‘No longer science-fiction’: Evolutions and applications of cell & gene therapies

By Maggie Lynch contact

- Last updated on GMT

(Image: Getty/Andrew Brookes)
(Image: Getty/Andrew Brookes)

Related tags: Gene therapy, cell and gene therapy, advarra, Fda, Dna, Human genome project, Viral vector, CRISPR

According to an industry expert, gene therapy must move rapidly to address unmet needs and will continue to do so given innovation and investments.

Now, more than ever before, cell and gene therapies are entering the clinical space and, as they become part of the clinical trial industry, these therapies demonstrate the rapidly evolving work in the biopharmaceutical field.

Daniel Eisenman, director of biosafety services at Advarra, a US-based compliance consulting services company, addressed ACRP on the ‘immense power’ of gene therapy. He presented a review of what the technology is capable of on the human level, as well as the impact it can have on the industry.

He began by stating that there are over 2,900 clinical trials in gene therapy that have been registered and are on the clinical trials database, while there are nearly 1,000 further gene therapy clinical trials currently enrolling human research participants.

Of these 2,900 clinical trials, Eisenman stated that there are almost 300 ongoing Phase III trials in gene therapy.

The largest area of study in gene therapy is oncology, with monogenic diseases not far behind. He added, “Given our technologies, [monogenic diseases] are low hanging fruit. It's easy for us to modify one single gene at a time.”

He further explained though that the field is trying to validate the concept before moving on to the more complex polygenic diseases.

Eisenman stated that gene therapy studies are taking off and the most common countries for these trials to take place are in the US, EU, and China. However, in recent months, South Korea, Australia, and the Asia Pacific region are beginning to take a greater stake in this research.

He said that the growth in gene therapy trials and research is due to a number of factors, one of which is the completion of the human genome project​. Eisenman added that with the completion of the human genome project and advancements in technology, commercialization, and the internet, the industry has reached a point where gene therapy technology is “much more relevant now.”

Regulations to meet growth

“Gene therapy is no longer science-fiction,”​ he said. “We’ve really turned that corner. The [US Food and Drug Administration] FDA issued its very first approval of a product in which engineered genetic materials were administered to humans in 2015. Then, 2017 was a landmark in that we had three FDA approvals for investigational products containing recombinant DNA.”

Former FDA commissioner, Scott Gottlieb, stated that he expected that by 2022 there will be 40 approved gene therapies. Additionally, the FDA’s center for biologics evaluation and research issued a statement in January 2019 that said that, with the field at a ‘turning point’, strategic changes within the agency would need to occur.

As a result, the FDA will add 50 additional reviewers for cell and gene therapy, and it anticipates 200 investigational new drug (IND) applications per year by 2020, and 10 to 20 approvals each year by 2025.

Eisenman cited this statement issued by the FDA and explained, “That gives you an idea of the extent of growth that is anticipated in the very next couple of years in this field. In their statement, they essentially draw parallels between gene therapy and where the field of monoclonal antibodies was in the 1990s.”

Bringing manufacturing benefits

Using the example of human insulin, Eisenman discussed how genetic engineering has enabled growth of the pharmaceutical industry. He stated that before the advent of modern recombinant DNA technology, human insulin was limited in its manufacturing capabilities.

“Originally, hospitals would go to slaughterhouses and get the discarded pancreases from cows and pigs, so they could extract animal insulin. It wasn’t human, it wasn’t pure, and it was potentially contaminated with animal pathogens,” ​Eisenman explained.

With recombinant DNA technology, products like human insulin can be made at an industrial scale.

“The benefits of this approach are that it’s a bioidentical, so its human insulin originating from the human insulin gene but made in bacteria. Its cleaner, it's cheap, and it's easy to mass produce. We can make bioreactors and fermenters where we can make hundreds of liters of culture to produce industrial-scale quantities of human insulin. It's much easier and better than going to a slaughterhouse and getting discarded pancreas,”​ said Eisenman.

Gene editing

Creating designer proteins for genome editing is another highly publicized tool for engineering therapeutics. Eisenman explained the genetic code is comprised of four letters, ATCG, each of which represents a nucleotide, and we can now buy these nucleotides commercially, as well as working with DNA synthesizers to make desired DNA sequences.

“At this point, all we need is a code and a computer so we can input the genetic sequence, and the equipment will produce the genetic material that we’d like so we can make designer proteins,”​ he said, with one particularly beneficial use for these proteins being the cutting or editing of DNA.

These designer proteins can be used to remove disease-causing mutations in DNA. Several approaches can then be utilized to replace the excised disease-causing DNA with a healthy copy of that gene.

Eisenman stated that plasmids, which are circles of DNA, are the most basic vector for delivering genetic materials, but they are very inefficient. Scientists have looked to nature to find better gene delivery vehicles and found viruses are ideal for the job.

“If we look at the life cycle of a virus, it infects a host cell by delivering its genetic material into that cell, which hijacks the machinery of that cell to mass produce progeny viruses,”​ he said.

Eisenman continued by explaining, “If we remove the genes involved in viral replication and pathology, what’s left is essentially a genetic syringe, a vehicle for delivering genetic material, and that’s why this technology utilizes viral vectors for gene delivery.”

He also stated that certain oncolytic viruses can also be effectively ‘reprogrammed’ to kill cancer cells while not causing disease in normal healthy cells. In fact, he explained, the first gene therapy product approved by the FDA was an oncolytic virus designed to be injected into melanoma to kill the cancer cells while leaving normal healthy cells unharmed. The virus was also engineered to stimulate the immune system to kill other melanoma cells elsewhere in the body, away from the injection site.

Cell-based vaccines, according to Eisenman, take cell lines or cancer cells and modify them to make them immunogenic, essentially enabling the immune system to become reactive against cancer cells.

Viral cancer vaccines can be used in cases where the gene encoding a tumor-specific antigen is put in a virus and delivered to the patient, with the aim being for the patient’s immune system to attack the gene coded by the virus, as well as any cancers that are expressing the tumor-specific antigen.

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