Ronald Crystal, MD

“What I want people to take away [from this] is to pay attention to this space. This is going to be something real, and there will be selective diseases where this will be a therapy that, over the next decade, will become real for you in terms of treating patients.”

At the recent Alzheimer’s Drug Discovery Foundation International Conference, Ronald G. Crystal, MD, gave a talk to the more than 800 attendees regarding the current state of gene therapy for 

 influenced Alzheimer disease and other neurodegenerative disorders. He detailed the ongoing development in the space and offered some insight into the current state of a small trial in patients with Alzheimer.

Crystal, who is the chairman of the Department of Genetic Medicine at Weill Cornell Medicine, urged clinicians to pay attention to this space of therapeutic development, citing the progress that gene therapy has made after decades of research. With regard to Alzheimer, the plan is to provide the 

 gene—which literature has suggested may offer a protective effect against Alzheimer disease—to individuals who are 

, Crystal offered his takeaways for the clinical community and discussed the current state of that research. This includes detailing the challenges of developing these therapies, particularly as it relates to the differences in approach to intracellular versus extracellular targets.

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The chairman of the Department of Genetic Medicine at Weill Cornell Medicine detailed the ongoing research in developing gene therapy for patients with Alzheimer disease.

Ronald Crystal, MD: The Possibilities of Gene Therapy in Neurodegenerative Disease

"You can use gene therapy to put genes directly into the nervous system, so that bypasses the blood-brain barrier problem, and if it works, it’s a single administration to cure the disease forever.”

Gene therapy has come to some of the forefront conversations in medicine across a wide spectrum of disorders. This is, in part, because it offers a number of advantages for patients with chronic diseases when it is safe and effective, allowing a single administration of therapy to essentially cure the disorder. As well, it often allows for direct-to-target engagement, offering a workaround for some of the challenges in administering therapies to patients.

For Ronald G. Crystal, MD, chairman, Department of Genetic Medicine, Weill Cornell Medicine, an expert in gene therapy, these 2 particular facets provide solid reasoning—as well as interest—for the potential of these types of treatment to make an impact in genetic forms of Alzheimer disease that are influenced by 

. This research began with genes intended to treat lysosomal storage diseases, which were delivered intravenously, and has since advanced to intravenous and intracisternal delivery.

To find out more about the state-of-the-art research being done in this field for Alzheimer disease, 

 sat down with Crystal. He recently gave a talk at the Alzheimer’s Drug Discovery Foundation International Conference about this very topic, and in this interview, he detailed some of his major talking points from that presentation, including how his research is targeting those individuals who are 

Ronald Crystal, MD: Developing Gene Therapy in Alzheimer Disease

“We’re not genetically modifying the whole individual. We’re genetically modifying 1 organ, where the disease is.”

While gene therapies have traditionally been conceptualized and developed for rare, hereditary disorders, they have begun to trickle into other fields. One of those fields is Alzheimer disease.

Ronald Crystal, MD, The chairman of the Department of Genetic Medicine at Weill Cornell Medicine, is helping to champion a gene therapy there. The difference with Alzheimer, despite it having at least a partial foundation in genetic risk factors, is that it is not a rare condition. This is what excites Crystal about the potential of a gene therapy for the condition.

The advantages of gene therapy as opposed to small molecule or monoclonal antibody treatments, as he puts it, are that they can be specifically directed to a given organ—in this case, the brain. 

At the Alzheimer’s Drug Discovery Foundation’s 19th Annual Conference in Jersey City, New Jersey, 

 sat with Crystal to speak about what is happening with gene therapy in Alzheimer and dementias, and the promise it holds.

Could the introduction of gene therapies into the Alzheimer space be the beginning of a new era of treatment?

Ronald Crystal, MD: Introducing Genetics into Alzheimer Disease

“The gene therapy strategy is to put the E2 even within the brain, produce E2, and then convert, essentially, the brain into a heterozygote or better.”

It has been known for quite some time that the apolipoprotein E4 (APOE4) gene’s presence in a person highly increases the risk of them developing Alzheimer disease, as well as the risk of early onset Alzheimer. However, with the recent developments in the genetics field bringing gene therapy to the forefront of many discussions, the strategy has made its way to the dementia realm.

Using a strategy to alter the genes of those with APOE4 with adeno-associated virus AAVrh.10-mediated gene transfer of APOE2 has shown promise in preclinical studies, prompting those such as Ronald Crystal, MD, a professor and the chairman of the Department of Genetic Medicine at Weill Cornell Medicine, to work toward bringing the therapy to humans.

With help from the Alzheimer’s Drug Discovery Foundation (ADDF), Crystal and colleagues are moving forward with a clinical trial of AACrh.10hAPOE2 CNS therapy in APOE4 homozygotes with early-onset Alzheimer disease. 

At the ADDF’s 19th Annual Conference in Jersey City, New Jersey, Crystal sat with 

 to share his experience with the therapy and its potential in the space.

The chairman of the Department of Genetic Medicine at Weill Cornell Medicine shared his experience with the therapy and its potential in the space.

Author | Ronald Crystal, MD

Articles

Ronald Crystal, MD: The Possibilities of Gene Therapy in Neurodegenerative Disease

Ronald Crystal, MD: Developing Gene Therapy in Alzheimer Disease

Ronald Crystal, MD: Introducing Genetics into Alzheimer Disease

Ronald Crystal, MD: APOE2 Gene Therapy for Alzheimer Disease