Treating Inherited blindness using CRISPR-CAS9

09 May 2024 Treating Inherited blindness using CRISPR-CAS9

This article covers ‘Daily Current Affairs’ and the topic details of ”Treating Inherited blindness using CRISPR-CAS9″. This topic is relevant in the “Science and Technology” section of the UPSC CSE exam.

Why in the News? 

A collaborative clinical study, including experts from the Children’s Hospital of Philadelphia (CHOP) and the Scheie Eye Institute at the University of Pennsylvania, determined that administering CRISPR-Cas9 gene editing to fourteen individuals afflicted with a type of inherited blindness was both safe and resulted in noticeable enhancements in vision for nearly half of the individuals who underwent treatment. The results were published in the New England Journal of Medicine.

About Leber Congenital Amaurosis

• Leber Congenital Amaurosis (LCA) is a rare genetic disorder characterised by severe vision impairment that is present from birth. This condition primarily affects the retina, the specialised tissue at the back of the eye responsible for sensing light and transmitting visual information to the brain. Individuals with LCA often experience profound vision loss or blindness due to abnormalities in the development or functioning of the retina.
• LCA is typically inherited in an autosomal recessive pattern, meaning that a child must inherit two copies of the defective gene – one from each parent – to develop the disorder. The genetic mutations associated with LCA can occur in several different genes, each of which plays a crucial role in the normal function of the retina. These mutations disrupt the production of proteins necessary for maintaining the health and function of retinal cells, leading to impaired vision.
• Symptoms of LCA: It vary widely among affected individuals, but commonly include poor visual acuity, sensitivity to light (photophobia), involuntary eye movements (nystagmus), and reduced or absent pupillary responses. In some cases, individuals with LCA may also exhibit other ocular abnormalities such as cataracts or retinal degeneration.

More about the clinical study

• The clinical trial, named BRILLIANCE, involved 14 participants, comprising 12 adults and two children, all afflicted with a rare inherited blindness condition known as Leber congenital amaurosis (LCA). This trial marks the pioneering use of gene therapy to address blindness in children from birth.
• Treatment and testing: 

1. The study assessed the participants’ visual capabilities post-treatment through tasks such as discerning coloured lights, navigating through a maze under varying light conditions, and reading from a chart.
2. Each participant received a single administration of a CRISPR gene therapy called EDIT-101. This therapy aims to rectify mutations in the CEP290 gene by replacing them with healthy DNA strands, thereby restoring the proper functioning of the CEP290 protein crucial for light detection in the retina.

• Findings: Of the 14 participants, 11 demonstrated overall improvements in vision, with six experiencing significant enhancements, enabling them to recognise objects and letters on a chart. Notably, EDIT-101 exhibited a favourable safety profile, with no severe adverse effects observed among participants. Some individuals reported mild adverse reactions, which were promptly resolved.

Inherited blindness and its types

Inherited blindness refers to vision loss that is passed down through families due to genetic mutations or abnormalities. It encompasses a spectrum of conditions that affect the eye’s structure or function, leading to varying degrees of visual impairment. These conditions are typically present from birth or develop early in life and may progress over time.

Several types of inherited blindness exist, each characterised by specific genetic mutations and associated symptoms:

• Leber Congenital Amaurosis (LCA): LCA is a rare genetic disorder that affects the retina, causing severe vision impairment from infancy. It is typically inherited in an autosomal recessive pattern and can result from mutations in various genes involved in retinal function. Individuals with LCA may experience poor visual acuity, sensitivity to light, and involuntary eye movements.
• Retinitis Pigmentosa (RP): RP is a progressive disorder that affects the retina’s photoreceptor cells, leading to gradual vision loss. It is often inherited in an autosomal dominant or autosomal recessive pattern, although sporadic cases can occur. Symptoms of RP may include night blindness, tunnel vision, and difficulty seeing in low-light conditions.
• Congenital Stationary Night Blindness (CSNB): CSNB is a non-progressive condition characterised by difficulty seeing in low-light environments, particularly at night. It is caused by abnormalities in the transmission of visual signals between the retina and the brain. CSNB can be inherited in an autosomal recessive or X-linked pattern.
• Achromatopsia: Achromatopsia, also known as complete colour blindness, is a rare genetic disorder characterised by the inability to perceive colour and extreme sensitivity to light. It is typically inherited in an autosomal recessive pattern and results from mutations in genes involved in cone photoreceptor function.
• Usher Syndrome: Usher syndrome is a genetic disorder characterised by hearing loss and progressive vision loss due to retinal degeneration. It is inherited in an autosomal recessive pattern and is caused by mutations in genes essential for both auditory and visual function.
• Stargardt Disease: Stargardt disease is a form of macular degeneration that affects central vision. It is typically inherited in an autosomal recessive pattern and is caused by mutations in the ABCA4 gene, which leads to the buildup of lipofuscin in the retina’s cells.

