Research to develop new therapies for rare diseases is ongoing at the Jackson Laboratory

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image: Researchers led by Cathleen Lutz, Ph.D., are using an exciting new method, preclinical genome editing, to develop safe and effective therapies for rare diseases and bring them to the clinic.
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Credit: The Jackson Lab

Researchers led by Cathleen Lutz, Ph.D., are using an exciting new method, preclinical genome editing, to develop safe and effective therapies for rare diseases and bring them to the clinic.

Unfortunately, the translation of accumulated knowledge into safe and effective therapies has lagged behind. There are many reasons to expect that situation is changing for the better, however, as powerful new gene-based therapies succeed in clinical trials and receive FDA approval.

Therapeutic strategies such as gene replacement and gene modulation (eg, blocking protein production with antisense oligonucleotides) are at the forefront of recent advances. But while they carry exciting promises for many applications and diseases, they are not without risk. In some cases they can provoke adverse immune responses, initiate cancer, and cause other serious side effects.

Researchers are therefore still working to develop safer therapies for rare genetic diseases that provide lasting benefits. Now Cathleen LutzPh.D., of The Jackson Laboratory (JAX) is leading a major effort to implement a new genomic research tool, preclinical genome editing, to treat rare neurological genetic disorders.


CRISPR has revolutionized gene editing, but as originally applied it involves DNA double-strand breaks that leave absolutely no room for error in the clinic. Researchers have continued to improve CRISPR methods, however, and have now advanced them to the point where they are able to make precise genomic alterations without cutting the DNA. Lutz, vice president of the Rare Disease Translational Center at JAX, will lead a multi-institutional team to develop and validate novel gene editing-based therapeutic approaches for four neurological conditions: spinal muscular atrophy, Friedrich’s ataxia, Huntington’s disease and Rett syndrome. Supported by A five-year, $22.8 million grant of the National Institute of Neurological Disorders and Stroke (NINDS), Lutz and collaborators from JAX, The Broad Institute, Massachusetts General Hospital, Boston Children’s Hospital, and UT Southwestern Medical Center will ultimately seek to advance at least one lead candidate therapy through a successful new trial drug demand (IND).

At JAX, Lutz will work closely with the associate professor Steven Murray, Ph.D., who leads the core preclinical mouse model to develop, validate, and optimize in vivo mouse models for each disease. Other contributors have extensive experience and resources for manufacturing virus-based gene editing therapy in tissue, possess deep experience in preclinical evaluation of gene editing therapies, and have successfully navigated the regulatory pathway for IND submission. Collectively they seek to bridge the gap between preclinical research that has yielded promising therapeutic strategies for rare diseases and the effective clinical delivery of safe and effective treatments to patients. Successful completion of project milestones has the potential to revolutionize the treatment of at least one of the diseases and provide a way forward for the other three, as well as a wide range of other rare genetic diseases.

From biology to clinic

The preclinical genome editing project is being launched at a time when FDA approval of therapies for some rare diseases is in the headlines, but the path to those approvals remains frustratingly difficult much of the time.

“There are many barriers to developing safe and effective treatments for rare diseases,” says Lutz, “including small patient groups, high costs and regulatory barriers. Our goal is to remove or overcome obstacles, bring a very promising new therapeutic strategy to the clinic, and directly benefit people with these diseases.”

NINDS focuses on neurological diseases, of course, but research supported by the Somatic Cell Gene Editing Program (SCGE) could have much broader implications in the rare disease community and the 7,000-10,000 rare genetic diseases affecting patients worldwide.

“Genetic mutations can cause some of the rarest and most devastating disorders of the nervous system and the whole body,” says Walter Koroshetz, MD, director of NINDS and co-chair of SCGE.

“Through large-scale efforts such as the somatic cell genome editing program, we are starting to bring tools into the clinic to edit these genetic mutations. While there are still challenges to overcome, the level of hope for effective treatments is high.”

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