Rare Diseases and the Promise of Gene Therapy: What You Need to Know
Harris W. Dalrymple, PhD (Med), PhD (Law)
Harris W. Dalrymple, PhD (Med), PhD (Law)
Executive Director, Center for Pediatric Clinical Development

Decoding of the human genome has revolutionized our understanding of the biological world. Now, the ability to edit genes has re-defined the way we think about medicine and treatment. Numerous life-threatening rare diseases are due to single gene mutations that manifest within several months of birth. With no effective treatment options, these monogenic diseases require constant and expensive care. Gene therapy has sparked great interest because of its possibility of providing a permanent cure.

How does gene therapy work?

Gene therapy involves introducing genetic material into a person’s cells to fight or prevent disease.

Several approaches to gene therapy are being tested, including:

  • Replacing a mutated gene that causes disease with a healthy copy of the gene
  • Inactivating, or “knocking out,” a mutated gene that is functioning improperly
  • Introducing a new gene into the body to help fight the disease

Gene Therapy can be broadly split into two main categories:

Ex vivo, which means exterior (where cells are modified outside the body and then transplanted back in again). It involves removal of a patient’s cells, treating the cells with gene therapy, and reinfusing them back into the patient, as in hematopoietic stem cell transplant and CAR T-cell therapy.

In vivo, which means interior (where genes are changed in cells still in the body). It involves direct injection of the gene therapy vector, carrying the desired gene, into the bloodstream or target organ.

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In general, a gene cannot be directly inserted into a person’s cell. It must be delivered to the cell using a carrier, or vector. Vectors used as delivery systems can be divided into:

  • Viral Vectors – Adenovirus, Adeno-Associated virus, Alphavirus, Herpesvirus, Lentivirus, Reterovirus and Vaccinia virus
  • Non-viral Vectors – Naked DNA, Oligonucleotides, Lipoplexes and polyplexes

In order to insert, delete or replace the gene, genome editing is being done with engineered nucleases or “molecular scissors.” Currently of 3 types of engineered nucleases are being used:

  • Zinc finger nucleases (ZFNs)
  • Transcription Activator-Like Effector-based Nucleases (TALENs)
  • CRISPR-Cas system

So far, most gene therapies under development are aimed at rare diseases, for which, in many cases, no effective treatment exists. The advantage of such a targeted approach is that the manipulation of the gene identified as the cause of the condition means that patients receive truly individualized and potentially curative treatment.

Learn more about Pediatric Gene Therapy: Considerations for Planning, Execution and Long Term Follow-Up

The Human Genome Project (HGP) was an international research effort to determine the DNA sequence of the entire human genome—the complete mapping and understanding of all the genes of human beings. The HGP revealed that there are approximately 20,000 human genes.

Gene therapy challenges

Gene therapy suffered major setbacks during its infancy when Jesse Gelsinger, an 18-year-old with a genetic liver disease, died from immense inflammatory complications four days after receiving gene therapy for his condition during a clinical trial in 1999. Adverse effects, mainly leukemias, triggered by the delivery vectors were also reported in European clinical trials. But after 30 years of development, and with the advent of safer vectors and recent discovery of powerful gene editing tools, the landscape is changing and gene therapy is becoming a clinical reality.

Recent clinical trials have shown remarkable therapeutic benefits and an excellent safety record. They provide evidence for the long-sought promise of gene therapy to deliver ‘cures’ for some otherwise terminal or severely disabling conditions. The European Medical Association has been on the forefront of gene therapy research with approvals of Glybera® in 2012 and Strimvelis® in 2016. Recently, this week Food and Drug Administration (FDA) panel unanimously recommended that the agency approve the first-ever gene altering treatment for Leukemia from Novartis. If the FDA. accepts the recommendation, which is likely, the treatment will be the first gene therapy ever to reach the market in U.S.

Gene therapy challenges include:

  • Giving a therapeutic dose
  • Delivering the gene to the right tissues and cells
  • Ensuring proper expression of the introduced genes — enough but not too much
  • Ensuring long-term effects
  • Product manufacturing challenges
  • Determining when best to intervene (some advocate for prenatal screening and fetal therapy).

Gene therapy price tag

Even though gene therapy can potentially cure a disease in a single dose, the cost could well run in the hundreds of thousands of dollars. UniQure, announced that it won’t “pursue the renewal of marketing authorization” for Glybera when it expires in October 2017. This has the industry wondering if this might cause a setback for gene therapies in the pipeline. Experts don’t think so. Some people have proposed spreading the payments over time. For disorders like sickle-cell disease, where the lifetime costs of care are very high, gene therapy could be a bargain and may be embraced by payers, especially when children are involved. But all such approaches face a possible disconnect as they move forward.

As it stands, gene therapy is a rather expensive and labor-intensive process. Patients are carefully identified and handled one at a time, and there are a limited number of medical centers in the entire world that can accommodate these therapies and for those that can, none are particularly close to the great majority of people who actually have sickle cell disease. Nearly 60% of the worldwide sickle cell patients come from India, Nigeria, and the Democratic Republic of the Congo. There are sickle-cell populations in many countries because of migration, but most of the new cases occur in sub-Saharan Africa.

It’s possible that gene therapy will become a disruptive technology in medicine but it will unlikely replace traditional drugs until we are able to figure out current challenges. It is also expected that the research/development model and the regulatory process for gene therapy, as well as the health insurance system, will need to adjust and evolve to prepare for the new era of commercial development that gene therapy promises.

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