:

Generating vector quantities sufficient to meet clinical demand while meeting regulatory requirements is challenging with current production systems, and technologies are needed for large-scale production of gene therapy products38,39

ADVANCES:

  • Microfluidization, a process where harvested cells are mechanically disrupted with a very high efficiency, has been used successfully to collect viruses for large-scale manufacturing of AAV40
  • For production of AAV-based therapies, transfection of plasmid DNA into eukaryotic cells has been limited by the lack of scalability of transfecting adherent cells. Utilizing a cell suspension format would enable rapid and scalable production39

Examples

Luxturna®

LUXTURNA™ * (voretigene neparvovec-rzyl), the first approved in vivo gene therapy product in the United States, is manufactured in the first licensed manufacturing facility in the U.S. for a gene therapy treating an inherited disease41

Large Scale Manufacturing

Several companies have built or are developing large-scale gene therapy manufacturing facilities for the production of gene therapy product candidates42,43,44,45

Dedicated Facilities

Dedicated gene therapy manufacturing facilities have been opened in anticipation of increasing demand from developers of cell and gene therapies, to help manufacture these treatments more quickly and efficiently46,47,48

Small target population

Challenge:

The small patient populations make recruitment and the approval process more challenging38,49,50

advances:

  • Regulators are working on the implementation of new policies to advance the development of safe and effective new gene therapies and accelerated approval pathways50,51
  • Advocacy groups are supporting companies in their efforts for rapid approval by regulatory bodies due to severity of the conditions52

Examples

Increasing Number of Clinical Trials

Worldwide increase in the number of gene therapy clinical trials (go to Chapter 3 for more details)53

Luxturna®

LUXTURNA™ * (voretigene neparvovec-rzyl) received approval by the U.S. Food and Drug Administration in 2017 based on the efficacy and safety established in a clinical development program with 41 patients (31 in a Phase 3 study)54

