University of South Florida

The end of the beginning: Gene therapy finally comes of age


The age of human gene therapy has at last begun in earnest. This new era presents both tremendous opportunities and hope for our patients, but also brings unprecedented challenges, as accelerated discoveries and expensive new treatments are creating new clinical, political and ethical challenges.

I’ll share some USF Health research efforts to advance gene therapy for neurological diseases – but, first, some context.

Following the discovery of the structure of DNA in the 1950s, medical researchers predicted we would soon decipher the molecular mechanisms of hereditary diseases, enabling us to then genetically engineer treatments for those disorders shortly thereafter.  Although progress over the next several decades was far slower than anticipated, the launch of the Human Genome Project in 1990 made that future seem imminent.

However, in the late 1990s, the tragic death of a young patient volunteer (due to a systemic reaction to an adenovirus vector), along with a series of technical and clinical trial failures made effective gene therapy again seem like a distant dream.  Nevertheless, progress resumed in the mid-2000s and technological advances finally translated into effective clinical treatments over the ensuing decade.

In 2018, the FDA issued its first approval for a true in vivo gene therapy of a hereditary disorder (hereditary retinal dystrophy), and another for hereditary transthyretin amyloidosis, both of which are devastating diseases with no truly effective previous treatments.  These approvals were quickly followed by several more, including treatments and a possible cure for hereditary spinal muscular atrophy (SMA), a progressive and fatal paralyzing disease of infants and children.

Over the last year, a host of new therapies entered the pipeline for testing and FDA consideration. Many have shown robust and often dramatic Phase 2 and 3 evidence of efficacy.

Several USF Health Morsani College of Medicine (MCOM) researchers are on the front lines of these studies:

  • Juan Sanchez-Ramos, MD, PhD, director of the USF Health Huntington’s Disease (HD) Center, received a $2 million NIH grant to develop and test a smart nanoparticle delivery system for placing gene therapies more precisely (and noninvasively) into areas of the brain affected by HD. He is also now launching an antisense oligonucleotide gene therapy study in HD patients. HD results from a triplicate repeat gene mutation, which mutates the huntingtin protein into a toxic form; this new therapy blocks production of the mutant protein, slowing or even arresting the disease.
  • Theresa Zesiewicz, MD, director of the USF Health Ataxia Research Center, is working with a group of industry partners to develop gene therapy strategies for Friedreich’s ataxia (another triplicate repeat disorder).
  • Tuan Vu, MD, director of the USF Health ALS Center, is exploring potential human studies of a gene therapy for one of the most common forms of hereditary amyotrophic lateral sclerosis (SOD1 ALS), in collaboration with the company that just secured FDA approval for its SMA gene therapy.
  • Bob Hauser, MD, director of the USF Health Center for Parkinson Disease (PD) and Movement Disorders, is collaborating with a pharma company on genetic modulation of the production of alpha-synuclein (a pivotal protein in the pathogenesis of PD) in animal models, and to consider how this might be adapted as a therapy for human PD.

Many other outstanding MCOM translational and clinical researchers are now also entering this rapidly expanding arena.

With these advances and many more to come, this modern era of gene therapy continues to build excitement.  However, scientific progress has been so rapid that the world’s health systems are struggling to keep up with the integration and adoption of these new technologies. In particular, the cost of targeted gene therapies can impede their widespread use in clinical practice; pharmaceutical companies have priced many of these new therapies (some of which may actually be lifetime cures), at the multimillion dollar mark for each patient treated.

Beyond gene therapy, new genetic engineering technologies have profound implications for humankind. The world’s scientific, ethical and governmental bodies are now striving to quickly define where the boundaries of this technology should be, and grappling with when and how to discourage premature human experimentation in sensitive areas.

As controversy in other areas where science and politics intersect has demonstrated, surmounting these challenges together as a worldwide community may, in the end, be the ultimate hurdle to overcome as we enter the brave new world of gene therapy.

Clifton L. Gooch, MD
Professor and Chair, Department of Neurology
USF Health Morsani College of Medicine

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