Three very different, recent developments related to Gene Therapy caught my attention. One was a company specific announcement, another a national funding decision, and the third a global policy recommendation. In the spirit of PBH, I will share how I connected these distinct developments – from Cambridge, MA; Bethesda, Maryland; and Geneva, Switzerland – and along the way discuss their broader implications.
In the last week of June, two biotech companies – Inetllia and Regeneron – announced a landmark development in the application of CRISPR Cas-9 technology in humans. They had demonstrated the first safe and effective in-vivo application of this novel technology in a Phase 1 clinical trial to treat Transthyretin (ATTR) Amyloidosis. This is the first ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of CRISPR. (Intellia). How incredibly exciting!
Transthyretin (ATTR) Amyloidosis is a “monogenic disease,” meaning it is caused by the mutation of a singular genetic mutation. A genetic mutation hinders the correct protein folding process for the protein Transthyretin. Now, this is taking me back to my Science Olympiad events on Designer Genes and Protein Modeling – Proteins have four key structures: the primary and secondary structures focus on the base amino-acid chain and resulting alpha helix or beta strand bonds formed along the chain. The tertiary structure folds the excess amino-acid chains into the final protein, cementing its properties and purposes. The connection of multiple protein tertiary-structures to each other is what makes up the quaternary structure.
The hereditary ATTR Amyloidosis occurs when a person is born with mutations in the TTR gene. This causes the liver to produce the protein Transthyretin with a tendency to misfold, thus changing its tertiary structure and inhibiting the protein’s function. Accumulation of the misfolded protein leads to the buildup of amyloid deposits in the body causing complications in the patient’s nerves, bone marrow, heart and kidney. If untreated, life expectancy of patients is 2-15 years after the onset of symptoms.
Intellia’s therapy (NTLA-2001) to treat ATTR Amyloidosis targets the Transthyretin (TTR) proteins. The therapy includes a lipid nanoparticle – similar to the mRNA vaccines (PBH) – and a two part gene editing system: a guide RNA specific to the disease causing gene, and the Cas-9 mRNA that encodes the enzyme that does the precision editing.
While additional clinical trials are underway, this exciting development opens the door to the possibility that in-vivo, single dose, gene therapy may be able to treat or cure other monogenic diseases. In order for this to come to fruition, we now have a proven safe and effective CRISPR Cas-9 platform, what is needed then is basic scientific research to identify the specific genes that cause each of the monogenic diseases.
This brings me to the second development: On July 15th, 2021 – less than a month after this breakthrough in in-vivo gene therapy – the NIH announced almost $80 million in new funding to support research efforts to discover the cause of single-gene diseases and disorders. There are 7000 Mendelian gene diseases affecting several hundred million individuals in the world. The current pace of identifying the genes that cause each of these diseases is about 300 a year. This new NIH funding has the potential to significantly accelerate the pace of these discoveries. The speedy discovery and availability of data surrounding specific mutations and mutagenic causes of disorders will be vital for researchers to better understand, identify, and ultimately develop new gene therapies, faster.
Yes, economic and affordability factors ultimately need to be considered. Especially given the vital role public funding, such as NIH grants, has played in the development of the science that is the basis of so many of these innovations. I will continue to learn and think about ways that these exciting innovations are made broadly affordable and accessible. Perhaps sharing my thoughts and learnings in a subsequent blog.
Beyond science, policy and economics, the other big question is – what are the ethical guardrails for gene editing in humans? There seems to be a growing consensus around the ethics of somatic gene editing, but what about human germline gene editing? More than a year ago, as I discussed in my earlier blog, A Look Back… Eugenics to CRISPR (PBH), I began to explore the ethical implications of novel gene editing technologies. As new advancements are made, and as our understanding evolves, there is an even more urgent need for global collaboration to evaluate and establish ethical guardrails and legal standards for the application of gene editing.
That brings me to the third recent development out of Geneva, Switzerland. On July 12, 2021- the WHO released its first global recommendations on human gene editing for the advancement of public health (WHO). The recommendations are based on over two years of consultations and hundreds of diverse perspectives. They cover both somatic gene editing – modifying a patient’s DNA to treat or cure disease – much like the Intellia therapy; as well as germline and heritable human gene editing. More needs to be done to generate a global consensus, build capacity across countries and establish some mechanism of enforcement. However, this WHO announcement is an important step towards ensuring that humanity can benefit from the immense potential of gene editing to diagnose, cure and treat disease, while still protecting our universal human values.
I hope this blog has brought to life the connections I saw across these three very different developments. Reflecting on these developments, I began to better understand how these various pieces fit into kind of a jigsaw puzzle, or an ecosystem. As I pictured this ecosystem, I observed a couple of virtuous cycles further accelerating the discovery and development of gene therapies.
Finally, these developments reinforce my belief in the need for, and the power of, public-private partnerships and global collaboration to address shared challenges especially in the area of bioethics, and for the prudent advancement of innovations that can improve the health of all our peoples. As a high school student, I am excited about these promising developments. I continue to be fascinated by what I am learning and the personal insights I am able to gain as I research and reflect on these developments through multidisciplinary lenses. This is my PBH at work!