  1. Kay MA. Nat Rev Genet 2011;12(5):316–328.
  2. Hanna E, et al. J Mark Access Health Policy 2017;5(1):1265293.
  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 February 13, 2019. Accessed February 13, 2019.
  4. Pacak CA, et al. Genet Vaccines Ther 2008;6:13.
  5. Gray SJ, et al. Hum Gene Ther 2011;22(9):1143–1153.
  6. Geisler A, Fechner H. World J Exp Med 2016;6(2):37–54.
  7. George LA, et al. N Engl J Med 2017;377(23):2215–2227.
  8.  LUXTURNA™ (voretigene neparvovec-rzyl). Mechanism of action. Available at: https://luxturnahcp.com/how-LUXTURNA-works/mechanism-of-action/. Accessed February 13, 2019.
  9. Shimizu K. Yakugaku Zasshi 2015;135(12):1349–1356.
  10. LUXTURNA™. News release December 21, 2017. FDA approves Spark Therapeutics’ retinal disease gene therapy Luxturna, a month ahead of schedule. Available at: https://biopharmconsortium.com/2017/12/21/fda-approves-spark-therapeutics-retinal-disease-gene-therapy-luxturna-a-month-ahead-of-schedule/. Accessed February 13, 2019.
  11. Munye MM, et al. Sci Rep 2016;6:23125.
  12. Colella P, et al. Mol Ther Methods Clin Dev 2018;8:87–104.
  13. Ahmed SG, et al. J Control Release 2018;273:99–107.
  14. Wang Z, et al. Mol Ther 2012;20(10):1902–1911.
  15. Lufino MMP, et al. Mol Ther 2008;16(9):1525–1538.
  16. Wang Z, et al. Protein Cell 2017;8(12):896–925.
  17. ScienceDaily. January 31, 2018. T cell therapy shows persistent benefits in young leukemia patients. Available at: https://www.sciencedaily.com/releases/2018/01/180131230101.htm. Accessed February 13, 2019.
  18. KYMRIAH®. Mechanism of action. Available at: https://www.hcp.novartis.com/products/kymriah/acute-lymphoblastic-leukemia-children/mechanism-of-action/. Accessed February 13, 2019.
  19. Naidoo J, Young D. Neurol Res Int 2012;2012:595410.
  20. Hibbitt O, Wade-Martins R. Physiologically-Regulated Expression Vectors for Gene Therapy. In: Targets in Gene Therapy. Available at: https://www.intechopen.com/books/targets-in-gene-therapy/physiologically-regulated-expression-vectors-for-gene-therapy. Accessed February13, 2019.
  21. Biswal MR, et al. Invest Ophthalmol Vis Sci 2014;55(12):8044–8053.
  22. Jaén ML, et al. Mol Ther Methods Clin Dev 2017;6:1–7.
  23. Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
  24. Mingozzi F, et al. Blood 2007;110(7):2334–2341.
  25. Basner-Tschakarjan E, Mingozzi F. Front Immunol 2014;5:350.
  26. Mingozzi F, High KA. Blood 2013;122(1):23–36.
  27. Kotterman MA, et al. Gene Ther 2015;22(2):116–126.
  28. Gray SJ, et al. Gene Ther 2013;20(4):450–459.
  29. Lykken EA, et al. J Neurodev Disord 2018;10:16.
  30. Learn.Genetics. Challenges in Gene Therapy. Available at: https://learn.genetics.utah.edu/content/genetherapy/challenges. Accessed February 13, 2019.
  31. Naso MF, et al. BioDrugs 2017;31(4):317–334.
  32. Norton TD, Miller EA. Front Immunol 2016;7:243.
  33. Romano G. ISRN Oncol 2012;2012:616310.
  34. FDA. News release October 18, 2017. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. Available at: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm581216.htm. Accessed February 13, 2019.
  35. Jin C, et al. EMBO Mol Med 2016;8(7):702–711.
  36. Ameri H. J Curr Ophthalmol 2018;30(1):1–2.
  37. LUXTURNA™ (voretigene neparvovec-rzyl). Mechanism of action. Available at: https://luxturnahcp.com/how-LUXTURNA-works/mechanism-of-action/. Accessed February 13, 2019.
  38. BioProcess Online. Overcoming The Manufacturing Hurdles Of Cell & Gene Therapy. Available at: https://www.bioprocessonline.com/doc/overcoming-the-manufacturing-hurdles-of-cell-gene-therapy-0001. Accessed February 13, 2019.
  39. Clément N, Grieger JC. Mol Ther Methods Clin Dev 2016;3:16002.
  40. Van der Loo JCM, Wright JF. Hum Mol Gen 2016;25(R1):R42–R52.
  41. Spark Therapeutics. Press Release. FDA Approves Spark Therapeutics’
  42. LUXTURNA™ (voretigene neparvovec-rzyl), a One-time Gene Therapy for Patients with Confirmed Biallelic RPE65 Mutation-associated Retinal Dystrophy. Available at: http://ir.sparktx.com/news-releases/news-release-details/fda-approves-spark-therapeutics-luxturnatm-voretigene-neparvovec. Accessed February 13, 2019.
  43. FiercePharma. Novartis’ brand-new gene therapy player AveXis will build $55M plant, hire 200. Available at: https://www.fiercepharma.com/manufacturing/novartis-brand-new-gene-therapy-player-avexis-will-build-55m-plant-hire-200. Accessed February 13, 2019.
  44. Orchard Therapeutics. Orchard Therapeutics Announces the Build-out of New Gene Therapy Manufacturing Facility in California. Available at: https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-build-out-new-gene-therapy. Accessed February 13, 2019.
  45. BioMarin. BioMarin's Gene Therapy Manufacturing Facility Recognized with Industry Award. Available at: https://investors.biomarin.com/2018-03-21-BioMarins-Gene-Therapy-Manufacturing-Facility-Recognized-with-Industry-Award. Accessed February 13, 2019.
  46. Phacilitate. Cell and Gene Therapy Manufacturing Capacity North America 2018. Available at: https://www.phacilitate.co.uk/sites/default/files/clarion_phacilitate/pdfs/cell_and_gene_therapy_manufacturing_capacity_north_america_2018.pdf. Accessed February 13, 2019.
  47. CCRM. Overview. Available at: https://www.ccrm.ca/cdmo-overview. Accessed February 13, 2019.
  48. Lonza. Lonza Opens World’s Largest Dedicated Cell-and-Gene-Therapy Manufacturing Facility in Pearland, Greater Houston, TX (USA). Available at: https://www.lonza.com/about-lonza/media-center/news/Tensid/2018-04-10-12-00-English.aspx. Accessed February 13, 2019.
  49. O’Reilly M, et al. Hum Gene Ther 2013;24(4):355–362
  50. FDA. Press announcement. July 11, 2018. Statement from FDA Commissioner Scott Gottlieb, M.D. on agency’s efforts to advance development of gene therapies. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613026.htm. Accessed February 13, 2019.
  51. FDA. Press announcement. January 15, 2019. Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm629493.htm. Accessed February 13, 2019.
  52. SMA News Today. October 18, 2018. AveXis asking FDA, EU to approve AVXS-101 as 1st gene therapy for SMA type 1. Available at: https://smanewstoday.com/2018/10/18/avexis-asks-fda-eu-to-approve-avxs-101-as-first-gene-therapy-for-sma-type-1. Accessed February 13, 2019.

