Vasodilator and Exercise Study for DMD (VASO-REx)

Summary

Examining two strategies as potential adjuvant therapies for Duchenne muscular dystrophy (DMD); aerobic exercise training (to induce adaptations in skeletal muscle and improve cardiovascular health) and tadalafil, an FDA-approved vasodilator (to optimize blood flow and muscle perfusion which is impaired and often overlooked in DMD). Target: improved muscle function, vascular health, and DMD treatment.

Timeline

Start

2024-06-05

Primary completion

2026-11

Completion

2026-11

Publications

• Background Lopez C, Taivassalo T, Berru MG, Saavedra A, Rasmussen HC, Batra A, Arora H, Roetzheim AM, Walter GA, Vandenborne K, Forbes SC. Postcontractile blood oxygenation level-dependent (BOLD) response in Duchenne muscular dystrophy. J Appl Physiol (1985). 2021 Jul 1;131(1):83-94. doi: 10.1152/japplphysiol.00634.2020. Epub 2021 May 20.
• Background Mendell JR, Sahenk Z, Lehman K, Nease C, Lowes LP, Miller NF, Iammarino MA, Alfano LN, Nicholl A, Al-Zaidy S, Lewis S, Church K, Shell R, Cripe LH, Potter RA, Griffin DA, Pozsgai E, Dugar A, Hogan M, Rodino-Klapac LR. Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. JAMA Neurol. 2020 Sep 1;77(9):1122-1131. doi: 10.1001/jamaneurol.2020.1484.
• Background Harper SQ. Molecular dissection of dystrophin identifies the docking site for nNOS. Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):387-8. doi: 10.1073/pnas.1220256110. Epub 2012 Dec 31. No abstract available.
• Background Duan D. Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy. Mol Ther. 2018 Oct 3;26(10):2337-2356. doi: 10.1016/j.ymthe.2018.07.011. Epub 2018 Jul 17.
• Background Percival JM, Adamo CM, Beavo JA, Froehner SC. Evaluation of the therapeutic utility of phosphodiesterase 5A inhibition in the mdx mouse model of duchenne muscular dystrophy. Handb Exp Pharmacol. 2011;(204):323-44. doi: 10.1007/978-3-642-17969-3_14.
• Background Thomas GD. Functional muscle ischemia in Duchenne and Becker muscular dystrophy. Front Physiol. 2013 Dec 18;4:381. doi: 10.3389/fphys.2013.00381.
• Background Kobayashi YM, Rader EP, Crawford RW, Iyengar NK, Thedens DR, Faulkner JA, Parikh SV, Weiss RM, Chamberlain JS, Moore SA, Campbell KP. Sarcolemma-localized nNOS is required to maintain activity after mild exercise. Nature. 2008 Nov 27;456(7221):511-5. doi: 10.1038/nature07414. Epub 2008 Oct 26.
• Background Sheffield-Moore M, Wiktorowicz JE, Soman KV, Danesi CP, Kinsky MP, Dillon EL, Randolph KM, Casperson SL, Gore DC, Horstman AM, Lynch JP, Doucet BM, Mettler JA, Ryder JW, Ploutz-Snyder LL, Hsu JW, Jahoor F, Jennings K, White GR, McCammon SD, Durham WJ. Sildenafil increases muscle protein synthesis and reduces muscle fatigue. Clin Transl Sci. 2013 Dec;6(6):463-8. doi: 10.1111/cts.12121. Epub 2013 Oct 29.
• Background Nelson MD, Rader F, Tang X, Tavyev J, Nelson SF, Miceli MC, Elashoff RM, Sweeney HL, Victor RG. PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology. 2014 Jun 10;82(23):2085-91. doi: 10.1212/WNL.0000000000000498. Epub 2014 May 7.
• Background Victor RG, Sweeney HL, Finkel R, McDonald CM, Byrne B, Eagle M, Goemans N, Vandenborne K, Dubrovsky AL, Topaloglu H, Miceli MC, Furlong P, Landry J, Elashoff R, Cox D; Tadalafil DMD Study Group. A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy. Neurology. 2017 Oct 24;89(17):1811-1820. doi: 10.1212/WNL.0000000000004570. Epub 2017 Sep 29.
• Background Hoffman EP. Pharmacotherapy of Duchenne Muscular Dystrophy. Handb Exp Pharmacol. 2020;261:25-37. doi: 10.1007/164_2019_256.
• Background Mah JK. An Overview of Recent Therapeutics Advances for Duchenne Muscular Dystrophy. Methods Mol Biol. 2018;1687:3-17. doi: 10.1007/978-1-4939-7374-3_1.
