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Biomedical Research Genetics

First CRISPR-based Gene Therapy Could be Approved in 2023

CRISPR-based gene therapies have yet to be approved by the FDA, despite their relative affordability and ease when compared to traditional gene therapies. This may change in 2023, as CRISPR Therapeutics and Vertex Pharmaceuticals announced that their biologics licensing applications (BLAs) to the U.S. Food and Drug Administration (FDA) were completed, including a request for priority review, which would shorten the FDA’s traditional twelve-month review of the application to eight months. This timeline opens the possibility for the first CRISPR gene-edited therapy to be available for interstate commerce within the year.

Background

CRISPR/Cas9 complexes were initially discovered in the natural immune systems of bacteria to protect them from viral invaders. The CRISPR component is a sequence complementary to a specific “target” sequence in a patient’s genome. It is sometimes referred to as the Guide RNA, as it guides the entire complex to the place within the genome where editing will occur. The Cas9 enzyme is the protein commonly depicted as a pair of metaphorical scissors, as it cuts DNA to allow for the insertion/deletion of intended genetic material. In the medical field, CRISPR genetic editing can be harnessed to potentially edit the genomes of individuals affected by currently incurable genetic diseases.

The CRISPR/Cas9 complex binds to and cuts the target sequence. / Javier Zarracina via vox.com

CRISPR/Cas9 is much more accessible than other FDA-approved gene therapies, due to its relative affordability and ease of use. Yet the FDA has shown caution when it comes to its approval. Major limitations of CRISPR-based medicines include:

  • The potential for off-targeting, wherein the complex incorrectly recognizes and binds to a sequence similar to the target sequence.
  • The triggering of the body’s immune response by CRISPR/Cas9, as it originates from bacteria.
  • The multi-faceted ethical concerns that come with genetic editing.

Methods and results

Despite concerns, researchers with CRISPR Therapeutics and Vertex Pharmaceuticals are in the final stages of clinical trials and are up for FDA approval with their CRISPR/Cas9 therapy for genetic blood disorders, called exagamglogene autotemcel (exa-cel).

Patients with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT) who are participating in these trials have stem cells collected from their own blood. These cells are then edited with CRISPR/Cas9 outside of the body. Once the edited cells are introduced back into the body the patients are treated in accordance with traditional hematopoietic stem cell transplant (HSCT) procedures to establish high levels of fetal hemoglobin (HbF) production. HbF is the protein that carries oxygen throughout the bloodstream during fetal development.

The addition of HbF to a patient with SCD allows for a reduction or potential elimination of vaso-occlusive crises, wherein sickled red blood cells block blood flow to specific tissues, depriving them of oxygen and triggering an extremely painful immune response.

Within patients with TDT, increased levels of HbF reduce or eliminate the life-long dependence on blood transfusions that come with the characteristic severe anemia of the disease.

A doctor drawing blood from a patient. / Nguyen Hiep via Unsplash.com

CRISPR Therapeutics and Vertex Pharmaceuticals are in stage III of clinical trials, assessing both adults and children with SCD/TDT. They presented the adult data from 75 patients (31 with SCD and 44 with TDT) at the European Hematology Association Congress in December 2022.

All of the 31 patients with severe SCD that had been experiencing recurrent vaso-occlusive crises saw an elimination of the crises at their follow-up after exa-cel infusion (follow-up ranging from 2.0 to 32.3 months).

Of the 44 blood-transfusion-dependent patients with TDT, 42 were transfusion-free after exa-cel infusion (follow-up ranging from 1.2 to 37.2 months) and two were at the 75% and 85% marks in transfusion-reduction.

These CRISPR-based therapies show solid potential to change the idea of “incurable” blood diseases.

This research supports the biologics licensing applications (BLA) of CRISPR Therapeutics and Vertex Pharmaceuticals. A BLA is a request to the FDA to introduce a biological product, in this case the exa-cel gene therapy, to the interstate market. Within the BLA, there is a request for Priority Review, which would shorten the FDA’s traditional twelve-month review of the application to eight months, potentially allowing for the first CRISPR gene therapy to be FDA-approved within 2023.