 

  1. Kay MA. Nat Rev Genet 2011;12(5):316–328.
  2. Pacak CA, et al. Genet Vaccines Ther 2008;6:13.
  3. Kay MA. Nat Rev Genet 2011;12(5):316–328.
  4. Gray SJ, et al. Hum Gene Ther 2011;22(9):1143–1153.
  5. Geisler A, Fechner H. World J Exp Med 2016;6(2):37–54.
  6. George LA, et al. N Engl J Med 2017;377(23):2215–2227.
  7. Shimizu K. Yakugaku Zasshi 2015;135(12):1349–1356.
  8. LUXTURNA™ (voretigene neparvovec-rzyl). Mechanism of action. Available at: https://luxturnahcp.com/how-LUXTURNA-works/mechanism-of-action/. Accessed February 13, 2019.
  9. LUXTURNA™. News release December 21, 2017. FDA approves Spark Therapeutics’ retinal disease gene therapy Luxturna, a month ahead of schedule. Available here. Accessed February 13, 2019.
  10. Munye MM, et al. Sci Rep 2016;6:23125.
  11. Colella P, et al. Mol Ther Methods Clin Dev 2018;8:87–104.
  12. Ahmed SG, et al. J Control Release 2018;273:99–107.
  13. Wang Z, et al. Mol Ther 2012;20(10):1902–1911.
  14. Lufino MMP, et al. Mol Ther 2008;16(9):1525–1538.
  15. Wang Z, et al. Protein Cell 2017;8(12):896–925.
  16. ScienceDaily. January 31, 2018. T cell therapy shows persistent benefits in young leukemia patients. Available at: https://www.sciencedaily.com/releases/2018/01/180131230101.htm. Accessed February 13, 2019.
  17. KYMRIAH®. Mechanism of action. Available at: https://www.hcp.novartis.com/products/kymriah/acute-lymphoblastic-leukemia-children/mechanism-of-action/. Accessed February 13, 2019.
  18. Naidoo J, Young D. Neurol Res Int 2012;2012:595410.
  19. Hibbitt O, Wade-Martins R. Physiologically-Regulated Expression Vectors for Gene Therapy. In: Targets in Gene Therapy. Available at: https://www.intechopen.com/books/targets-in-gene-therapy/physiologically-regulated-expression-vectors-for-gene-therapy. Accessed February13, 2019.
  20. Biswal MR, et al. Invest Ophthalmol Vis Sci 2014;55(12):8044–8053.
  21. Jaén ML, et al. Mol Ther Methods Clin Dev 2017;6:1–7.
  22. Basner-Tschakarjan E, Mingozzi F. Front Immunol 2014;5:350.
  23. Sack BK, Herzog RW. Curr Opin Mol Ther 2009;11(5):493–503.
  24. Mingozzi F, et al. Blood 2007;110(7):2334–2341.
  25. Basner-Tschakarjan E, Mingozzi F. Front Immunol 2014;5:350.
  26. Mingozzi F, High KA. Blood 2013;122(1):23–36.
  27. Kotterman MA, et al. Gene Ther 2015;22(2):116–126.
  28. Gray SJ, et al. Gene Ther 2013;20(4):450–459.
  29. Lykken EA, et al. J Neurodev Disord 2018;10:16.
  30. Gray SJ, et al. Gene Ther 2013;20(4):450–459.
  31. Learn.Genetics. Challenges in Gene Therapy. Available at: https://learn.genetics.utah.edu/content/genetherapy/challenges. Accessed February 13, 2019.
  32. Naso MF, et al. BioDrugs 2017;31(4):317–334.
  33. Norton TD, Miller EA. Front Immunol 2016;7:243.
  34. Romano G. ISRN Oncol 2012;2012:616310.
  35. FDA. News release October 18, 2017. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. Available at: https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm581216.htm. Accessed February 13, 2019.
  36. Jin C, et al. EMBO Mol Med 2016;8(7):702–711.
  37. Ameri H. J Curr Ophthalmol 2018;30(1):1–2.
  38. BioProcess Online. Overcoming The Manufacturing Hurdles Of Cell & Gene Therapy. Available at: https://www.bioprocessonline.com/doc/overcoming-the-manufacturing-hurdles-of-cell-gene-therapy-0001. Accessed February 13, 2019.