• Background Verhaart IEC, Aartsma-Rus A. Therapeutic developments for Duchenne muscular dystrophy. Nat Rev Neurol. 2019 Jul;15(7):373-386. doi: 10.1038/s41582-019-0203-3.
• Background Ramos JN, Hollinger K, Bengtsson NE, Allen JM, Hauschka SD, Chamberlain JS. Development of Novel Micro-dystrophins with Enhanced Functionality. Mol Ther. 2019 Mar 6;27(3):623-635. doi: 10.1016/j.ymthe.2019.01.002. Epub 2019 Feb 1.
• Background Lai Y, Thomas GD, Yue Y, Yang HT, Li D, Long C, Judge L, Bostick B, Chamberlain JS, Terjung RL, Duan D. Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. J Clin Invest. 2009 Mar;119(3):624-35. doi: 10.1172/JCI36612. Epub 2009 Feb 23.
• Background Khan N, Eliopoulos H, Han L, Kinane TB, Lowes LP, Mendell JR, Gordish-Dressman H, Henricson EK, McDonald CM; Eteplirsen Investigators and the CINRG DNHS Investigators. Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy. J Neuromuscul Dis. 2019;6(2):213-225. doi: 10.3233/JND-180351.
• Background Charleston JS, Schnell FJ, Dworzak J, Donoghue C, Lewis S, Chen L, Young GD, Milici AJ, Voss J, DeAlwis U, Wentworth B, Rodino-Klapac LR, Sahenk Z, Frank D, Mendell JR. Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production. Neurology. 2018 Jun 12;90(24):e2146-e2154. doi: 10.1212/WNL.0000000000005680. Epub 2018 May 11.
• Background Mendell JR, Engel WK, Derrer EC. Duchenne muscular dystrophy: functional ischemia reproduces its characteristic lesions. Science. 1971 Jun 11;172(3988):1143-5. doi: 10.1126/science.172.3988.1143.
• Background Rando TA. Role of nitric oxide in the pathogenesis of muscular dystrophies: a "two hit" hypothesis of the cause of muscle necrosis. Microsc Res Tech. 2001 Nov 15;55(4):223-35. doi: 10.1002/jemt.1172.
• Background Dietz AR, Connolly A, Dori A, Zaidman CM. Intramuscular blood flow in Duchenne and Becker Muscular Dystrophy: Quantitative power Doppler sonography relates to disease severity. Clin Neurophysiol. 2020 Jan;131(1):1-5. doi: 10.1016/j.clinph.2019.09.023. Epub 2019 Nov 4.
• Background Mutlu A, Alkan H, Firat T, Karaduman AA, Yilmaz OT. How do physical capacity, fatigue and performance differ in children with duchenne muscular dystrophy compared with their healthy peers? Neurosciences (Riyadh). 2018 Jan;23(1):39-45. doi: 10.17712/nsj.2018.1.20170242.
• Background Gentil C, Leturcq F, Ben Yaou R, Kaplan JC, Laforet P, Penisson-Besnier I, Espil-Taris C, Voit T, Garcia L, Pietri-Rouxel F. Variable phenotype of del45-55 Becker patients correlated with nNOSmu mislocalization and RYR1 hypernitrosylation. Hum Mol Genet. 2012 Aug 1;21(15):3449-60. doi: 10.1093/hmg/dds176. Epub 2012 May 15.
• Background Nelson MD, Rosenberry R, Barresi R, Tsimerinov EI, Rader F, Tang X, Mason O, Schwartz A, Stabler T, Shidban S, Mobaligh N, Hogan S, Elashoff R, Allen JD, Victor RG. Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy. J Physiol. 2015 Dec 1;593(23):5183-200. doi: 10.1113/JP271252. Epub 2015 Nov 2.
• Background Boehler JF, Ricotti V, Gonzalez JP, Soustek-Kramer M, Such L, Brown KJ, Schneider JS, Morris CA. Membrane recruitment of nNOSmicro in microdystrophin gene transfer to enhance durability. Neuromuscul Disord. 2019 Oct;29(10):735-741. doi: 10.1016/j.nmd.2019.08.009. Epub 2019 Aug 23.
• Background Balke JE, Zhang L, Percival JM. Neuronal nitric oxide synthase (nNOS) splice variant function: Insights into nitric oxide signaling from skeletal muscle. Nitric Oxide. 2019 Jan 1;82:35-47. doi: 10.1016/j.niox.2018.11.004. Epub 2018 Nov 29.
