Gene Therapy: An Emerging Approach
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This document discusses gene therapy, including its history, mechanisms, approaches, challenges, and future directions. Some key points: - As of March 2019, there were over 3,800 gene therapy clinical trials registered on ClinicalTrials.gov. - Gene therapy introduces genetic material into a person's cells to treat or prevent disease, often using modified viruses as vectors to deliver the gene. - Approaches include gene replacement/addition therapy, gene editing, and epigenetics. Vectors commonly used are retroviruses, lentiviruses, and adeno-associated viruses (AAVs). - Challenges include pre-existing immunity to viral vectors, potential immune responses against transduced cells, and safety issues like
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Gene Therapy: An Emerging Approach
- 1. 1. ClinicalTrials.gov. Search of gene therapy. https://clinicaltrials.gov/ct2/results?cond=&term=gene+therapy&cntry=&state=&city=&dist= (Accessed April 2019). 2. Beitelshees M, et al. Discov Med 2017;24(134):313–22. •As of March 2019, there were 3831 “Gene Therapy” trials registered on ClinicalTrials.gov1 1
- 2. 2 Property of Pfizer Inc., Not for distribution ■ What Is Gene Therapy and How Does It Work? ■ Gene therapy is an experimental treatment that involves introducing genetic material into a person’s cells to fight or prevent disease. ■ A gene can be delivered to a cell using a carrier known as a “vector.” The most common types of vectors used in gene therapy are viruses. The viruses used in gene therapy are altered to make them safe, although some risks still exist with gene therapy. ■ The technology is still in its infancy, but it has been used with some success. Mark Lundie, Ph.D; Medical Director, Rare Diseases, Pfizer Canada ■ 1972 : Friedmann and Roblin publish "Gene therapy for human genetic disease?" in Science ■ 1990 :First patient to be treated with gene therapy – 4 yr old girl with adenosine deaminase (ADA) deficiency ■ 1999 : Following Jesse Gelsinger’s death the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices. ■ 2012 : Glybera became the first treatment to be approved for clinical use in Europe ■ 2017: Kymriah approved in US for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia. ■ 2017 : Luxterna (Spark therapeutics) approved for retinal dystrophy due to a mutation of the RPE65 gene
- 3. 3 Property of Pfizer Inc., Not for distribution Genetic medicine Genetic Medicine Represents a Third Wave of Innovation Second wave ~1980s First Wave ~1900s Third wave Now Small molecule Biologics Symptomatic/ Risk Reduction Disease Modifying Potentially Transformational etanercept Dyslipidaemia medication rituximab aspirin nonacog alfa adalimumab Anti-hypertensive medication
- 4. Add a functioning gene Permanently remove, modify, or add a gene Modify gene expression *Figure from National Institutes of Health: https://commonfund.nih.gov/epigenomics/figure 1. Kumar SR, et al. Mol Ther Methods Clin Dev 2016;3:16034. 2. Cox DBT, et al. Nat Med 2015;21(2):121–31. 3. Lomberk GA, et al. Epigenomics 2016;8:831–42. 4. Epigenetic Therapy as Cancer Treatment. https://www.slideshare.net/janelle_leggere/efficacy-of-epigenetic-therapy-as-cancer-treatment?from_action=save (Accessed April 2019). Genetic Medicine: Approaches Genomic DNA PAM crDNA 5´ 5´ 3´ 3´ tracrRNA Cas9 Nuclease DNA inaccessible, gene inactive Gene Replacement / Addition Therapy Gene Editing2 Epigenetics3,4* 4
- 5. Adapted from: Kumar SR, et al. 2016 Kumar SR, et al. Mol Ther Methods Clin Dev 2016;3:16034. Gene Replacement / Addition Therapy Vector Therapeutic gene In vivo Ex vivo Capsid 5
