Rare Diseases Report 2022

Rett syndrome: Looking to the future and the promise of gene therapy


 

The Taysha microRNA technology has yielded promising results in mouse studies for Rett syndrome; results indicate a lengthening of lifespan and delayed onset of gait abnormalities.51 TSHA-102 is in the preclinical stage but offers promise that it will be the first gene therapy for Rett syndrome to enter clinical trials.

As the field of gene therapy advances, several promising technologies are on the horizon that could potentially have disease-altering impacts on Rett syndrome. These therapies are divided into two broad categories: those at the gene level and those at the transcription and protein level. A few of these approaches are highlighted below.

Gene replacement involves adding a full or partial copy of MECP2 to neuronal cells. This type of therapy presents challenges, from delivery of the new gene to dosage concerns, because MECP2 can be toxic if overexpressed.52-54 Groundbreaking work was done in mouse models involving truncated MECP2, exhibiting phenotypic rescue and validating the gene-replacement approach.18 This strategy is being pursued by Neurogene, which has a uinique technology that allows for tuning of the gene’s expression to get the correct protein levels in the patient. Promising data was presented this year at the American Society of Gene and Cell Therapy conference.55

Early gene replacement therapy studies also laid the foundation for the minMECP2 and microRNA approach being used by Taysha Gene Therapies (discussed above).51

“Correcting” DNA mutations. A different approach at the genetic level involves “correcting” mutations in MECP2 at the DNA level. This is possible because, in a large subset of Rett syndrome patients who have the same missense or nonsense mutations, by using CRISPR, a gene editing tool (discussed above) a single base pair can be corrected.56,57 Previous research, in a Rett syndrome-model of induced pluripotent stem cells, showed that this type of editing is possible – and effective.52 An approach with particular promise involves use of a class of CRISPR proteins known as base editors that are able to specifically alter a single base of DNA.57 The technique has the potential to address many of the mutations seen in Rett syndrome; research on this type of technology is being pursued by Beam Therapeutics, and has the potential to impact Rett syndrome.58

Another promising “correction” approach is exonic editing, in which a much larger section of DNA – potentially, exons 3 and 4, which, taken together, comprise 97% of known MECP2 mutations seen in Rett syndrome – are replaced.59

In both CRISPR and exonic editing therapeutic approaches, endogenous levels of MECP2 expression would be maintained. Of note, both approaches are being pursued for use in treating other genetic disorders, which provides a boost in scaling-up work on addressing safety and efficacy concerns that accompany gene-editing approaches.58 One advantage to the DNA correction approach is that is has the potential to be a “one-and-done” treatment.

“Correcting” RNA. Beyond directly editing DNA, several therapeutic approaches are exploring the ability to edit RNA or to provide the protein directly to cells as enzyme replacement therapy. Such an RNA correction strategy leverages a technology that takes advantage of cells’ natural RNA editor, known as adenosine deaminase acting on RNA (ADAR), which corrects errors in cells’ RNA by providing specific guides to the cell. ADAR can be targeted to fix mutations in the MECP2 RNA transcript, resulting in a “corrected” MECP2 protein.60,61 This technology has delivered promising proof-of-concept evidence in cells and in murine models, and is in the therapeutic pipeline at VICO Therapeutics.62

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