Advancing Gene-Targeted Therapies for Central Nervous System Disorders Proceedings of a Workshop (2019) / Chapter Skim
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2 Exploring the Current Landscape of Central Nervous System Gene-Targeted Therapies
2 Exploring the Current Landscape of Central Nervous System Gene-Targeted Therapies
Pages 5-16
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From page 5... ...
. • The availability of naturally occurring large animal models of a genetic disease can expedite development of gene therapy by helping to define the dose range and magnitude and onset of treatment response, and to establish safety (Reape)
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Spinraza® in 2016 for spinal muscular atrophy (SMA) ; Luxturna™ in 2017 for a rare form of inherited retinal dystrophy; and most recently in 2019, the gene replacement therapy Zolgensma® for the treatment of SMA1 -- were built on a long history of gene therapy products that were tested in clinical trials, but never made it to the clinic, said Lamya Shihabuddin.
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From page 7... ...
-approved drug to treat SMA (Paton, 2017) , a rare autosomal-recessive neuromuscular disorder and the leading genetic cause of infant mortality, caused by mutations or deletions in the survival motor neuron 1 (SMN1)
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. Preclinical studies established proof of mechanism and biology, determined the pharmacokinetic and pharmacodynamic relationship, optimized delivery methods, and demonstrated a lack of toxicity, said Bennett (Paton, 2017)
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. These studies allowed them to demonstrate, for example, in an open-label Phase 2 study in infants with SMA type 1 that the survival benefit in patients treated with nusinersen differed markedly from the natural history of the disease and that benefits were greatest when infants were treated as early in the disease as possible, even before symptom onset (Finkel et al., 2016)
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They used an independent reading center with two masked adjudicators using a detailed grading protocol with clearly defined parameters for what constituted errors, passes, and fails. Secondary endpoints included full-field light sensitivity threshold testing, monocular MLMT performance, and visual acuity, as well as exploratory endpoints assessing visual fields, she said, adding that participants or parents also completed a visual function questionnaire to assess activities of daily living relevant to vision loss (Russell et al., 2017a)
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, which is able to cross the blood–brain barrier and reach motor neurons in the spinal cord. Inside the AAV9 capsid shell, a double-stranded piece of DNA has been created from the relevant parts of the transgene controlled by a promoter that enables sustained production of the missing SMN1 protein and flanked by inverted terminal repeats, which accelerate transcription of the transgene and production of a full-length functioning protein (Powell et al., 2015)
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From page 12... ...
as those in the intervention group who received voretigene at the beginning of the trial. SOURCES: Presented by Kathleen Reape, April 23, 2019; Russell et al., 2017a,b.
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NOTES: AAV2 = adeno-associated virus serotype 2; AAV9 = AAV serotype 9; BGH Poly A = bovine growth hormone polyadenylation; CB = chicken b-actin; cDNA = complementary DNA; CMV = cytomegalovirus; ITR = inverted terminal repeat; scAAV = self-complementary AAV; SMA = spinal muscular atrophy; SMN = survival motor neuron; SV = simian virus. SOURCE: Presented by Petra Kaufmann, April 23, 2019.
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"It's a real gift of altruism on the part of families to participate over often more than a year in a study when there is no treatment," she said. She credited not only the families, but also the SMA Foundation for funding the Pediatric Neuromuscular Clinical Research Network study, and the National Institute of Neurological Disorders and Stroke for funding the National Network for Excellence in Neuroscience Clinical Trials SMA Infant Biomarker Study, which enrolled and for 24 months followed 26 infants with genetically confirmed SMA and 27 age, sex, and birthweightmatched healthy infants.
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Because animals do not develop PD in nature, the models used in preclinical studies may not accurately reflect the disease process in humans. Preclinical studies, he said, should be designed not to be successful, but to inform clinical trials so that those trials will be successful.
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