ROCHESTER INSTITUTE OF TECHNOLOGY – DUBAI

BIOL.101 – General Biology I

GENOMICS: Gene therapy

An organism's complete set of DNA is called its genome. Virtually every single cell in the body
contains a complete copy of the approximately 3 billion DNA base pairs, or letters, that make
up the human genome. With its four-letter language, DNA contains the information needed to
build the entire human body. A gene traditionally refers to the unit of DNA that carries the
instructions for making a specific protein or set of proteins. Each of the estimated 20,000 to
25,000 genes in the human genome codes for an average of three proteins. Located on 23 pairs
of chromosomes packed into the nucleus of a human cell, genes direct the production of
proteins with the assistance of enzymes and messenger molecules. Specifically, an enzyme
copies the information in a gene's DNA into a molecule called messenger ribonucleic acid
(mRNA).

Gene therapy involves altering the genes inside your body's cells in an effort to treat or stop
disease. Genes contain your DNA: the code that controls much of your body's form and
function, from making you grow taller to regulating your body systems. Genes that don't work
properly can cause disease. Gene therapy replaces a faulty gene or adds a new gene in an
attempt to cure disease or improve your body's ability to fight disease. Gene therapy holds
promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease,
diabetes, haemophilia and AIDS. Researchers are still studying how and when to use gene
therapy. Currently, in the United States, gene therapy is available only as part of a clinical trial.
Gene therapy products are biological products regulated by the FDA’s Centre for Biologics
Evaluation and Research (CBER). Clinical studies in humans require the submission of an
investigational new drug application (IND) prior to initiating clinical studies in the United
States. Marketing a gene therapy product requires submission and approval of a biologics
license application (BLA).

CURRENT RESEARCH:

The engineering and profiling of non-viral nanoparticles for gene delivery has undergone
remarkable advances and increases in throughput. These technologies are likely to have a
tremendous impact on gene therapy in the future by building on the clinical success of
nanoparticle-delivery of siRNAs and the first approval of an siRNA-based drug, Onpattro for
the treatment of hereditary ATTR amyloidosis, in 2018. One possible advantage of
nanoparticles is the potential to circumvent detection by the immune system that limits viral
delivery. Human gene therapy seeks to modify or manipulate the expression of a gene or to
alter the biological properties of living cells for therapeutic use. Additionally, chemically
defined nanoparticle formulations present unique opportunities for functionalization and tissue
targeting that may ultimately be critical to success of in vivo gene transfer outside of the retina
and liver.
Beyond the first generation of gene therapies that have focused on delivery of transgenes, gene
editing technologies are enabling an entirely new modality for treatments based on precise
modification of human genome sequences. While gene editing therapies first entered clinical
trials in 2010 as an approach to prevent HIV infection of T cells, the first example of disease-
modifying efficacy was demonstrated only in the past year in clinical trials of CRISPR-based
gene editing for sickle cell disease and beta-thalassemia (CTX001). This pioneering success,
combined with a promising safety record thus far for gene-edited T cells and HSCs in human
trials, has set the stage for highly anticipated results from ongoing and imminent clinical trials
of in vivo genome editing, including a current trial of AAV-based gene editing in the retina
(EDIT-101) and a planned trial for non-viral nanoparticle-based delivery of CRISPR to the
liver (NTLA-2001). Nevertheless, expanding to target tissues outside of the retina and liver
comes with many challenges. Assuredly, the products of this Consortium will significantly
accelerate the progression of gene editing therapies over the next ten years and beyond.
Current gene editing technologies use nuclease-based systems to cut DNA strands and
stimulate DNA repair pathways to introduce desired sequence changes. While these
technologies are only currently beginning to be tested clinically, multiple waves of next-
generation editing technologies are lined up at the heels of these efforts to improve specificity,
accuracy, efficiency, and applicability to different classes of disease. For example, the
inventions of base editing and prime editing have enabled the precise alteration of genomic
sequences in the absence of DNA breaks and without the reliance on the activity of endogenous
DNA repair pathways. RNA-targeted editing technologies allow for transient and reversible
modification of gene expression without necessitating permanent changes to genome
sequences, potentially leading to greater efficiency and safety.
Finally, epigenome editing technologies have the advantage of tunability, reversibility, and the
potential for sustained outcomes after transient editor activity that are heritable through cell
division. In parallel to these advanced editing modalities, the roster of possible DNA-targeting
systems continues to expand, particularly with the exponentially increasing diversity of
CRISPR-Cas’s systems derived from engineered variants, various bacterial species, and
distinct classes of CRISPR targeting mechanisms. The rapid pace of technological innovation
in these editing fields is certain to both transform how we currently think about gene
therapies but also dramatically broaden the scope of human disease to which these
approaches can be applied.

SCIENTIFIC INQUIRY:

Hence, to summarize, it cannot be argued that these advances in gene therapy and genomics
have been revolutionary for the medicinal field. Gene therapy has some potential risks. A gene
can't easily be inserted directly into your cells. Rather, it usually has to be delivered using a
carrier, called a vector. It is also evident that as the practice of this technology starts becoming
more common, researchers will be able to learn more about previously incurable diseases and
disorders. The possibilities of gene therapy hold much promise. Clinical trials of gene therapy
in people have shown some success in treating certain diseases. The successful
implementations of such techniques and the curiosity of medical practitioners allowed the
building of tools for human gene editing, ex-vivo and in-vivo gene therapies.
The future for biotechnology appears to be remarkably bright and as more information is gained
on genomics, the medical field will be likely to correlate genotype and the risk for a disease
more accurately. The curiosity of humans led to innovations that gave answers to some of our
domestic and even industrial needs. We want to know why things are how they are and why
they are like that. We have the insatiable thirst for answers to questions in our conscious and
sub-conscious minds. The cost of these technologies is also likely to drop as they become a
common tool in medicine. This era of gene therapy seems to be progressing greatly as advances
are visible in viral vectors and organ development. Overall, the investments in these sciences
are necessary in order to build astonishing treatments for tomorrow.
REFERENCES:

Bryn Mawr Communications. (n.d.). Genomics to Gene Therapy in Neurology - Practical

Gene Therapy. (n.d.). Genome.gov. https://www.genome.gov/genetics-glossary/Gene-

Dunbar, C. E., High, K. A., Joung, J. K., Kohn, D. B., Ozawa, K., & Sadelain, M. (2018).
Gene therapy comes of age. Science, 359(6372).
https://doi.org/10.1126/science.aan4672

Gowing, G., Svendsen, S. P., & Svendsen, C. N. (2017). Ex vivo gene therapy for the
treatment of neurological disorders. In Progress in Brain Research (pp. 99–132).
Elsevier BV. https://doi.org/10.1016/bs.pbr.2016.11.003

Milani, M., Annoni, A., Bartolaccini, S., Biffi, M., Russo, F., Di Tomaso, T., Raimondi, A.,
Lengler, J., Holmes, M. V., Scheiflinger, F., Lombardo, A., Cantore, A., & Naldini, L.
(2017). Genome editing for scalable production of alloantigen‐free lentiviral vectors
for in vivo gene therapy. Embo Molecular Medicine, 9(11), 1558–1573.
https://doi.org/10.15252/emmm.201708148

Primer on Medical Genomics: Part XIV: - ProQuest. (n.d.).