The Future of Gene Therapy and Genetic Diseases

Summary

Peek into the future of gene therapy and its capacity to treat – maybe eliminate – genetic diseases like cancers and hemophilia. Plus, hear how gene therapy may be on the frontier of reversing the effects of aging.

It’s a future scientists have been working toward for years: how to treat complex health problems with gene therapy. Researchers have also been making progress. Diagnoses once thought to be fatal are now being looked at in a new light.

This is a welcome sight for physicians, caregivers, and – most of all – for the patients living with these genetic diseases. 

One disease that’s impacting lives worldwide is cancer. Nearly 40% of the world’s population will be diagnosed with it at some stage of life.

Typically, cancer treatment takes three forms: chemotherapy, surgery, or radiation therapy. Targeted drug therapies also exist, which work by identifying and attacking cancer cells individually.

But the treatment that many believe has the most potential is immunotherapy.

Immunotherapy uses a patient’s immune system to target and destroy cancerous tumors, and a specific type of immunotherapy known as chimeric antigen receptor (or CAR) T-cell therapy has particular promise.

Over the last few years, progress with this new class of gene-based treatment has accelerated.

CAR T-cell Therapy is when a patient’s own immune cells – the white blood cells called T cells – are genetically altered to target and attack a specific cancer within the body. These cells are first removed from the patient’s blood. Their genes are then altered to produce proteins called CARs, which allow the T cell to better recognize – and attack – specific cancer cells. When the altered immune cells are reintroduced into the patient’s bloodstream, these proteins latch onto cancerous cells, destroying the cancerous cells.

CAR T-cell Therapy has the ability to revolutionize cancer treatment and prevent relapse, as these cells can potentially continue to attack cancerous cells in a patient’s body for years. But it’s not a solution for everyone. Only about 40% of patients have long-term responses.

But if this therapy achieves what scientists believe it can, chemotherapy could be a thing of the past, and when it comes to the future of gene therapy and genetic diseases, there’s reason for optimism.

Transcript

DDx SEASON 4, EPISODE 3

The Future of Gene Therapy and Genetic Diseases

RAJ: This season of DDx is brought to you by Novartis Gene Therapies. 

Opening

KIM: Helen Obando is a teenager with two futures. In the first scenario, Helen is fighting for her life, while in the second, she’s living it.

She was born with sickle cell disease.1

It occurs when a gene variation causes red blood cells to become jagged crescents, which get caught in arteries, causing extreme pain as well as organ and soft tissue damage.1,3 

Until recently, Helen’s life was defined by trips to the hospital, excruciating bouts of pain, and the knowledge that she probably wouldn’t live beyond the age of 40.2

Previously, the only cure for sickle cell disease was a bone marrow transplant. It’s a painful and high-risk procedure, which can be life-threatening if the patient’s body rejects the transplant.1,2.4

But now, Helen no longer dreams of a future free from disease. She’s actually experiencing it.1,2

Show Intro 

RAJ: This is DDx, a podcast from Figure 1 about how doctors think.

I’m Dr. Raj Bhardwaj.

This season I’m joined by co-host Kim Handysides as we take a deep dive into gene therapy.

Today we’re talking about the future of gene therapy and its capacity to treat — and maybe even eliminate — certain genetic diseases. 

We’ll begin by looking at how gene therapy is being used to mitigate certain cancers and hemophilia, and how gene therapy may be on the frontier of reversing the effects of aging.

Kim explains.

Chapter 1 

KIM: It’s a future scientists have been working toward for years: How to treat complex health problems with gene therapy. And researchers have been making progress. Diagnoses once thought to be fatal are now being looked at in a new light.5

This is a welcome sight for physicians, caregivers, and — most of all — for the patients living with these diseases.

Five gene therapy treatments are already approved for use in the United States,6 while hundreds of others are the subject of research trials.7

Remember Helen Obando? In 2019 she was the first American teenager cured of sickle cell disease by an experimental gene therapy. She’s been symptom-free ever since.2

And Helen’s case might just represent gene therapy’s potential to treat other genetic diseases, too.

Let’s start by talking about a disease that’s the leading cause of death worldwide: cancer.

Nearly 40% of the world’s population will be diagnosed with it at some stage of life.8

Typically, cancer treatment takes three forms: chemotherapy, surgery, or radiation therapy.

