Genetic Therapeutics, Genetic Vaccines & Genomic Editing technologies (collectively referred to here as Genomic Medicine) includes a wide range of RNA and DNA modalities that satisfy the range of genetic perturbations that are required to treat disease. Genomic Medicine will be the most disruptive innovation in medicine in our generation largely due to the convergence of three factors: biology is an information science, genomic medicines are information medicines, and the genomic medicine toolbox is diverse and validated. These three factors enable mainstream scientists to become genomic medicine developers, democratizing drug development and accelerating the pace of innovation.
This article aims to introduce Genomic Medicines and the initial concepts driving the technology. Follow up articles will dive deeper into key concepts.
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Introduction
Genomic Medicines deliver RNA or DNA into cells to treat disease at its molecular and genetic root causes. This represents a novel approach for therapeutics and vaccines, that follows on the incumbent approaches of small molecules and protein drugs, for example aspirin & chemotherapeutics for the former and monoclonal antibodies or other secreted proteins for the latter. Genomic Medicines have tremendous potential and are quickly becoming the most disruptive opportunity in medicine for our generation.
Biology is Information
Biology is an information science. In a simplistic first order approximation, DNA provides us with our an inherited hard-coded comprehensive set of instructions that define our genetic selves; RNA provides our dynamic run-time state of those genes being utilized. At any given time, RNA is being transcribed from our genome (DNA), and then translated into proteins that ultimately provide our cell’s functions and structure. DNA & RNA encode much of their information in their 4 letter AGC(T or U) alphabet, which now can be read and written easily. There is much more complexity in biology than stated here, but this model provides a useful framework as we consider the importance of Genomic Medicine.
Disease is caused, in large part, on the individual’s genetic makeup and how their genetics interact with environmental factors. Genetic involvement in disease can be simple or complex, with disease categorized as monogenic: changes in a single gene causes the disease phenotype, chromosomal: alterations in a patient’s chromosome causes disease, or complex: multiple genetic factors interacting to create disease, including epigenetic and other factors. In all cases, the ability to manipulate gene function to affect a patient’s biological state is key to modern molecular medicine.
Genomic Medicine is Information Medicine
Current dominant molecular medicine modalities, including protein and small molecule drugs, are analog technologies. They affect their gene/protein target through 3D structure interactions. Substantial time, effort and expertise is required to develop analogue molecules, whereby many molecules need to be created and screened to find one that provides the desired effect to the target of interest. Often these efforts fail due to the drug interactions being too weak or not specific, they do not modulate the target sufficiently or modulate unintended targets respectively. In contrast, Genomic Medicines are digital. The active RNA & DNA molecules of Genomic Medicines are designed primarily based on their sequence constrained to their 4 letter alphabet. Through computational, rational, and empirical methods, the sequence-based design rules are becoming well known. We are now at a stage where, once we know what manipulation is required of a disease gene, we can design and obtain an RNA or DNA molecule to affect that gene in a matter of days.
Ongoing advances in delivery technologies allow for reliable transport of RNA or DNA payloads to different tissues and cell types. Once we know how to deliver RNA or DNA to a given tissue or cell type, essentially all of the genetic targets in that tissue and cells are available to be targeted. And unlike the 3D limitations of small molecule and protein therapeutics, whereby only a small proportion of genes encode proteins that have ‘druggable’ 3D structures, Genomic Medicines interact at the sequence level and as such, can act on any gene of interest, providing a near completely druggable genome.
The potential of transitioning from analog medicine to information medicine cannot be understated. This will be akin to computational transition from analog to digital technologies.
The Genomic Medicine Toolbox
The Genomic Medicine Toolbox is diverse, expanding and increasingly clinically validated. Loosely defined, it is the collection of Genomic Medicine modalities that involve the delivery of RNA, DNA, other polynucleic acid or protein constructs, whose sequence specifically affect genes to treat disease. These modalities are being developed by a wide range of Biopharmaceutics companies, academics, and other organizations, and new Genomic Medicine modalities are being created at an unprecedented rate. The Genomic Medicine Toolbox can be categorized into the general types of manipulation done to the gene of interest. Further differentiation across types will include if the effect to the gene of interest is transient or permanent.