• Background Asai A, Sahani N, Kaneki M, Ouchi Y, Martyn JA, Yasuhara SE. Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy. PLoS One. 2007 Aug 29;2(8):e806. doi: 10.1371/journal.pone.0000806.
• Background De Arcangelis V, Strimpakos G, Gabanella F, Corbi N, Luvisetto S, Magrelli A, Onori A, Passananti C, Pisani C, Rome S, Severini C, Naro F, Mattei E, Di Certo MG, Monaco L. Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy. J Cell Physiol. 2016 Jan;231(1):224-32. doi: 10.1002/jcp.25075.
• Background Webster C, Silberstein L, Hays AP, Blau HM. Fast muscle fibers are preferentially affected in Duchenne muscular dystrophy. Cell. 1988 Feb 26;52(4):503-13. doi: 10.1016/0092-8674(88)90463-1.
• Background Batra A, Vohra RS, Chrzanowski SM, Hammers DW, Lott DJ, Vandenborne K, Walter GA, Forbes SC. Effects of PDE5 inhibition on dystrophic muscle following an acute bout of downhill running and endurance training. J Appl Physiol (1985). 2019 Jun 1;126(6):1737-1745. doi: 10.1152/japplphysiol.00664.2018. Epub 2019 Apr 4.
• Background McDonald CM, Henricson EK, Abresch RT, Florence JM, Eagle M, Gappmaier E, Glanzman AM; PTC124-GD-007-DMD Study Group; Spiegel R, Barth J, Elfring G, Reha A, Peltz S. The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. Muscle Nerve. 2013 Sep;48(3):343-56. doi: 10.1002/mus.23902. Epub 2013 Jun 26.
• Background Hoffman EP, Connor EM. Orphan drug development in muscular dystrophy: update on two large clinical trials of dystrophin rescue therapies. Discov Med. 2013 Nov;16(89):233-9.
• Background Fowler EG, Staudt LA, Heberer KR, Sienko SE, Buckon CE, Bagley AM, Sussman MD, McDonald CM. Longitudinal community walking activity in Duchenne muscular dystrophy. Muscle Nerve. 2018 Mar;57(3):401-406. doi: 10.1002/mus.25743. Epub 2017 Jul 28.
• Background McDonald CM, Henricson EK, Abresch RT, Han JJ, Escolar DM, Florence JM, Duong T, Arrieta A, Clemens PR, Hoffman EP, Cnaan A; Cinrg Investigators. The cooperative international neuromuscular research group Duchenne natural history study--a longitudinal investigation in the era of glucocorticoid therapy: design of protocol and the methods used. Muscle Nerve. 2013 Jul;48(1):32-54. doi: 10.1002/mus.23807. Epub 2013 May 16.
• Background Bloom TJ. Age-related alterations in cyclic nucleotide phosphodiesterase activity in dystrophic mouse leg muscle. Can J Physiol Pharmacol. 2005 Nov;83(11):1055-60. doi: 10.1139/y05-085.
• Background Witting N, Kruuse C, Nyhuus B, Prahm KP, Citirak G, Lundgaard SJ, von Huth S, Vejlstrup N, Lindberg U, Krag TO, Vissing J. Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy. Ann Neurol. 2014 Oct;76(4):550-7. doi: 10.1002/ana.24216. Epub 2014 Jul 15.
• Background Leung DG, Herzka DA, Thompson WR, He B, Bibat G, Tennekoon G, Russell SD, Schuleri KH, Lardo AC, Kass DA, Thompson RE, Judge DP, Wagner KR. Sildenafil does not improve cardiomyopathy in Duchenne/Becker muscular dystrophy. Ann Neurol. 2014 Oct;76(4):541-9. doi: 10.1002/ana.24214. Epub 2014 Jul 10.
• Background Zhang L, Zhang Z, Zhang RL, Cui Y, LaPointe MC, Silver B, Chopp M. Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke. Brain Res. 2006 Nov 6;1118(1):192-8. doi: 10.1016/j.brainres.2006.08.028. Epub 2006 Sep 7.
• Background Ledermann HP, Schulte AC, Heidecker HG, Aschwanden M, Jager KA, Scheffler K, Steinbrich W, Bilecen D. Blood oxygenation level-dependent magnetic resonance imaging of the skeletal muscle in patients with peripheral arterial occlusive disease. Circulation. 2006 Jun 27;113(25):2929-35. doi: 10.1161/CIRCULATIONAHA.105.605717. Epub 2006 Jun 19.
• Background Slade JM, Towse TF, Gossain VV, Meyer RA. Peripheral microvascular response to muscle contraction is unaltered by early diabetes but decreases with age. J Appl Physiol (1985). 2011 Nov;111(5):1361-71. doi: 10.1152/japplphysiol.00009.2011. Epub 2011 Jul 28.