Targeted drug therapies also exist, which work by identifying and attacking cancer cells individually.9

But the treatment that many believe has the most potential is immunotherapy.9

Immunotherapy uses a patient’s immune system to target and destroy cancerous tumors.9 And a specific type of immunotherapy known as Chimeric antigen receptor (or CAR) T-cell therapy has particular promise.10

Over the last few years, progress with this new class of gene-based treatment has accelerated.9

CAR T-cell Therapy is when a patient’s own immune cells — the white blood cells called T cells — are genetically altered to target and attack a specific cancer within the body. These cells are first removed from the patient’s blood. Their genes are then altered to produce proteins called CARs, which allow the T cell to better recognize – and attack – specific cancer cells. When the altered immune cells are reintroduced into the patient’s bloodstream, these proteins latch onto cancerous cells, destroying the cancerous cells.9,10

It’s a breakthrough some adult lymphoma patients are already experiencing.9

CAR T-cell Therapy has the ability to revolutionize cancer treatment and prevent relapse,11 as these cells can potentially continue to attack cancerous cells in a patient’s body for years.10 But it’s not a solution for everyone. Only about 40% of patients have long-term responses.10

But if this therapy achieves what scientists believe it can, chemotherapy could be a thing of the past.11

Gene therapy is also targeting another disease — hemophilia.12

Hemophilia is caused by variations in genes that encode proteins needed for blood clotting.13 In this case, the gene therapy aims to deliver a working version of the gene to a patient to restore the production of proper clotting proteins.14

It’s been more than 30 years since the British pathologist George Brownlee and his colleagues at Oxford University first identified and cloned the Factor IX (F9) gene,15 a variation of which can cause hemophilia-B.3

Discovering the variant gene was the first step. Scientists have since worked out a way to deliver rewritten DNA into liver cells.13

Like the old adage “If you give a person a fish, you feed them for a day, but if you teach that person to fish, you feed them for a lifetime.”

Gene therapy can teach liver cells to produce the missing blood-clotting factors in people suffering from one type of hemophilia.14

However, the pursuit of gene therapy has been much more arduous in the case of hemophilia-A, the more common form of the disease.16 The challenge here is the neighboring Factor VIII (F8) gene. Like F9, the F8 gene is also responsible for producing a protein for clotting.16 

But unlike F9, the size of F8 is enormous — at least by the standards of genes.17

Editing genes isn’t easy – one of the limitations is the size of the gene that needs to be introduced into human cells, often by specially-designed, but tiny, viruses.18

The F8 gene was too big for the original technology – like buying a big TV and then finding out it won’t fit in the trunk of your car. So scientists are working on how to build a delivery mechanism for larger genes – like trading a hatchback for a pick-up truck.17

And while challenges remain,12 it’s a source of hope for those living with hemophilia.19

Gene therapy is also being used to combat the aging process in mice.20

Back in the early 1990s, a geneticist at the University of California at San Francisco named Cynthia Kenyon21 discovered something remarkable in the genetic code of a tiny worm known as C. elegans. She isolated a gene called DAF-2, and she noticed that a variation in the gene caused the worms to live longer — sometimes twice their normal lifespan of about 20 days.22

And what’s more, the worms were living longer because their cells were aging more slowly. Kenyon’s discovery unlocked the genetic secrets of aging and demonstrated that gene therapy had the potential to extend the lifespan of almost any animal.23

Scientists have identified more than 300 genes in humans that are related to cellular senescence and aging,24 and these genes are now the subject of exciting research. For example, scientists in China created a new gene therapy that can reverse some of the effects of aging in mice and extend their lifespan.20 

The team identified and deactivated a gene called KAT-7, which is responsible for cellular aging. After 6 to 8 months, the mice in the study showed a decrease in biological signs of aging and their lifespan had been increased by 25%.20

There are a lot of steps to be taken between successful animal studies and useful gene therapies in humans, but there is now a lot of optimism that gene therapy could prolong human life by extending the vigor of our cells, too.20 Can you imagine a world where we all live to be centenarians?

Closing

KIM: When it comes to the future of gene therapy, there’s reason for optimism.

Just 40 years ago, most genetic diseases were thought to be untreatable. They’ve been seen as a permanent part of the human condition. But today we are tantalizingly close to revolutionizing not just genetic disease, but cancer, and even aging.

Research will continue to move from mice to humans, and more people will experience futures free of disease, just like Helen Obando.

Show Extro

RAJ: Special thanks to Dr. Peter Kannu, chair of the University of Alberta’s Department of Medical Genetics and leading expert in genomic medicine, for sharing his expertise in the research of this episode.   

This is DDx, a podcast by Figure 1.

Figure 1 is an app that lets doctors share clinical images and knowledge about difficult-to-diagnose cases.