Turning Genes Off (Silencing Disease-Causing Genes)
Silencing, or turning off, genes that cause disease can have a significant improvement to a patient’s health. Whether an inherited mutation turns a normal gene into one that causes disease, such as in certain rare diseases, or a mutation is caused due to environmental insult such as in cancers, turning its function off can have a big impact. Example Genomic Medicines that turn off disease causing genes include:
- Small interfering RNA (siRNA) - small non-coding RNA molecules that sequence specifically degrade mRNA of a specified gene
- Micro RNA (microRNA) - small endogenous RNA used regulate networks of genes; delivery of microRNA or microRNA inhibitors can control such regulation
- Antisense oligonucleotides (ASOS) - single strand DNA or RNA that block translation of mRNA to its given protein
- CRISPR for gene deletion or disruption - the CRISPR/Cas9 gene editing system allows for sequence specific cutting of DNA; this can be used to disrupt or delete a gene of interest.
Transient gene silencing approaches, including siRNA & ASO, have approved drugs that are significantly improving the lives of patients. The clinical pipelines for these modalities are strong, particularly for rare disease indications with targets where delivery has been demonstrated. Gene editing technologies are in various stages of clinical testing.
Turning Genes On (Expressing Proteins)
Being able to express a protein in a patient’s cell has a wide range of applications. Including to: a) replace a protein that is expressed too low, missing, or not working with a functional version, b) to express antigens to teach the immune system of a harmful pathogen, or c) to express a protein that itself provides a therapeutic function in the cell. Genomic Medicines that turn genes on include:
- DNA - DNA can be delivered into cells using viral vectors (eg. AAV) and other approaches. Often a stand-alone DNA fragment (eg. episomal DNA) is delivered to the nucleus, enabling sustained gene expression without integrating directly into the genome.
- messenger RNA (mRNA) - mRNA is the intermediary between genes in our DNA and the translation to proteins. By delivering mRNA to cells, transient expression of a given gene of interest is obtained.
- CRISPR - The CRISPR/Cas9 gene editing system and certain analogs has the ability to insert DNA at a sequence specific site. This can allow for the insertion of an entire gene, or gene fragment, with such advances currently under development.
There are a handful of DNA based gene therapy drugs that are approved, particularly for rare diseases and as key marketed COVID-19 vaccines. In 2020 mRNA platforms became approved for the first time and contributed immensely to society through their impact as the leading COVID-19 vaccines. The clinical pipelines and breadth of companies developing both DNA and RNA modalities is extensive. It is anticipated that many new therapeutics and vaccines will be developed in the coming years using these platforms.
Editing Genes (Changing a Gene)
Novel gene editing approaches allow us to fix genetic problems directly in a patient’s genome. New technologies are being developed that are precise and specific to the gene of interest. These technologies promise to make long term fixes in a patient’s genome or to enable the engineering of cells in various cellular therapies.
- CRISPR - The CRISPR/Cas9 gene editing system can be used to delete and then insert a gene fragment of a given gene, creating the ability for gene editing.
- Alternative Gene Editing platforms including Base Pair Editing, Prime Editing, and others - Engineering of CRISPR Cas proteins has led to the creation of multiple novel capabilities. These include base editing, where a single nucleotide can be changed; prime editing that can enable gene insertions, deletions and base conversions; as well as new technologies being developed.
Gene editing platforms have started to achieve promising early clinical data. The field is optimistic that later stage clinical validation, followed by marketed approvals will progress in the coming years.
Delivery of Other Functional Proteins & RNA
The delivery of RNA into cells creates tremendous possibilities for creative drug development. Essentially any protein can now be expressed in a target cell through the delivery of mRNA. Additionally, there are many RNA regulators that act through their secondary and tertiary structures that can now be delivered into cells. These includes endogenous molecules like long non-coding RNA (lnRNA), tRNA regulators and others. Some interesting possibilities include:
- Intracellular proteins - RNA delivery of proteins that then take action in the cell, like epigenetic regulators, novel gene editing proteins, and others.
- Secreted proteins - in vivo expression of therapeutic proteins that then leave the cell to act on disease is a compelling alternative to delivering the proteins themselves. For example, the delivery of therapeutic or prophylactic monoclonal antibodies, and the expression regulatory proteins.
- Non-Coding RNA - Many endogenous RNA control gene regulation based on secondary & tertiary structure instead of sequence driven base-pair binding. Long-Non-Coding RNA (lncRNA) represent a large proportion of the genome, with the majority of their function unknown.
Next Steps
Like all therapeutics, the development and use of Genomic Medicine requires careful regulation by the FDA and other national authorities. In future articles, I’ll aim to discuss the clinical status of the various modalities, dive deeper into the technologies, and explore various implications of these disruptions.