Gene and Cell Therapy: Success Stories and Future Challenges

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The gene and cell therapy community has come a long way since the founding of Molecular Therapy by the American Society of Gene & Cell Therapy (ASGCT) 20 years ago. The field has transitioned from basic science to clinical applications and has witnessed the approval of several gene and cell therapy products in the US, Europe, and elsewhere in the world. The very first approved products were Gendicine (2003) and Oncorine (2005) in China. With the first approvals in the West, gene therapy has become a clinical reality and, even though the first approved gene medicine in Europe (Glybera, 2012) has since been withdrawn from the market apparently for commercial reasons, other recent approvals have been successful. Imlygic oncolytic immunotherapy for advanced melanoma; Strimvelis autologous-transduced CD34+ cells for ADA-SCID; Kymriah CD19-directed chimeric antigen receptor (CAR)-T cells for refractory or relapsed B cell acute lymphoblastic leukemia; Yescarta CD19-directed CAR-T cells for refractory or relapsed large B cell lymphoma; and Luxturna for progressive vision loss due to RPE65 mutations have all made it to the clinic with very good results. There is no doubt that these success stories have greatly encouraged further development of gene and cell therapy products in both academia and industry.

The International Society for Cell and Gene Therapy annual review of approved gene and cell therapy products worldwide recently listed a total of 44 unique products, 37 of which were cell or tissue therapies.¹ One third of these products were intended for use in oncological or hematological diseases. Among the less-advertised products are several interesting autologous, allogenic, umbilical cord blood cell, and mesenchymal stem cell-derived treatments for various indications that span oncology and hematology to eye diseases and include both regenerative and vaccination approaches. In addition to these 44 approved products, there are many unproven or insufficiently proven cellular therapies that are commercially available in some parts of the world.

Oligonucleotide-based therapies have been under clinical development for more than two decades. This group comprises products such as antisense oligonucleotides, aptamers, and small interfering RNAs (siRNAs). So far, six such drugs have been approved for clinical use.² These include Vitravene antisense oligonucleotide for cytomegalovirus retinitis; Macugen aptamer against vascular endothelial growth factor (VEGF) for age-related macular degeneration; Kynamro (also known as Mipomersen) antisense oligonucleotide against apolipoprotein B for homozygous familial hypercholesterolemia; Exondys 51 (also known as Eteplirsen) exon-skipping oligonucleotide for Duchenne muscular dystrophy; Defitelio oligonucleotide for severe hepatic veno-occlusive disease; and Spinraza (also known as Nusinersen) antisense oligonucleotide that targets and blocks an internal splice site for Spinal muscular atrophy.

In the future, we can expect several new gene and cell therapies to enter clinical testing that target a broad array of conditions, including various types of cancer, inborn errors of metabolism, neurological and eye diseases, and ischemic conditions. So far, no gene-editing products have moved to advanced clinical testing, although a few phase I trials are ongoing, including zinc-finger nucleases targeted to CCR5 gene to combat HIV infection and programmed death-1 (PD-1) knockout T cells generated using CRISPR/Cas9 technology for esophageal cancer. Currently, the adeno-associated virus (AAV) seems to be the most popular vector, although lentivirus, retrovirus, adenovirus, several other virus vectors, non-viral carriers, and various nanoparticles are also being tested in the clinic. Both ex vivo and direct in vivo applications are popular as well as combination therapies involving currently available approved therapies, such as monoclonal antibodies in oncology.

While gene and cell therapy products have entered the clinic, the high cost of these therapies has raised questions about the true cost-benefit analysis of the new therapies. For very rare devastating diseases, these high costs may be justified if the treatment effect is significant and sustainable, but, for more common diseases, price tags ranging from $300,000 to $750,000 are not currently sustainable. The pricing of gene and cell therapy products requires creative new approaches as well as mechanisms to make these therapies available to patients in less developed countries. Another emerging issue is that some diseases, such as sickle cell anemia, inborn errors of metabolism, or ADA-SCID, appear to be unevenly distributed among various subpopulations. It will be important to consider the specific needs of various subpopulations when making overall governmental and insurance policy decisions. Finally, there are important ethical issues with regards to the potential misuse of gene-modifying technologies for genetic enhancement. A step toward this end occurred recently with the use of CRISPR/Cas9 technology in China for the manipulation of human embryos. While these approaches are clearly not acceptable, the scientific community has to stay alert in order to protect the reputation of effective gene and cell therapies against potential negative publicity and concerns raised by a few individual researchers pursuing unethical experiments.