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CRISPR: A Transformation in Human Therapeutics

What is CRISPR?

CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats) is a revolutionary gene editing tool whose efficacy and ease of use has already accelerated innovation across multiple diverse industries. Biologically speaking, it is defence mechanism utilized by the bacteria for invading pathogens, but recently researchers have repurposed this entire gene editing technology giving it a newer face of CRISPR and have diversified its applications.1

CRISPR- How Does it Work?

This new gene editing technology has a complex working mechanism6. CRISPR-Cas9 was inspired from a naturally occurring genome editing system in bacteria. The bacteria capture extracts of DNA from foreign viruses and use them to create DNA segments known as CRISPR arrays. The CRISPR arrays makes the bacteria to “remember” the viruses (or closely related ones). If the viruses invade again, the bacteria produce RNA segments from the CRISPR arrays to target the viruses’ DNA. The bacteria then use Cas9 or a similar enzyme to disintegrate the DNA, which kills the virus.

CRISPR:  A Transformation in Human TherapeuticsResearchers create a small piece of RNA with a short “guide” sequence that binds to a specific target sequence of DNA in a genome. The RNA also binds to the Cas9 enzyme. The modified RNA is used to recognize the DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location. Once the DNA is snipped, researchers use the cell’s own DNA repair mechanism to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.7

The indication for CRISPR has been increasing with every developing day. Following are some indications where CRISPR has shown some progression with respect to trials –

  • CANCER: CRISPR being tested at the Hangzhou Cancer Hospital9 follows the extraction of immune T cells from the patient. Using CRISPR, the cells are modified to disintegrate the gene that encodes for a protein called PD-1. The modified cells are then reinfused into the patient with a higher capacity to attack cancer cells
  • BLOOD DISORDER: The first CRISPR trial in Europe and the US8, enrolled their first patient in February of 2020, and aims to treat beta-thalassemia and sickle cell disease, two blood disorders that affect oxygen transport in the blood. The therapy, developed by CRISPR Therapeutics and Vertex Pharmaceuticals, consists in harvesting bone marrow stem cells from the patient and using CRISPR technology to make them produce fetal haemoglobin, a natural form of the oxygen-carrying protein that binds oxygen much better than the adult form
  • CYSTIC FIBROSIS: Researchers have proven that it is possible to use CRISPR in human lung cells derived from patients with cystic fibrosis and fix the most common mutation behind the disease. The next step will be testing it in humans, which both Editas Medicine and CRISPR Therapeutics plan to do10

From indications such as hemoglobinopathies, regenerative medicine to in-vivo cell editing to customise treatment, CRISPR is holding promise to revolutionize genetic medicine.5

As the use of CRISPR unfolds every day, multiple companies have initiated and started to invest their efforts into this new technology

Here is the list of few companies trying CRISPR in different verticals 3

  • SEREPTA THERAPEUTICS: Announced their research collaboration with Duke University to get the exclusive licence for its intellectual property and technology related to CRISPR/Cas9 technology developed in the laboratory of Charles A Gersbach for DMD (Duchenne muscular dystrophy)2
  • MAMMOTH BIOSCIENCES: CRISPR based diagnostic tests for in-clinic and at-home usage. The healthcare applications including determining which flu strain you have and screening for malaria and cancer, and the test itself can live in disposable paper strips the size of a credit card
  • INSCRIPTA: Their focus is on developing CRISPR associated natural and synthetic nucleases
  • eGENESIS: They aim at using CRISPR-Cas9 technology in field of xenotransplantation
  • SYNTHETIC GENOMICS: They used CRISPR to tweak genes in microalgae to increase lipid production by 50%
  • BEAM THERAPEUTICS: Bio Paletteand Beam therapeutics announced exclusive license agreements for the use of base editing technologies in human therapeutics. Their ex-vivo approach involves editing cells (such as blood & immune cells) outside the body before introducing them into the patients

Challenges Faced by CRISPR

CRISPR therapeutics currently in the discovery stage for many indications face a lot of challenge in delivery, safety and pharmacology. In the long run, there would be further challenges added to the pile such as its logistic issues, further clinical development, set-up specific to CRISPR and its commercialization4.

Finding the right patient pool for ultra-orphan indication would limit the clinical development of the therapy.

Later, the companies would be required to address the pricing issue as well.

Apart from the pricing issue, CRISPR is a technology which FDA doesn’t regulate, as it can’t be marketed as a product. In an interview with Mckinsey, Katrine bosley4 explained that FDA has reviewed zinc-finger technology and allowed it to enter clinical trials. It’s technically different from CRISPR/Cas9, but like TALEN (Tran-scripter activator like effector nuclease), it’s relevant to the regulation of gene editing in that all these technologies involve making a durable change to DNA.

With advancement, another factor to be taken into consideration is the design of clinical trial. The design of the trial is required to be modified according to the available patient pool for the targeted ultra-orphan indication.


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