About CRISPR-Cas9

• CRISPR-Cas9 is a revolutionary gene-editing technology that has transformed the field of molecular biology and holds significant potential for various applications in medicine, agriculture, and biotechnology.
• CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) refers to a natural defence mechanism found in bacteria and archaea, which they use to fend off viral attacks. Cas9 (CRISPR-associated protein 9) is an enzyme that plays a key role in this system by acting as molecular scissors to precisely cut DNA at specific locations.
• The CRISPR-Cas9 system has been adapted for use as a powerful tool for editing the genetic code of living organisms, including humans. It allows researchers to make targeted modifications to the DNA sequence by guiding the Cas9 enzyme to the desired location in the genome using a short RNA molecule known as a guide RNA (gRNA).
• Once at the target site, Cas9 induces a double-strand break in the DNA, which triggers the cell’s natural repair mechanisms. These mechanisms can then be harnessed to introduce desired changes, such as inserting, deleting, or modifying specific genes.

Other different Gene editing technologies

• Transcription Activator-Like Effector Nucleases (TALENs): TALENs are engineered proteins that can be designed to bind to specific DNA sequences and induce double-strand breaks, similar to CRISPR-Cas9. TALENs consist of a DNA-binding domain derived from transcription activator-like effectors (TALEs) fused to a nuclease domain. They offer high specificity and have been used for targeted gene editing in a variety of organisms, including plants, animals, and human cells.
• Zinc Finger Nucleases (ZFNs): ZFNs are another class of engineered proteins designed to target specific DNA sequences and induce double-strand breaks. They consist of zinc finger domains, which bind to DNA sequences and are fused to a nuclease domain. ZFNs were one of the first gene editing technologies developed and have been used for genome editing in various organisms, including plants, animals, and human cells.
• Meganucleases: Meganucleases, also known as homing endonucleases, are naturally occurring enzymes that recognise and cleave specific DNA sequences. Like CRISPR-Cas9, they can be engineered to target desired genomic sites and induce double-strand breaks. Meganucleases offer high specificity but are less commonly used than other gene editing technologies due to their large size and limited availability of target sites.
• Base Editing: Base editing is a relatively new gene editing approach that enables precise modification of single DNA bases without inducing double-strand breaks. Base editors consist of a catalytically inactive Cas9 enzyme fused to a deaminase enzyme capable of converting one DNA base to another. This technology allows for the targeted conversion of cytosine (C) to thymine (T) or adenine (A) to guanine (G), enabling the correction of specific point mutations associated with genetic diseases.
• Prime Editing: Prime editing is an advanced gene editing technique that combines CRISPR-Cas9 with a reverse transcriptase enzyme to precisely edit DNA sequences without requiring double-strand breaks. Prime editors are programmed with a guide RNA that directs the Cas9 enzyme to a specific genomic site, where it introduces a single-strand DNA nick. The reverse transcriptase then uses an engineered prime editing guide RNA (pegRNA) to copy and paste the desired edit into the genome, resulting in precise modifications with minimal disruption to the DNA.

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Prelims practise questions

Q1. Consider the following statements: 

1. Prime Editing has the ability to edit larger DNA sequences.
2. Base Editing allows for targeted conversion of cytosine to thymine or adenine to guanine.

Which of the above statements is/are correct?

(a) 1 only

(b) 2 only

(c) Both 1 and 2

(d) Neither 1 nor 2

ANSWER: C

What is the function of the guide RNA (gRNA) in CRISPR-Cas9 gene editing?

(a) To induce double-strand breaks in DNA

(b) To bind to specific DNA sequences

(c) To copy and paste desired edits into the genome

(d) To act as molecular scissors

ANSWER: B

Mains practise question

Q1. Discuss the ethical considerations surrounding the use of gene editing technologies, such as CRISPR-Cas9, in human embryos for the purpose of preventing genetic diseases. What are the potential benefits and risks associated with this approach?

Himanshu Mishra

I am a content developer and have done my Post Graduation in Political Science. I have given 2 UPSC mains, 1 IB ACIO interview and have cleared UGC NET JRF too.