Recent advances in the field of genome editing have moved us closer to the dream of repairing defective genes in human patients. Over the last 20 years, successive dynasties of programmable nuclease technologies have been applied to this problem. From zinc-finger nucleases, through TALENs to CRISPR--Cas- nucleases there has been a trend towards increasing flexibility of such systems. Several of the systems have been adapted to use alternative effector moieties to the nucleases embedded in the first versions of these systems, allowing target cell modification via better tolerated and more controllable changes to chromosomal DNA. What is missing however, is a flexible and effective method for introducing new genetic material at a defined locus of a genome without creating double-strand (ds) breaks. Such ds breaks are lethal if not rapidly repaired, and they are also recognized as a threat to genome integrity and hence can easily trigger programmed cell death in target cells. Pencil Biosciences has created, and is developing, a fully-synthetic genome modulation system (ApGet) and seeks funding to adapt the system to deliver highly-efficient knock-in of donor DNA sequences at key target sites. The ApGet system is small in size (~0.7 kb), modular and non-CRISPR in composition. It is capable of recruiting diverse effector proteins to specific sites in the host genome by means of RNA-guides. Pencil plans to replace some of ApGet's components with others allowing knock-ins via a fundamentally different mechanism that does not induce a dsDNA break. The aim is to recruit donor DNA to target sites of interest in order to deliver safe, well-tolerated and highly efficient knock-in edits for gene repair and the generation of engineered cell therapies. In the long term gene editing may make a significant contribution to reducing the burden of genetic diseases, which in the UK alone affect more than 3 million people. Many of these diseases would be best treated with a 'one and done' treatment involving a knock-in-mediated replacement of the defective section of an allele.

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Pencil Biosciences aims to develop a novel and artificial genome-editing tool, that retains the programmability of the CRISPR-Cas system but overcomes the challenges associated with the currently available genome-editing technologies. It intends to achieve this by aggregating the advances in various fields of science, especially genetic engineering and synthetic chemistry and infusing desired characteristics in an artificial and synthetic molecule. The CRISPR-Cas9 system is a re-purposed, powerful RNA-guided DNA targeting platform for genome editing. Unfortunately, it has many disadvantages such as off-target editing, a large size that restricts efficient delivery, a requirement for PAM sequences and immunogenicity etc. An optimal genome-editing tool should be able to edit any targeted locus in a genome with a high degree of specificity and without any undesired effects. However, in a real world, such a tool doesn't exist as nature developed it for a (partially) different purpose. Scientists have therefore recognized the necessity to improve the existing tools' scope, especially in the context of eukaryotic genome modulation and human therapeutic applications. Some of their efforts have already started yielding fantastic advances towards this objective. Nevertheless, one big drawback of these advances is their narrow focus. Oftentimes improvement in one area of the genome-editing tool does not offer any solutions to existing issues in another area. Pencil Biosciences aim to overcome these challenges with its holistic approach in solving the problems and by pooling the advances made in the different areas of modern sciences.