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

KIF1A-Related Research

Whole exome sequencing in Serbian patients with hereditary spastic paraplegia

This year we’ve seen several studies investigating the genetics of hereditary spastic paraplegia (HSP), an umbrella of genetic neurological disorders that causes progressive mobility loss. There are over 80 known genes that cause HSP, including KIF1A, but many with symptomatic diagnosis don’t know their genetic mutation. In this week’s article, researchers in Serbia expanded genetic testing for adult HSP patients.

The authors’ previous work had used a gene panel that featured 13 HSP-associated genes. In this follow-up study, they used Whole Exome Sequencing (WES), a technique that checks for mutations across all coding genes (exomes). Whole Exome Sequencing can still miss certain types of mutations, like insertions, deletions, or extra/missing copies of a gene, but it is great at identifying single nucleotide mutations across the genome, allowing a more comprehensive search for HSP-related genes.

Using WES, researchers were able to identify likely causative mutations in 5 of 9 patients with negative results from the gene panel. In addition, they identified 7 mutations in 44 HSP patients who had no previous genetic testing, including a patient with a M210I KIF1A mutation and adolescent onset HSP.

This study highlights the fast advancement in our understanding of genetics, and the importance of renewed screening for patients without diagnoses. Broader access to genetic testing tends to benefit children first as it is used in prenatal and newborn screening, but there are many adults around the world living with rare disorders who stand to benefit as well. By reassessing samples from patients who had received negative results in the past, this study provided them with a second chance at answers about their HSP diagnosis.

Want to learn more about HSP? Check out a recent overview by our guest bloggers from Columbia University!

Rare Roundup

FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy

Gene-based therapies are in the news so often, and in so many contexts, that it can be difficult to know when and where progress is being made. We know that gene therapies are on the horizon, so it’s important to take note when groups make tangible progress.

This week the FDA approved Lenmeldy, a new gene therapy to treat metachromic leukodystrophy (MLD), a rare and fatal genetic disorder. In patients with MLD, immune cells lack an enzyme called ARSA that breaks down certain fat molecules in the nervous system, causing severe neurodegeneration.

This single-dose gene therapy works by genetically modifying patient stem cells to include an extra copy of the ARSA gene, and then transplanting those cells back into the patient. To date, 37 patients have received Lenmeldy, which “reduced risk of severe motor impairment or death.”

This type of transfusion administration would not likely be viable for KAND; KIF1A is expressed in neurons, which cannot be removed and replaced like immune cells. But this breakthrough is a cause for celebration for the rare disease community.

It also highlights the many challenges we face in developing these types of therapeutics; with these promising results and FDA approval, there are still many questions about making Lenmeldy accessible to the patients who need it. The gene therapy is currently the world’s most expensive medicine, priced at $4.25 million. As we continue to advance and develop similar therapies, it will take concerted efforts by patients, policymakers, and scientists to make treating genetic disorders more feasible.

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