  39. Clément N, Grieger JC. Mol Ther Methods Clin Dev 2016;3:16002.
  40. Van der Loo JCM, Wright JF. Hum Mol Gen 2016;25(R1):R42–R52.
  41. Spark Therapeutics. Press Release. FDA Approves Spark Therapeutics’ LUXTURNA™ (voretigene neparvovec-rzyl), a One-time Gene Therapy for Patients with Confirmed Biallelic RPE65 Mutation-associated Retinal Dystrophy. Available at: http://ir.sparktx.com/news-releases/news-release-details/fda-approves-spark-therapeutics-luxturnatm-voretigene-neparvovec. Accessed February 13, 2019.
  42. FiercePharma. Novartis’ brand-new gene therapy player AveXis will build $55M plant, hire 200. Available at: https://www.fiercepharma.com/manufacturing/novartis-brand-new-gene-therapy-player-avexis-will-build-55m-plant-hire-200. Accessed February 13, 2019.
  43. Orchard Therapeutics. Orchard Therapeutics Announces the Build-out of New Gene Therapy Manufacturing Facility in California. Available at: https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-build-out-new-gene-therapy. Accessed February 13, 2019.
  44. BioMarin. BioMarin's Gene Therapy Manufacturing Facility Recognized with Industry Award. Available at: https://investors.biomarin.com/2018-03-21-BioMarins-Gene-Therapy-Manufacturing-Facility-Recognized-with-Industry-Award. Accessed February 13, 2019.
  45. Phacilitate. Cell and Gene Therapy Manufacturing Capacity North America 2018. Available at: https://www.phacilitate.co.uk/sites/default/files/clarion_phacilitate/pdfs/cell_and_gene_therapy_manufacturing_capacity_north_america_2018.pdf. Accessed February 13, 2019.
  46. Phacilitate. Cell and Gene Therapy Manufacturing Capacity North America 2018. Available at: https://www.phacilitate.co.uk/sites/default/files/clarion_phacilitate/pdfs/cell_and_gene_therapy_manufacturing_capacity_north_america_2018.pdf. Accessed February 13, 2019
  47. CCRM. Overview. Available at: https://www.ccrm.ca/cdmo-overview. Accessed February 13, 2019.
  48. Lonza. Lonza Opens World’s Largest Dedicated Cell-and-Gene-Therapy Manufacturing Facility in Pearland, Greater Houston, TX (USA). Available at: https://www.lonza.com/about-lonza/media-center/news/Tensid/2018-04-10-12-00-English.aspx. Accessed February 13, 2019.
  49. O’Reilly M, et al. Hum Gene Ther 2013;24(4):355–362.
  50. FDA. Press announcement. July 11, 2018. Statement from FDA Commissioner Scott Gottlieb, M.D. on agency’s efforts to advance development of gene therapies. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613026.htm. Accessed February 13, 2019.
  51. FDA. Press announcement. January 15, 2019. Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm629493.htm. Accessed February 13, 2019.
  52. SMA News Today. October 18, 2018. AveXis asking FDA, EU to approve AVXS-101 as 1st gene therapy for SMA type 1. Available at: https://smanewstoday.com/2018/10/18/avexis-asks-fda-eu-to-approve-avxs-101-as-first-gene-therapy-for-sma-type-1. Accessed February 13, 2019.
  53. Hanna E, et al. J Mark Access Health Policy 2017;5(1):1265293.
  54. 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 February 13, 2019. Accessed February 13, 2019.