Conclusions and Proposals for Future Work

Gaucher’s Disease was observed in the clinic as early as the late 1800’s, and remarkable strides have been taken since then toward discovering the molecular underpinnings surrounding the disease. Since its discovery, the general trajectory towards the understanding of Gaucher’s Disease has proceeded as follows: appearance in the clinic and documentation of symptoms, molecular characterization of these symptoms, genetics and enzymology surrounding the disease, and treatment options. Current research surrounding Gaucher’s Disease appears to be treatment-based. Although the Gaucher’s Disease knowledge set has come a long way, more still needs to be done in order to develop a more complete picture.

Understanding of Pathophysiology

The Gaucher’s Disease literature seems to be skewed in an “extreme” fashion. Specifically, the characterization and molecular underpinnings of Gaucher’s Disease are well documented, and specific treatment options have been tested and proved useful. However, the “middle ground” of Gaucher’s Disease research needs to be investigated more fully. Questions concerning how accumulations of the glucosphingolipid GlcCer result in a wide variety of symptoms that cover the bases of many organ systems (ie. hepatosplenomegaly to anemia to bone deformities) remains unclear. Pavlova et al. serves as the most current publication for the pathogenesis of Gaucher’s Disease, but more studies are required to confirm these findings. Understanding the bridge between the genetic/enzymatic basis of disease to clinical presentation could prove useful in designing therapies that prevent future symptoms rather than treat current symptoms.

The symptoms of Gaucher's Disease are well documented, but the physiological mechanics bridging GlcCer accumulation in the macrophage and the symptoms of Gaucher's Disease still need to be elucidated. Source:
The symptoms of Gaucher’s Disease are well documented, but the physiological mechanics bridging GlcCer accumulation in the macrophage and the symptoms of Gaucher’s Disease still need to be elucidated. Source: Beutler and Grabowski 2001

Early Diagnosis

A common problem with diagnosing Gaucher’s Disease is that its symptoms often overlap with the symptoms of other diseases. More efficient biomarkers should be designed in order to selectively target GlcCer. It is also difficult to ascertain which specific mutation is the cause of Gaucher’s Disease – one mutation that causes Gaucher’s Disease could result in more efficacious treatment options than other mutations due to the differential disruption of GlcCerase’s normal three-dimensional structure. Additionally, methods of detecting the mutations that cause Gaucher’s Disease early on should be implemented so that treatment could begin sooner, leading to a decrease in the severity of clinical presentation.

Further Utilization of Gene Therapy

Gene therapy is often an underused approach to treating Gaucher’s Disease. It is most commonly utilized when patients are resistant to enzyme replacement therapy. However, gene therapy could be utilized as a broader-scope treatment option because it has the potential to correct the source of Gaucher’s Disease. If a type of DNA repair complex could be designed for even the most common mutation found in patients with Gaucher’s Disease (N370S substitution), cells that are formed after the implementation of the DNA repair complex could possess a properly folded GlcCerase that has the capability of catabolizing GlcCer. Additionally, methods of inserting the normal GBA gene into Gaucher patients in order to promote the expression of functional GlcCerase should be investigated more thoroughly, a suggestion by Dahl et al. This will allow accumulations of GlcCer to be broken down by normal GlcCerase and hopefully lead to an improvement in clinical symptoms.

Gene therapy involves the implementation of a foreign gene into a patient with a given disease. In the case of Gaucher's Disease, this would involve the implementation of the wild-type GBA gene into the patient. AAV stands for aden-associated virus, which is simply a small virus carrying the foreign gene. Source: cisncancer.org
Gene therapy involves the implementation of a foreign gene into a patient with a given disease. In the case of Gaucher’s Disease, this would involve the implementation of the wild-type GBA gene into the patient. AAV stands for aden-associated virus, which is simply a small virus carrying the foreign gene. Source: cisncancer.org

2 Replies to “Conclusions and Proposals for Future Work”

  1. Zack – Nicely done! I know that Gaucher’s is something that can be screened for because it is a “Jewish Genetic Disease” (for example, my brother and sister were screened as undergrads in a campus screening drive). Is there anything in the literature suggesting that the best way to treat Gaucher’s is to prevent it (i.e. screen adults before they have kids rather than managing symptoms post-birth)? Do you see the symptoms as manageable or do you think money is better spent on screening (I ask because some diseases are so rare that realistically money isn’t being pumped into their treatment developments, but this one has a particularly high rate of incidence in this specific population.) I think that your details on the science were very clear and thorough; I am looking for more details here on the disease and its relationship to society at large. Thanks!

    1. Thanks for your thoughts, Zach! I definitely think that screening is a good strategy to combat Gaucher’s Disease, especially given the high carrier rate and birth incidence among the Jewish population. Screening is actually utilized quite frequently and can be performed using a simple blood or saliva test. This may actually be a better strategy than treating symptoms post-birth because sometimes patients with type I GD don’t even show symptoms. With that being said, even if screening was performed, it may be difficult to “fix” the result before birth. GlcCerase activity assays would need to be performed once the child is born to determine the severity of the disease state. I definitely agree that it would be best to catch the disease earlier rather than later, and screening is a great way to do so. Thanks!

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