• Background Towse TF, Slade JM, Ambrose JA, DeLano MC, Meyer RA. Quantitative analysis of the postcontractile blood-oxygenation-level-dependent (BOLD) effect in skeletal muscle. J Appl Physiol (1985). 2011 Jul;111(1):27-39. doi: 10.1152/japplphysiol.01054.2009. Epub 2011 Feb 17.
• Background Forbes SC, Walter GA, Rooney WD, Wang DJ, DeVos S, Pollaro J, Triplett W, Lott DJ, Willcocks RJ, Senesac C, Daniels MJ, Byrne BJ, Russman B, Finkel RS, Meyer JS, Sweeney HL, Vandenborne K. Skeletal muscles of ambulant children with Duchenne muscular dystrophy: validation of multicenter study of evaluation with MR imaging and MR spectroscopy. Radiology. 2013 Oct;269(1):198-207. doi: 10.1148/radiol.13121948. Epub 2013 May 21.
• Background Willcocks RJ, Rooney WD, Triplett WT, Forbes SC, Lott DJ, Senesac CR, Daniels MJ, Wang DJ, Harrington AT, Tennekoon GI, Russman BS, Finanger EL, Byrne BJ, Finkel RS, Walter GA, Sweeney HL, Vandenborne K. Multicenter prospective longitudinal study of magnetic resonance biomarkers in a large duchenne muscular dystrophy cohort. Ann Neurol. 2016 Apr;79(4):535-47. doi: 10.1002/ana.24599. Epub 2016 Feb 19.
• Background Forbes SC, Willcocks RJ, Triplett WT, Rooney WD, Lott DJ, Wang DJ, Pollaro J, Senesac CR, Daniels MJ, Finkel RS, Russman BS, Byrne BJ, Finanger EL, Tennekoon GI, Walter GA, Sweeney HL, Vandenborne K. Magnetic resonance imaging and spectroscopy assessment of lower extremity skeletal muscles in boys with Duchenne muscular dystrophy: a multicenter cross sectional study. PLoS One. 2014 Sep 9;9(9):e106435. doi: 10.1371/journal.pone.0106435. eCollection 2014.
• Background Hurley DM, Williams ER, Cross JM, Riedinger BR, Meyer RA, Abela GS, Slade JM. Aerobic Exercise Improves Microvascular Function in Older Adults. Med Sci Sports Exerc. 2019 Apr;51(4):773-781. doi: 10.1249/MSS.0000000000001854.
• Background Towse TF, Slade JM, Meyer RA. Effect of physical activity on MRI-measured blood oxygen level-dependent transients in skeletal muscle after brief contractions. J Appl Physiol (1985). 2005 Aug;99(2):715-22. doi: 10.1152/japplphysiol.00272.2005. Epub 2005 Mar 31.
• Background Yoo JK, Pinto MM, Kim HK, Hwang CL, Lim J, Handberg EM, Christou DD. Sex impacts the flow-mediated dilation response to acute aerobic exercise in older adults. Exp Gerontol. 2017 May;91:57-63. doi: 10.1016/j.exger.2017.02.069. Epub 2017 Feb 16.
• Background Kim SH, Choi YH, Cheon JE, Shin SM, Cho HH, Lee SM, You SK, Kim WS, Kim IO. Transient flow response after femoral artery catheterization for diagnostic neuroangiography in infants and children: Doppler US assessment of the ipsilateral femoral artery. Pediatr Radiol. 2015 Jan;45(1):86-93. doi: 10.1007/s00247-014-3071-4. Epub 2014 Jul 6.
• Background Ely MR, Ratchford SM, La Salle DT, Trinity JD, Wray DW, Halliwill JR. Effect of histamine-receptor antagonism on leg blood flow during exercise. J Appl Physiol (1985). 2020 Jun 1;128(6):1626-1634. doi: 10.1152/japplphysiol.00689.2019. Epub 2020 May 14.
• Background Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology. 2003 Jul;62(1):121-5; discussion 125-6. doi: 10.1016/s0090-4295(03)00359-5.
• Background Taivassalo T, Jensen TD, Kennaway N, DiMauro S, Vissing J, Haller RG. The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain. 2003 Feb;126(Pt 2):413-23. doi: 10.1093/brain/awg028.
