#ScienceSaturday posts share exciting scientific developments and educational resources with the KAND community. Each week, Dr. Dominique Lessard and Dr. Dylan Verden of KIF1A.ORG summarize newly published KIF1A-related research and highlight progress in rare disease research and therapeutic development.

Rare Disease Research

Genome-wide Sequencing and the Clinical Diagnosis of Genetic Disease: The CAUSES Study

Genetic sequencing has created a new era of clinical diagnosis for many disorders – while diseases are often defined by their symptoms, knowing the root cause can help us better understand how these symptoms manifest, and how to approach treatment. However, genetic screening presents its own challenges: We all have many variants, or mutations, relative to the general population, and not all of these mutations create disease. Interpreting sequencing results to uncover which mutations are relevant for a patient is very difficult – we’ve discussed variants of uncertain significance (VUS) in recent Science Saturdays.

This week’s study that took place in Canada tackled clinical genetics in a holistic approach, bringing together “genome analysts, MD clinical geneticists, genetic counsellors, a PhD laboratory geneticist, and the referring physician” for each patient. These teams discussed patient genetics and symptoms to rank mutations by their likelihood to cause the observed disease traits, and the referring physician and a genetic counselor met with families to discuss the results. These teams continued to follow up with families over the course of five years, reassessing their diagnoses with new genetic information and progression of symptoms. Sometimes these diagnoses shifted – mutations that initially appeared significant were seen as less likely contributors, and mutations that were likely causal were determined in 17% of patients who didn’t have an initial diagnosis.

Studies like this show the importance of leveraging all our scientific and clinical resources when working with undiagnosed patients. Our understanding of genes and people is always advancing, and staying with patients throughout their diagnostic journey offers better chances of helping individuals with rare or uncertain disorders.

Rare Roundup

NORD adds Telehealth to its digital state report cards

In the era of COVID, telehealth has become further integrated into our idea of healthcare; helping patients while minimizing contact allowed physicians to limit the spread of COVID-19. But its benefits go beyond the pandemic, especially for patients whose diseases make lengthy travel to see specialists difficult. Telehealth lowers barriers to healthcare access and empowers patients to be proactive in seeking medical help.

Because traveling for healthcare is a source of undue burden on many rare disease patients, the National Organization of Rare Diseases (NORD) in the United States, has added telehealth to the Report Card it gives for each U.S. state’s healthcare system. The report card system was created in 2015 to provide information about states’ abilities to address the needs of rare disease communities, and is an incredible tool for informing patients and policymakers about targets for improvement.

The Telehealth Report Card currently rates each state as a Pass or Fail, but NORD intends to continue compiling data and provide more nuanced information about state-level implementation of telehealth for rare disease patients.

Enhancing gene therapy regulatory interactions, by Peter Marks

Developing gene therapies for genetic diseases is a novel and unique undertaking, but its therapeutic pipeline is still heavily entwined with that of traditional pharmaceuticals. Peter Marks, director of the Center for Biologics Evaluation and Research (CBER) in the U.S. FDA, has reflected on the challenges and opportunities facing the use of gene therapies to treat disease. Marks states that because many potential gene therapies may use the same delivery system, standardization offers hope for accelerating development and approval of such treatments.

“Specifically, current gene therapies use a vector backbone, currently most commonly adeno-associated virus (AAV) or a lentivirus, to deliver the transgene. Considering the ‘device-like’ quality of this vector backbone allows one to consider whether, within specific limits, one could reuse information related to the vector backbone to expedite the development of multiple gene therapy products.”

As technologies change, the regulations we use to evaluate and approve their use should advance as well. Dr. Marks’ thoughts provide insight into the ways researchers and clinicians may be able to set gene therapies up for success to help patients in need.

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