- 6. 6 Property of Pfizer Inc., Not for distribution AAV Vector Background • Single-stranded genome containing gene of interest (GOI), transcriptional regulatory elements (enhancer and promoter) and AAV-ITR (AAV-inverted terminal repeats) • Size limit about 4.8-5.0 kB • Extrachromosomal GOIEnh/Pro • Genome is encapsulated in a shell consisting of a viral capsid (cap) protein • Different capsid serotypes can direct virus to specific tissues (e.g. AAV9 for muscle) Intron PolyA AAV Vector Consists of Two Components
- 7. Thomas CE, et al. Nat Rev Genet 2003;4:346–58. Delivery: Vectors The success of gene therapy critically depends on effective vehicles for gene transfer, which are based on viral platforms (but are not viruses) RETROVIRUS LENTIVIRUSAdeno-associated virus (AAV) 7 Retrovirus Lentivirus AAV Genetic material ssRNA ssRNA ssDNA Tropism Dividing cells only Dividing and nondividing cells Dividing and nondividing cells Vector genome forms Integrated Integrated Nonintegrated (Primarily episomal) Carrying capacity 8 kb 8 kb <5 kb
- 8. Figure adapted from Mingozzi F, High KA. (2013).5 1. Ohmori T, et al. J Thromb Haemost 2015;13(Suppl 1):S133–S142. 2. Rapti K, et al. Mol Ther 2012;20:73–83. 3. Nathwani AC, et al. N Engl J Med 2014;137(21):1994–2004. 4. George LA. Blood Adv 2017;1(26):2591– 2599. 5. Mingozzi F, High KA. Blood 2013;122:23–36. Immunologic Challenges in Gene Therapy • Pre-formed neutralizing antibodies to vector capsid1 • Humoral immunity may prevent retreatment2,3 Humoral Immunity Cellular Immunity • Pieces of capsid displayed on transduced cells4 • T cells respond to vector capsid1,4 • T cells attack / kill transduced cells4 • Loss of cells expressing the donated gene and producing clotting factor3,4 Vector T cell
- 9. 1. George LA, et al. N Eng J Med 2017;377:2215–2227. 2. Nathwani AC, et al. N Engl J Med 2014;371(21):1994–2004. 3. Kattenhorn LM, et al. Hum Gene Ther 2016;27(12):947-961. 4. Baruteau J, et al. J Inherit Metab Dis 2017;40(4):497–517. 5. Grieger JC, et al. Mol Ther 2016;24(2):287–297. Future considerations • Durable efficacy and long-term safety • Minimizing Immune response • Optimizing viral vectors • Multigene disorders. • Germ line vs somatic cell line gene therapy • Insertional mutagenesis. 9
- 10. 1. George LA, et al. N Eng J Med 2017;377:2215–2227. 2. Nathwani AC, et al. N Engl J Med 2014;371(21):1994–2004. 3. Kattenhorn LM, et al. Hum Gene Ther 2016;27(12):947-961. 4. Baruteau J, et al. J Inherit Metab Dis 2017;40(4):497–517. 5. Grieger JC, et al. Mol Ther 2016;24(2):287–297. Other considerations • Capsid and DNA engineering • Viral tropism for selection of target organ • DNA optimization (highly expressing gene variants, optimized codons, strong promotors) • Reduce immunogenicity; allow for broader treatable populations, possibly allow repeat infusions • Manufacturing • Scalability from experimental studies to clinical supply 10
- 11. 11 Property of Pfizer Inc., Not for distribution Dosing and Immunological response One ‘Quadrillion’ (1000 Trillion) 100 Trillion One Trillion One Hundred Billion
- 12. For Proactive Use Pfizer Inc / MRC approved 06/23/2017 Importance of Transforming AAV Production Capabilities Enable Broader Gene Therapy Application 12 AAV=adeno-associated virus; vg=vector genome. ~1 x 1012 vg/roller bottle 40,000x Roller Bottles ~4x iCELLis 500 Attached Cell Reactor ~1x 250 L Cell Suspension Bioreactor From: Lab-Scale Culturing To: Contemporary, Scalable Processes ~1 x 1016 vg/iCELLis 500 cell reactor ~4 x 1016 vg/250 L cell suspension bioreactor
- 13. 13 Property of Pfizer Inc., Not for distribution Potential to Transform Therapy for Monogenic Rare Diseases Liver Hemophilia B, Hemophilia A Muscle Duchenne Muscular Dystrophy CNS and LSDs GAN, ALS, MPS’s Disorder associated with lifelong need for 1x to 3x weekly infusions Incurable disorder with shortened life expectancy Progressive, degenerative disorders leading to incapacitation and, potentially, early death Gene therapy offers the potential to provide one-time, transformational treatment