I’m Dr. Raj Bhardwaj, co-host and story editor of DDx.

You can follow me on Twitter at Raj BhardwajMD.

Head over to figure one dot com slash ddx, where you can find full show notes, photos and speaker bios.

This episode was brought to you by Novartis.

Thanks for listening.

References: 

  1. Kolata G. At 16, She’s a Pioneer in the Fight to Cure Sickle Cell Disease. The New York Times. Published January 11, 2020. Accessed November 7, 2021. https://www.nytimes.com/2020/01/11/health/sickle-cell-disease-cure.html
  2. Kolata G. Pioneering Gene Therapy Freed Her of Sickle Cell. Is a Cure at Hand? The New York Times. Published September 14, 2021. Accessed November 7, 2021. https://www.nytimes.com/2021/09/14/health/sickle-cell-cure.html
  3. Prakash V, Moore M, Yáñez-Muñoz RJ. Current Progress in Therapeutic Gene Editing for Monogenic Diseases. Mol Ther. 2016;24(3):465-474.
  4. Inusa BPD, Hsu LL, Kohli N, et al. Sickle Cell Disease-Genetics, Pathophysiology, Clinical Presentation and Treatment. Int J Neonatal Screen. 2019;5(2):20.
  5. Wang Y, Hu L-F, Zhou T-J, et al. Gene therapy strategies for rare monogenic disorders with nuclear or mitochondrial gene mutations. Biomat. 2021;277:121108.
  6. Petrich J, Marchese D, Jenkins C, et al. Gene Replacement Therapy: A Primer for the Health-system Pharmacist. J Pharm Pract. 33(6):846-855.
  7. Is gene therapy available to treat my disorder?MedlinePlus Genetics. NIH. Accessed November 7, 2021. https://medlineplus.gov/genetics/understanding/therapy/availability/
  8. Cancer Statistics. National Cancer Institute. Accessed November 5, 2021. https://www.cancer.gov/about-cancer/understanding/statistics
  9. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. National Cancer Institute. Accessed November 7, 2021. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
  10. CAR T-Cell Therapy, a Breakthrough Treatment for Cancer Patients. Health Matters. Accessed November 8, 2021. https://healthmatters.nyp.org/car-t-cell-therapy-a-breakthrough-treatment-for-cancer-patients/amp/
  11. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69.
  12. Batty P, Lillicrap D. Hemophilia Gene Therapy: Approaching the First Licensed Product. Hemasphere. 2021;5(3):e540.
  13. High KA. Gene therapy for hemophilia: the clot thickens. Hum Gene Ther. 2014;25(11):915-922
  14. Hemophilia. American Society of Gene & Cell Therapy. Accessed November 8, 2021. https://patienteducation.asgct.org/disease-treatments/hemophilia
  15. Cowan H. The scientist behind the treatment of haemophilia B. Reader’s Digest. Accessed November 8, 2021. https://www.readersdigest.co.uk/health/health-conditions/the-scientist-behind-the-treatment-of-haemophilia-b
  16. Hemophilia. MedlinePlus Genetics. NIH. Accessed November 7, 2021. https://medlineplus.gov/genetics/condition/hemophilia/
  17. Doshi BS, Arruda VR. Gene therapy for hemophilia: what does the future hold?. Ther Adv Hematol. 2018;9(9):273-293.
  18. Powell SK, Rivera-Soto R, Gray SJ. Viral expression cassette elements to enhance transgene target specificity and expression in gene therapy. Discov Med. 2015;19(102):49-57.
  19. Schutgens R. Gene Therapy in Hemophilia: From Hype to Hope. Hemasphere. 2018;2(2):e37
  20. Pollard MQ. Chinese scientists develop gene therapy which could delay ageing. Reuters. Published January 19, 2021. Accessed November 7, 2021. https://www.reuters.com/article/us-china-genes-ageing-idUSKBN29P02V
  21. Cynthia Kenyon, PhD. UCSF Profiles. Accessed November 8, 2021. https://profiles.ucsf.edu/cynthia.kenyon
  22.  Kenyon C, Chang J, Gensch E, et al. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366(6454):461-464.
  23. Can Kenyon’s Roundworms Lead Us to the Fountain of Youth? University of California San Francisco. Published July 7, 2006. Accessed November 7, 2021. https://www.ucsf.edu/news/2006/07/102096/can-kenyons-roundworms-lead-us-fountain-youth
  24.  GenAge. Human Ageing Genomic Resources. Accessed November 8, 2021. https://genomics.senescence.info/