• Background Miller NF, Alfano LN, Iammarino MA, Connolly AM, Moore-Clingenpeel M, Powers BR, Tsao CY, Waldrop MA, Flanigan KM, Mendell JR, Lowes LP. Natural History of Steroid-Treated Young Boys With Duchenne Muscular Dystrophy Using the NSAA, 100m, and Timed Functional Tests. Pediatr Neurol. 2020 Dec;113:15-20. doi: 10.1016/j.pediatrneurol.2020.08.013. Epub 2020 Aug 27.
• Background Benitez-Porres J, Lopez-Fernandez I, Raya JF, Alvarez Carnero S, Alvero-Cruz JR, Alvarez Carnero E. Reliability and Validity of the PAQ-C Questionnaire to Assess Physical Activity in Children. J Sch Health. 2016 Sep;86(9):677-85. doi: 10.1111/josh.12418.
• Background Gregor RJ, Broker JP, Ryan MM. The biomechanics of cycling. Exerc Sport Sci Rev. 1991;19:127-69. No abstract available.
• Background Power LC, Gusso S, Hornung TS, Jefferies C, Derraik JGB, Hofman PL, O'Grady GL. Exercise Cardiac Magnetic Resonance Imaging in Boys With Duchenne Muscular Dystrophy Without Cardiac Disease. Pediatr Neurol. 2021 Apr;117:35-43. doi: 10.1016/j.pediatrneurol.2020.12.011. Epub 2020 Dec 30.
• Background Laszlo G. Standardisation of lung function testing: helpful guidance from the ATS/ERS Task Force. Thorax. 2006 Sep;61(9):744-6. doi: 10.1136/thx.2006.061648.
• Background McDonald CM, Widman L, Abresch RT, Walsh SA, Walsh DD. Utility of a step activity monitor for the measurement of daily ambulatory activity in children. Arch Phys Med Rehabil. 2005 Apr;86(4):793-801. doi: 10.1016/j.apmr.2004.10.011.
• Background Washington SL 3rd, Shindel AW. A once-daily dose of tadalafil for erectile dysfunction: compliance and efficacy. Drug Des Devel Ther. 2010 Sep 7;4:159-71. doi: 10.2147/dddt.s9067.
• Background Exercise Physiology In Special Populations. New York: Churchill Livingston Elsevier, 2008.
• Background Taivassalo T, Shoubridge EA, Chen J, Kennaway NG, DiMauro S, Arnold DL, Haller RG. Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Ann Neurol. 2001 Aug;50(2):133-41. doi: 10.1002/ana.1050.
• Background Henrie AM, Nawarskas JJ, Anderson JR. Clinical utility of tadalafil in the treatment of pulmonary arterial hypertension: an evidence-based review. Core Evid. 2015 Nov 2;10:99-109. doi: 10.2147/CE.S58457. eCollection 2015.
• Background Sabri MR, Beheshtian E. Comparison of the therapeutic and side effects of tadalafil and sildenafil in children and adolescents with pulmonary arterial hypertension. Pediatr Cardiol. 2014 Apr;35(4):699-704. doi: 10.1007/s00246-013-0840-z. Epub 2013 Nov 20.
• Background Shiva A, Shiran M, Rafati M, Zamani H, Babazadeh K, Saeedi M, Ala S. Oral Tadalafil in Children with Pulmonary Arterial Hypertension. Drug Res (Stuttg). 2016 Jan;66(1):7-10. doi: 10.1055/s-0034-1395510. Epub 2015 Jan 22.
• Background Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary arterial hypertension. Pediatr Cardiol. 2012 Jun;33(5):683-8. doi: 10.1007/s00246-012-0180-4. Epub 2012 Mar 9.
• Background Yamazaki H, Kobayashi N, Taketsuna M, Tajima K, Suzuki N, Murakami M. Safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension: a sub-group analysis based on Japan post-marketing surveillance. Curr Med Res Opin. 2017 Dec;33(12):2241-2249. doi: 10.1080/03007995.2017.1354832. Epub 2017 Jul 20.
• Background Ferguson-Sells L, Velez de Mendizabal N, Li B, Small D. Population Pharmacokinetics of Tadalafil in Pediatric Patients with Pulmonary Arterial Hypertension: A Combined Adult/Pediatric Model. Clin Pharmacokinet. 2022 Feb;61(2):249-262. doi: 10.1007/s40262-021-01052-8. Epub 2021 Aug 11.
• Background Martin EA, Barresi R, Byrne BJ, Tsimerinov EI, Scott BL, Walker AE, Gurudevan SV, Anene F, Elashoff RM, Thomas GD, Victor RG. Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy. Sci Transl Med. 2012 Nov 28;4(162):162ra155. doi: 10.1126/scitranslmed.3004327.

Drugs

Indications