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CRISPR-CAS9 AND INHERITED BLINDNESS

Context

  • Scientists have said they used a human gene editing tool, CRISPR-Cas9, to restore vision in people with a rare form of inherited or congenital blindness.

Details

  • Leber congenital amaurosis (LCA), a rare form of inherited blindness affecting about one in 40,000 people, results in severe vision loss at an early age.
  • LCA is caused by a mutation in the CEP290 gene, which affects the function of the protein CEP290 critical for sight.
  • The trial was named "BRILLIANCE." Participants received a single dose of a CRISPR gene therapy called EDIT-101.
  • EDIT-101: This therapy targets the mutation in the CEP290 gene, removing the faulty DNA sequence and inserting a healthy strand, restoring normal function of the CEP290 protein.
  • Improved Vision: 11 out of 14 participants experienced improved vision after receiving the treatment.

Inherited Blindness

  • Inherited blindness refers to vision loss or blindness that is caused by genetic mutations passed down from parents to their offspring.
  • Inherited blindness can manifest in various forms, including congenital blindness (present at birth) or progressive vision loss over time.
  • Inherited blindness can be inherited through different genetic patterns, including autosomal recessive, autosomal dominant, X-linked recessive, and mitochondrial inheritance.
  • Numerous genes have been implicated in inherited blindness, affecting various aspects of ocular development, function, and maintenance.

Types of Inherited Blindness:

  • Retinitis Pigmentosa (RP): RP is a group of inherited retinal disorders characterized by progressive degeneration of the retina, leading to night blindness, tunnel vision, and eventual blindness.
  • Leber Congenital Amaurosis (LCA): LCA is a severe form of inherited retinal dystrophy that presents at birth or early infancy, resulting in severe visual impairment or blindness.
  • Congenital Stationary Night Blindness (CSNB): CSNB is a rare inherited condition characterized by night blindness and other visual abnormalities, typically stable or slowly progressive over time.
  • Usher Syndrome: Usher syndrome is a genetic disorder characterized by a combination of hearing loss and vision impairment, often leading to deafness and blindness over time.
  • Choroideremia: Choroideremia is a rare X-linked recessive disorder characterized by progressive degeneration of the choroid, retina, and retinal pigment epithelium, leading to vision loss.

CRISPR-Cas9

  • CRISPR-Cas9 is a revolutionary genome editing technology that allows precise modification of DNA sequences within cells.
  • CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) and Cas (CRISPR-associated) proteins were initially discovered as a bacterial immune system against viruses.
  • CRISPR-Cas9 has widespread applications in genetic research, biotechnology, agriculture, and medicine.

Components and Mechanism:

  • CRISPR Array: Consists of repetitive DNA sequences (CRISPR repeats) interspersed with unique DNA sequences (spacers) derived from viral or plasmid DNA.
  • Cas9 Protein: An RNA-guided endonuclease enzyme that cuts DNA at specific target sequences guided by a single-guide RNA (sgRNA).
  • sgRNA: A synthetic RNA molecule designed to complement a target DNA sequence and guide Cas9 to the desired genomic location.
  • DNA Cleavage: Cas9 generates a double-strand break (DSB) at the target site, which can be repaired by cellular DNA repair mechanisms, leading to gene knockout, knock-in, or modification.

Applications in Genetic Research:

  • Gene Editing: CRISPR-Cas9 enables precise manipulation of genes in various organisms, facilitating the study of gene function and genetic diseases.
  • Functional Genomics: CRISPR-Cas9 screens allow systematic interrogation of gene function by targeting individual or multiple genes simultaneously.
  • Model Organisms: CRISPR-Cas9 has been used to generate genetically modified model organisms for studying disease mechanisms and therapeutic interventions.

Biotechnological and Agricultural Applications:

  • Biomedical Engineering: CRISPR-Cas9 is utilized in synthetic biology and metabolic engineering to engineer microbes for bioproduction of biofuels, pharmaceuticals, and other bioproducts.
  • Crop Improvement: CRISPR-Cas9 offers a powerful tool for precise genome editing in crops to enhance traits such as yield, disease resistance, nutritional content, and stress tolerance.
  • Livestock Engineering: CRISPR-Cas9 is applied in livestock breeding to improve traits related to productivity, health, and welfare.

Therapeutic Applications:

  • Gene Therapy: CRISPR-Cas9 holds promise for treating genetic disorders by correcting disease-causing mutations in patient cells, either ex vivo or in vivo.
  • Cancer Therapy: CRISPR-Cas9 is being investigated for targeted disruption of oncogenes or activation of tumor suppressor genes in cancer cells, as well as for engineering immune cells for cancer immunotherapy.
  • Infectious Diseases: CRISPR-Cas9-based strategies are explored for combating infectious diseases by targeting viral genomes or host factors essential for pathogen replication.

Ethical Considerations:

  • Off-Target Effects: Concerns exist regarding potential off-target effects of CRISPR-Cas9, leading to unintended mutations at genomic loci similar to the target sequence.

Germline Editing: Germline editing, altering DNA in sperm, eggs, or embryos, raises ethical and safety concerns regarding heritable genetic modifications