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

Unfortunately, the translation of the accumulated knowledge to safe and effective therapies has lagged. There are many reasons to predict that the 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 (e.g., blocking protein production with anti-sense oligonucleotides) are at the forefront of the recent progress. But while they carry exciting promise 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 hard at work to develop safer therapies for rare genetic diseases that provide lasting benefit. Now Cathleen Lutz, Ph.D., of The Jackson Laboratory (JAX) is spearheading a major effort to implement a new genomic research tool—preclinical genomic editing—to cure rare neurological genetic diseases.

Beyond CRISPR
CRISPR has revolutionized gene editing, but as originally applied it involves double strand DNA breaks that leave absolutely no room for error in the clinic. Researchers have continued to enhance CRISPR methods, however, and they 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 new 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, $22.8M grant from the National Institute of Neurological Disorders and Stroke (NINDS), Lutz and collaborators at 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 investigational new drug (IND) application.

At JAX, Lutz will work closely with Associate Professor Steven Murray, Ph.D., who leads the preclinical mouse model core to develop, validate and optimize in vivo mouse models for each disease. Other collaborators have extensive experience and resources for producing virus-based gene-editing therapy delivery to tissues, possess deep expertise in preclinical evaluation of gene-editing therapeutics, and have successfully navigated the regulatory path to IND submission. Collectively they seek to close the gap between preclinical research that has produced promising rare disease therapy strategies and the actual clinical delivery of safe and effective treatments to patients. Successful completion of the project milestones has the potential to revolutionize treatment for 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 the clinic
The preclinical genome editing project is being launched at a time when FDA approval of therapies for a few rare diseases are in the headlines, but the path to such approvals remains frustratingly difficult most of the time.

"There are many obstacles to developing safe, effective treatments for rare diseases," says Lutz, "including small patient populations, high costs and regulatory barriers. Our goal is to remove or move past the obstacles, bring a highly promising new therapy strategy to the clinic, and directly benefit individuals with these diseases."

NINDS focuses on neurological diseases, of course, but the research supported by the Somatic Cell Gene Editing Program (SCGE) may have much larger implications across the rare disease community and the estimated 7,000-10,000 rare genetic diseases that affect patients worldwide.

"Genetic mutations can cause some of the most rare and devastating disorders of the nervous system and throughout the body," says Walter Koroshetz, M.D., director of NINDS and co-chair of SCGE.

"Thanks to large-scale efforts like the Somatic Cell Genome Editing Program, we are starting to bring tools into the clinic to edit out these gene mutations.  While there are still challenges to overcome, the level of hope for effective treatments is high."