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Precision Medicine and the Implications for Gaucher Disease (Podcast Recap)

Precision Medicine — The Future of Treatment for Gaucher Disease?

The idea behind precision medicine is simple: You are unique, and your treatment should reflect that. The medical community is moving away from “one-size-fits-all” care for certain diseases. By analyzing a person’s genetic makeup, we can identify therapies that will likely be effective for them.

Precision medicine helps people get the right treatment for them – and helps them avoid therapies that won’t be effective. For cancer treatments, for example, doctors often analyze the tumor’s genetic makeup and then prescribe specific drugs that will target the genetic mutations.

As the field of precision medicine expands, doctors and scientists are turning their attention to rare diseases, like Gaucher disease. In this month’s podcast, we talk about precision medicine and some of the hopes and challenges this treatment method presents for people living with rare diseases.

Joining us is Dr. Pramod Mistry, professor of medicine, pediatrics, and cellular and molecular physiology and the director of Yale Lysosome Disease Center and the Gaucher Disease Treatment Center. Dr. Mistry’s work focuses on inherited metabolic liver diseases – particularly Gaucher disease.

How Precision Medicine Works

The concept of precision medicine has been around for years, even before it had a name. Doctors aim to integrate a person’s symptoms with scientific evidence they’ve gathered from treating other patients with the same disease. This combination of information helps doctors make decisions about the timing and type of treatment a person should receive.

But clinical trials have shown that in many cases, only small numbers of people benefit from certain therapies, like blood pressure drugs. “You can prescribe blood pressure medications to 10 different people, but only one person will show improvement in their blood pressure readings. Most doctors don’t know the genetic differences between each patient, so they prescribe the same medication to everyone. And some patients simply don’t respond to it,” says Dr. Mistry.

The Precision Medicine Initiative

Precision medicine as we think of it today developed when former President Barack Obama introduced the Precision Medicine Initiative. The goal of the initiative is to enhance healthcare based on an understanding of an individual’s risk of disease and response to therapies. In this era of genomic medicine, doctors identify specific genetic differences in individuals and use the information to guide treatment.

Dr. Mistry notes, “Doctors use detailed information from a person’s genetic background to identify their risk for a certain disease, like high blood pressure. Then, they select treatments that are most likely to produce a therapeutic effect.”

This tailored approach to treatment is already widely used in cancer therapy and for diseases like inflammatory bowel disease. For people living with Gaucher disease, their doctor may one day select medications and time their treatment based on their particular genetic makeup.

Pharmacogenomics: Guiding Treatment Using Genes

Pharmacogenomics is the study of how individual genes affect a person’s response to medications. Doctors use pharmacogenomics to identify patients who might benefit from particular drugs and to determine what an appropriate medication dose might be. Pharmacogenomic testing helps doctors choose the most effective and least dangerous medications for patients with certain cancers, heart disease, acute and chronic pain, and psychiatric disorders such as depression.

And pharmacogenomic testing is playing a role in Gaucher disease treatment as well, to help determine the right dosage of the medication Cerdelga®. When people take medications, enzymes in the body metabolize, or break down, the drugs into substances that the body can excrete. An enzyme called cytochrome p450 2d6 is responsible for metabolizing Cerdelga. Scientists recently discovered that due to genetic differences, people metabolize Cerdelga at different rates.

This finding means that people can take the same dose but have different responses. Some patients may have Cerdelga blood levels in the proper therapeutic range, so the medicine is effective and improves symptoms. Others may have blood levels that are either too high or too low. If too low, they may not experience relief of symptoms. If too high, there is increased risk for possible adverse side effects.

Because of this difference, doctors must order genetic testing before prescribing Cerdelga. The testing determines whether a person is a slow or rapid metabolizer, so doctors can know whether to prescribe the treatment once or twice daily.

And a small number of patients are ultra-rapid metabolizers. Even when they take large doses of Cerdelga, their bodies cannot sustain therapeutic blood levels of the medication. For these people, Cerdelga is ineffective, and doctors should not prescribe it.

Genetic Testing: Part of a Comprehensive Treatment Plan

Dr. Mistry explains that even though pharmacogenomic testing can indicate when a certain medication is unlikely to work, choosing among potentially effective treatments can’t be based solely on the results of a single metabolic test. Even within families with a history of Gaucher disease, there is often extraordinary variability in the pattern of the disease itself.

