Zinc finger transcription factors: the on/off switch for genes inspired by frogs

Have you ever noticed how easily frogs cling to almost any surface? Their sticky little fingers easily grab and hold just about anything they want. It turns out that frogs have protein structures that do the same thing, and these structures could be the key to unlocking therapies for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two of the most common neurological conditions. debilitating effects affecting millions of people. today.

Studying the African clawed frog in 1985, researchers discovered that the frog’s proteins had finger-like protrusions, bound by zinc ions, that tightly gripped tiny segments of genes. Each protrusion, aptly called a “zinc finger”, functioned as a guiding device: it could recognize and bind to specific DNA sites, activating or silencing them.

Humans also possess zinc finger proteins, which are part of a class of proteins called transcription factors. These protein molecules are, in essence, on/off switches for the genes contained in every cell in our body.

Fast forward nearly 35 years to 2018: Pfizer has partnered with genomic medicine company Sangamo Therapeutics to capitalize on this molecular discovery. And today, that collaboration continues to design human-derived zinc finger technologies that target the genetic mutation that causes the most inherited form of ALS as well as FTD.

What are ALS and DFT?

ALS is a rare disease that progressively causes motor neurons around the brain and spinal cord to deteriorate and die. Over time, patients with the disease slowly lose their ability to speak, walk, and eat; eventually they may develop complete paralysis. Physicist Stephen Hawking, for example, had ALS. Lou Gehrig too, and ALS is also known as Lou Gehrig’s disease.

According to Amy Pooler, PhD, vice president and head of neuroscience at Sangamo, ALS doesn’t have a single cause. Instead, multiple genes are implicated, indicating a need for more targeted and personalized approaches to treating the disease.1

FTD (sometimes still called Picks disease) is a rare degenerative disease that frequently causes dementia and personality changes in people considered “too young” for dementia.2 Because symptoms often appear in people between the ages of 45 and 65, those affected are often misdiagnosed with a psychiatric illness.3 As the disease progresses, people with FTD may lose the ability to use language correctly; they may also develop muscle spasms or weakness, stiffness, poor coordination and balance, or difficulty swallowing.4

In the United States, ALS affects about 30,000 people.5 About 60,000 people in the United States have FTD, which accounts for 10-20% of all dementia diagnoses.6 Over 90% of ALS cases are sporadic, meaning they occur in patients with no family history of the disease. The remaining 10% of ALS cases are due to genetic inheritance.seven Mutation in C9ORF72 are the most common hereditary form of ALS and cause 25% to 40% of all hereditary cases of ALS and 25% of cases of FTD.8.9

The C9ORF72 Mutation

Both ALS and FTD are linked to a mutation in the C9ORF72 gene called “repeat expansion”, in which a segment of nucleotides repeats excessively, much like a scratched record.ten The replicated section of the gene is a hexanucleotide (GGGGCC) which can be copied thousands of times and produce a wide variety of abnormal RNA and protein molecules.

In a next step, the partnership between Pfizer and Sangamo aims to decipher how the C9ORF72 the mutation causes the disease. This answer could open the door to the first therapies to counter the impact of these mutations.

“What is interesting about this collaboration is that it explores an approach to a class of mutations and, by extension, a group of diseases,” says Christine Bulawa, PhD, principal director of the unit of Pfizer Rare Disease Research in Cambridge, Massachusetts. “We are targeting a subset of ALS, but if successful, the approach could be applicable to other diseases caused by this type of molecular defect at the DNA level – a small string of nucleotides that tends to expand and lengthen. the longer they last, the more serious the disease.”

ALS treatment and zinc finger technology

Combat C9ORF72 mutations, zinc finger technology has the potential to bind to repetitive segments of nucleotides and turn off the gene, silencing its harmful effects. However, this ALS treatment works differently from gene therapies that replace a mutated gene with a healthy version. The genetic inheritance of ALS is dominant, which means that even if you have a healthy copy of C9ORF72, your mutated copy can take over, causing you to develop the disease. This is why it is important to create a therapy that can effectively “knock down” or disable mutations C9ORF72.

“Our strategy is to mitigate the adverse effects of the mutant form of C9ORF72, to reduce the abnormal RNA and protein molecules that are produced from the expanded repeat,” says Bulawa. “It’s a totally different approach to gene editing. We do not reduce or remove any of the repetitions. We’re basically making a potential therapy that can bind to mutated nucleotides and then block them from being expressed.”

To achieve this goal – to create an on/off switch for the gene – zinc finger technology relies on a modified protein that has two domains. First, the zinc finger domain is designed to target GGGGCC and bind specifically to its excessive repeats. Second, the repressor domain disables repeat expansion and reduces replication of abnormal RNA and protein molecules.

As a result, this technology could help move ALS treatment into the next phase, bringing researchers one step closer to stopping this degenerative nerve disease.

“Current treatments available for ALS really focus on symptom management. But there is a critical unmet need for effective, disease-modifying treatments, something different,” says Pooler. “We believe with [this] approach, by targeting disease at the DNA level – the gene level – this represents a novel therapeutic approach that could be transformative for patients living with these devastating diseases.11

References

  1. Pooler A. Zinc finger protein technology shows promise as a treatment for ALS. June 14, 2021. Accessed November 2, 2021. https://www.youtube.com/watch?v=hWx7Vtx39Fs.
  2. Frontotemporal dementia. Johns Hopkins Medicine. Accessed May 23, 2022. https://www.hopkinsmedicine.org/health/conditions-and-diseases/dementia/frontotemporal-dementia
  3. Frontotemporal dementia. Mayo Clinic. Accessed May 23, 20222. https://www.mayoclinic.org/diseases-conditions/frontotemporal-dementia/symptoms-causes/syc-20354737
  4. Frontotemporal dementia. Johns Hopkins Medicine. Accessed May 23, 2022. https://www.hopkinsmedicine.org/health/conditions-and-diseases/dementia/frontotemporal-dementia
  5. 5. ALS – amyotrophic lateral sclerosis. HopkinsMedicine.org. Accessed July 8, 2022. https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/als/conditions/als_amyotrophic_lateral_sclerosis.html
  6. Facts about frontotemporal degeneration. The Association for Frontotemporal Degeneration. Accessed May 23, 2022. https://www.theaftd.org/wp-content/uploads/2009/02/Fast-Facts-Final-6-11.pdf
  7. Overview: Sporadic and familial ALS. ALS.org. Accessed November 2, 2021. https://www.als.org/research/research-we-fund/scientific-focus-areas/genetics
  8. Overview: Sporadic and familial ALS. ALS.org. Accessed November 2, 2021. https://www.als.org/research/research-we-fund/scientific-focus-areas/genetics
  9. Devenney, E., Hornberger, M., Irish, M., Mioshi, E., Burrell, J., & Tan, R. et al. Frontotemporal dementia associated with C9ORF72 Mutation. JAMA Neurology. 2014 ; 71(3): 331. doi: 10.1001/jamaneurol.2013.6002. Published March 2014. Accessed July 8, 2022.
  10. C9orf72. MedlinePlus.gov. Modified August 18, 2022. Accessed July 8, 2022. https://medlineplus.gov/genetics/gene/c9orf72/#conditions
  11. Pooler A. Zinc finger protein technology shows promise as a treatment for ALS. June 14, 2021. Accessed November 2, 2021. https://www.youtube.com/watch?v=hWx7Vtx39Fs.

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