Although the exa-cel CRISPR gene therapy is not approved just yet, it is an exciting innovation for CRISPR research and patients affected by “incurable” genetic diseases.

References
  • Frangoul, H., Altshuler, D., Cappellini, M. D., Chen, Y.-S., Domm, J., Eustace, B. K., Foell, J., de la Fuente, J., Grupp, S., Handgretinger, R., Ho, T. W., Kattamis, A., Kernytsky, A., Lekstrom-Himes, J., Li, A. M., Locatelli, F., Mapara, M. Y., de Montalembert, M., Rondelli, D., … Corbacioglu, S. (2021). CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. New England Journal of Medicine, 384(3), 252–260. https://doi.org/10.1056/nejmoa2031054
  • Kingwell, K. (2023, April 3). First CRISPR therapy seeks landmark approval. Nature News. https://www.nature.com/articles/d41573-023-00050-8
  • Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013). Genome engineering using the CRISPR-cas9 system. Nature Protocols, 8(11), 2281–2308. https://doi.org/10.1038/nprot.2013.143
  • Vertex and CRISPR therapeutics complete submission of rolling biologics license applications (Blas) to the US FDA for exa-Cel for the treatment of sickle cell disease and transfusion-dependent beta thalassemia. Vertex Pharmaceuticals. (2023, April 3). https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-complete-submission-rolling
  • Vertex and CRISPR therapeutics present new data on more patients with longer follow-up treated with exagamglogene autotemcel (exa-cel) at the 2022 European Hematology Association (EHA) Congress. Vertex Pharmaceuticals. (2022, June 11). https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-present-new-data-more-patients
Categories
Neurology

Social Media Use During Pandemic Linked to Increased Tic Severity in Adolescents with Tourette’s

A study being conducted at the University of Florida is investigating a correlation between the use of social media during the COVID-19 pandemic and a change in tic severity for adolescents with Tourette syndrome.

Background

Tourette syndrome is a type of tic syndrome often present at a young age even as early as 2 years old. Tics are sudden movements, jolts, or sounds that those with tic syndromes feel the urge or are compelled to do. Often times it is compared to the urge of a sneeze where the person will feel great discomfort if they do not perform the tic. That being said, tics have the urge to be suppressed but not without causing discomfort to the individual.

Often times, people confuse and associate Tourette’s syndrome with coprolalia. Coprolalia is a specific type of phonic or vocal tic in which people shout obscene language. This specific type of tic is very rare and only affects around 10% of those diagnosed with Tourette’s Syndrome.

Study

After analysis of a patient population of surveys completed by adolescent individuals (n=20) with ages ranging from 11 to 21 years old, the researchers found statistically significant data showing that social media use, and increased social media use during the pandemic, causes an increase in tic severity and frequency.

  • 90% reported using social media more frequently during the pandemic
  • 65% reported using social media for an average of 6 hours per day
  • 50% reported that social media negatively impacted their tics
  • 85% reported that their tic frequencies worsened during the pandemic

This study was recently highlighted by both the University of Florida and the American Academy of Neurology (AAN) for its findings related to the implications of the pandemic on the mental health of adolescents. The researchers plan to add new participants to the study to strengthen the data and gain new insights.

This research is important as it can help to identify possible stressors for those with tics and work towards providing relief from tic symptoms for those with Tourette’s.

This article is based on the following sources

– American Academy of Neurology. (2022, February 28). Study: Tic severity linked with social media use for teens during pandemichttps://www.aan.com/PressRoom/Home/PressRelease/4961
– Centers for Disease Control and Prevention. (2020, May 13). Five Things You May Not Know About Tourette Syndromehttps://www.cdc.gov/ncbddd/tourette/features/tourette-five-things.html
– Mayo Clinic. (2018, August 8). Tourette syndrome – Symptoms and causeshttps://www.mayoclinic.org/diseases-conditions/tourette-syndrome/symptoms-causes/syc-20350465
– Tourette Association of America. (2016, May 21). Understanding coprolalia: A misunderstood symptomhttps://tourette.org/resource/understanding-coprolalia/
– University of Florida News. (2022, March). Heavy social media use may be linked to increase in tic severityhttps://news.ufl.edu/2022/03/social-media-use-and-tic-severity/