And even in the future, when there may be information about everyone’s unique genome, pharmacogenomic testing will be an integral part of the treatment solution – but not the only factor. While doctors may use a person’s genotype (genetic makeup) and phenotype (symptoms or characteristics we can observe) to help guide treatment, they will continue to review the current health status of each person, identifying any unmet individual needs.

The Benefits – and Challenges – of Datasets

To make treatment recommendations, doctors rely on peer-reviewed information from clinical studies and from data collected from individual treatment centers, the International Collaborative Gaucher Group (ICGG) Registry, and other registries. This data helps doctors make evidence-based decisions about best practices and effective treatments. Additionally, doctors review individual profiles of patients with Gaucher disease.

The challenge for physicians is using large datasets, like the ICGG Registry, to guide decision-making about one particular individual. These datasets don’t have information about the unique biological makeup of people in the registry, so they can’t account for genetic differences among individuals.

Challenges to Collecting Better Genetic Data

As precision medicine gains a foothold, researchers are moving toward ongoing data collection (“big data”) to identify observable disease trends. The goal of these data collection efforts is to link genomic datasets, which are obtained by sequencing parts of whole genomes (the complete set of genes in an organism) to each person’s medical information. This data would then be available to the medical community as a whole, helping doctors understand specific subtypes of diseases like Gaucher disease.

And while there are currently efforts to create and maintain such databases — almost 300 veterans are participating in a data capture initiative through the Department of Veteran’s Affairs — there are still challenges for the Gaucher disease community:

  • The disease is extremely rare.
  • The course of the disease varies greatly from person to person.
  • There is no efficient way to share information about Gaucher disease and its genetic variants among physicians. Databases like the ICGG Registry exist but don’t include biorepositories for entire DNA samples.

Are Biorepositories a Viable Option for Gaucher Disease?

A Gaucher disease biorepository would store DNA samples from people living with Gaucher disease, allowing doctors to sequence entire genomes. Doctors could then use blood serum samples more effectively to identify biomarkers so they can fine-tune and enhance current treatment options. And while some doctors, including Dr. Mistry, advocate for the creation of such biorepositories, there is still hesitation over the implications of such a widespread collection of personal genetic material.

Today, the laws regarding privacy and security surrounding samples of genetic materials in biorepositories are unclear. Many question whether to even have independent biorepositories alongside registries for rare diseases like Gaucher disease. Recent revelations of repeated hacking of confidential data from supposedly secure databases are frightening. Cost is a factor as well: Registries can cost millions of dollars to manage each year. There simply isn’t funding available to support the creation of biorepositories.

Infrastructure and logistics are also challenging, raising questions like:

  • Where would biorepositories be located or stored?
  • What type of security would be required and who would be allowed access?
  • What kinds of freezers would be used to store DNA samples?
  • Who would run these freezers?
  • What safety parameters should be in place to ensure the biorepository isn’t lost in an accident or power outage?

Some larger medical programs have developed and maintained biorepositories for serum and tissue specimens, and individual researchers often try to preserve the material with which they work. However, even these programs collect and save material from only hundreds of individuals. Dr. Mistry notes that for a rare condition like Gaucher disease, it’s going to take genetic information and detailed, accurate phenotypic annotation from thousands of people to hone in on specific genetic factors influencing disease progression and treatment.

Gaucher Disease Research and Precision Medicine Today

Recently, the link between Gaucher disease, Parkinson’s disease, and Lewy Body Dementia (LBD) has struck fear into the hearts of many. It is important to remember that 95% of individuals with Gaucher disease never experience these neurological complications. For the 5% at risk, how can we identify them early and start therapies that may prevent Parkinson’s disease or LBD from developing?

There are efforts underway to discover genetic factors that may make a person with Gaucher disease more likely to develop these neurological complications. Researchers from the Parkinson’s disease community currently lead studies examining thousands of genomes to determine the specific genetic factors leading to Parkinson’s disease.

The Future of Gaucher Disease Treatment

For a person living with Gaucher disease, the implications are huge.

“One day in the future, you might go to your doctor, concerned about your risk for developing Parkinson’s disease or LBD. Based on the results of a blood test, your doctor could identify whether or not you are at risk. If you are at risk, your doctor can then discuss therapies that not only treat Gaucher disease but help prevent the development of neurological complications,” says Dr. Mistry. The identification of biomarkers through DNA sequencing will be a critical part of precision medicine in Gaucher disease and a host of other conditions as well.

“I hope that the Precision Medicine Initiative will propel the development of clinical phenotype data capture and the creation of biorepositories storing DNA samples. It will greatly enhance our ability to care for people with Gaucher disease, wherever they are,” says Dr. Mistry.


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