Eszter Hars, Ph.D., President and CEO, SDS Alliance
- Jul 10, 2022

SDS & Science Snapshots (2022-07-10)

In this issue: CRISPR-Cas9 turns 10; The promise of Gene Therapy for Rare Disease and Shwachman-Diamond Syndrome (SDS)

Welcome to our weekly updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email connect@SDSAlliance.org or message us on Facebook! This is all for you!

CRISPR-Cas9 turns 10 years old

CRISPR debuted 10 years ago, in a paper hardly anyone noticed: in June 2012, a joint press release went out from the U.S. Department of Energy and the Lawrence Berkeley National Laboratory announcing a new paper in Science “Programmable DNA Scissors Found for Bacterial Immune System”.

In it, the authors pointed out that the discovery could lead to a new “editing tool for genomes.” The paper has now been cited by more than 15,000 publications and downloaded nearly 65,000 times. In it, the now famous Nobel Prize winning authors - Jennifer Doudna and Emmanuelle Charpentier - explained the inner workings of a system called CRISPR/Cas9.

Although the incredible impact wasn't immediately recognized by the public, now a decade later there is hardly anyone who hasn't hear the term. CRISPR has been used to manipulate the genomes of organisms across every branch of the tree of life, including humans. It’s now being tested to treat dozens of inherited diseases - including many rare diseases - , with companies planning to ask regulators for approval of the first CRISPR-based medicine as soon as later this year.

Read an article by STAT about their interview with Dr. Doudna at the University of California, Berkeley, where she directs the Innovative Genomics Institute.

Read the article HERE

So, what exactly is the CRISPR-CAS9 technology?

In short, according to the NIH-NCI, it is laboratory tool used to change or “edit” pieces of a cell’s DNA. CRISPR-Cas9 uses a specially designed RNA molecule to guide an enzyme called Cas9 to a specific sequence of DNA. Cas9 then cuts the strands of DNA at that point and removes a small piece, causing a gap in the DNA where a new piece of DNA can be added. CRISPR-Cas9 is a breakthrough in science that will have important uses in many kinds of research. In cancer research, it may help to understand how cancer forms and responds to treatment as well as new ways to diagnose, treat, and prevent it.

Watch this great overview by TED-Ed. We have added some more on our "Understanding SDS Science" page, too.

Want to learn more? Check out this amazing resource by the Innovative Genomics Institute, here.

The promise of Gene Therapy for Rare Disease and Shwachman-Diamond Syndrome (SDS)

The majority of the 10,000+ rare diseases are genetic in nature - meaning there is a "typo" or change in the sequence of a gene that is necessary for the healthy function of the human body. If we could fix the specific defect in the genome, in the right organs or tissues, we would be able to deliver cures for the millions of people suffering from rare diseases. Shwachman-Diamond Syndrome (SDS) falls into this category, too. There are a lot of factors that make SDS a fantastic target for gene editing. It is a singe gene disorder - caused by a mutation is just one gene - and the particular mutation (or "typo") is very uniform. Specifically, Over 90% or people with SDS have mutations in a gene called SBDS, and almost all of these patients have at least one "splice site mutation" (258+2T>C). Another aspect that makes SDS a great model disease is the target organ that would need to be reached: the bone marrow. The bone marrow is much easier to reach than the brain, for example. Ex vivo gene editing technology is feasible: Hematopoietic stem cells can be obtained from patients in the same way as people donate stem cells for transplant. Once harvested, the cells can be "edited" - the mutation fixed. Then, the "fixed" cells can be infused back into patients, just like during a traditional stem cell transplant.

Of course this is all easier said than done, and a lot of research efforts is ahead of us. The good news is that a whole research laboratory under the direction of Dr. Brendel at Boston Children's Hospital is dedicated to this work. They are focused on developing approaches to customize the CRISPR-Cas9 machine to efficiently edit the most common SDS causing mutations in SBDS. This work is still in the early stages and likely years away from getting into patients, but certainly an approach that we must explore. We will provide more details and insights, soon. We are dedicated to support this work in any way we can. In particular, our mouse model project seeks to provide a critical tool to accelerate this work, as it harbors the exact human sequence that needs to be targeted by CRISPR-Cas9.

Dr. Brendel published a review article recently highlighting how and why "Humanized mice are precious tools for evaluation of hematopoietic gene therapies and preclinical modeling to move towards a clinical trial".

"The most significant contributions made by these humanized mice are the identification of normal and leukemic hematopoietic stem cells, the characterization of the human hematopoietic hierarchy, screening of anti-cancer therapies and their use as preclinical models for gene therapy applications. This review article focuses on several gene therapy applications that have benefited from evaluation in humanized mice such as chimeric antigen receptor (CAR) T cell therapies for cancer, anti-viral therapies and gene therapies for multiple monogenetic diseases. Humanized mouse models have been and still are of great value for the gene therapy field since they provide a more reliable understanding of sometimes complicated therapeutic approaches such as recently developed therapeutic gene editing strategies, which seek to correct a gene at its endogenous genomic locus. Additionally, humanized mouse models, which are of great importance with regard to testing new vector technologies in vivo for assessing safety and efficacy prior to clinical trials, help to expedite the critical translation from basic findings to clinical applications. "

Read the full article, below.