Peay HL, Fischer R, Mange B, Paquin RS, Smith EC, Sadosky A, Russo L, Ricotti V, Rensch C, Morris C, Martin AS, Ganot A, Beaverson K, Mansfield C. Patients' and caregivers' maximum acceptable risk of death for non-curative gene therapy to treat Duchenne muscular dystrophy. Mol Genet Genomic Med. 2021 May;9(5):e1664. doi: 10.1002/mgg3.1664.

BACKGROUND: Gene therapy offers etiologically-targeted treatment for genetic disorders. Little is known about acceptance of mortality risk among patients with progressive, fatal conditions. We assessed patients’ and caregivers’ maximum acceptable risk (MAR) of mortality for gene therapy to treat Duchenne muscular dystrophy.

METHODS: Threshold technique was used to assess tolerance for mortality risks. Gene therapy was described as non-curative with 10-year benefit duration. MAR was analyzed using interval regression for therapy initiated “now”; in the last year of walking well; the last year able to bring arms to mouth; and in newborns (caregivers only).

RESULTS: 285 caregivers and 35 patients reported greatest MAR for therapy initiated in last year of lifting arms (mean MAR 6.3%), followed by last year of walking (4.4%), “now” (3.5%), and newborn (2.1% caregivers only). About 35% would accept ≥ 200/2000 risk in the last year of lifting arms. Non-ambulatory status predicted accepting 1.8 additional points in MAR “now” compared with ambulatory (p=0.010). Respondent type (caregiver or patient) did not predict MAR.

In this first quantitative study to assess MAR associated with first-generation Duchenne gene therapy, we find relatively high tolerance for mortality risk that increases with progression. This has implications for protocol development and informed consent processes.

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