Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease

  1. Surender Rajasekaran  Is a corresponding author
  2. Caleb P Bupp
  3. Mara Leimanis-Laurens
  4. Ankit Shukla
  5. Christopher Russell
  6. Joseph Junewick
  7. Emily Gleason
  8. Elizabeth A VanSickle
  9. Yvonne Edgerly
  10. Bryan M Wittmann
  11. Jeremy W Prokop
  12. André S Bachmann  Is a corresponding author
  1. Pediatric Critical Care Medicine, Helen DeVos Children’s Hospital, United States
  2. Spectrum Health Office of Research and Education, United States
  3. Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, United States
  4. Medical Genetics, Spectrum Health and Helen DeVos Children’s Hospital, United States
  5. Department of Pharmacy, Helen DeVos Children’s Hospital, United States
  6. Department of Diagnostic Radiology, Spectrum Health and Helen DeVos Children's Hospital, United States
  7. Metabolon, United States
  8. Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, United States

Abstract

Background:

Polyamine levels are intricately controlled by biosynthetic, catabolic enzymes and antizymes. The complexity suggests that minute alterations in levels lead to profound abnormalities. We described the therapeutic course for a rare syndrome diagnosed by whole exome sequencing caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC), characterized by neurological deficits and alopecia.

Methods:

N-acetylputrescine levels with other metabolites were measured using ultra-performance liquid chromatography paired with mass spectrometry and Z-scores established against a reference cohort of 866 children.

Results:

From previous studies and metabolic profiles, eflornithine was identified as potentially beneficial with therapy initiated on FDA approval. Eflornithine normalized polyamine levels without disrupting other pathways. She demonstrated remarkable improvement in both neurological symptoms and cortical architecture. She gained fine motor skills with the capacity to feed herself and sit with support.

Conclusions:

This work highlights the strategy of repurposing drugs to treat a rare disease.

Funding:

No external funding was received for this work.

Introduction

Ornithine decarboxylase (ODC) is a rate-limiting enzyme in the biosynthesis of polyamines (putrescine, spermidine, spermine), which orchestrate essential physiological and pathologic processes including embryogenesis, organogenesis, and neoplastic cell growth (Bello-Fernandez et al., 1993; Pendeville et al., 2001). We recently described a new autosomal dominant genetic disorder (Bachmann-Bupp syndrome, OMIM #619075) caused by a heterozygous de novo variant in the ODC1 gene in a 3-year-old girl with phenotypic features that included alopecia universalis and global developmental delay (Figure 1; Bupp et al., 2018). The nonsense variant caused premature abrogation of 14-aa residues in the C-terminus of the protein (ODC, p·K448X, Figure 2), leading to enhanced function. Red blood cells from the patient exhibited elevated ODC activity and putrescine levels compared to healthy controls. Four additional patients with similar mutations and phenotypic features of this syndrome have since been reported (Rodan et al., 2018) and at least four more cases have been identified.

Patient phenotypes and metabolites before and after eflornithine treatment.

Panel A shows the timeline of events for the patient with milestones marked on the top and clinical observations below. Panels B-C show hair growth and muscle tone are the most noticeable phenotype changes with treatment. Follicular cysts recurred on back, neck, and posterior scalp (bottom left images). First hair growth was eyebrows 1 month into treatment (bottom right images). Panel D shows MRI before and after eflornithine treatment. Neonatal: Axial T1 (TR 483 ms, TE 9 ms, and flip angle 63 degrees), T2 (TR 3250 ms, TE 220 ms, and flip angle 90 degrees), and T2-FLAIR (TR 8002 ms, TE 122 ms, and flip angle 90 degrees) show marked abnormal signal of cerebral white matter (*) and several subependymal cysts (arrows). Five years of age: Axial T1 (TR 809 ms, TE 16 ms, and flip angle 111 degrees), T2 (TR 4850 ms, TE 107 ms, and flip angle 142 degrees), and T2-FLAIR (TR 6002 ms, TE 91 ms, and flip angle 90 degrees) show decrease in cerebral white matter volume, but normalization of signal and resolution of subependymal cysts.

ODC1/ODC clinical variant c.1342 A > T/ p.K448X and support for eflornithine treatment.

Panel A shows the gene structure for ODC1 (ornithine decarboxylase 1) with active site amino acids labeled in blue and the last exon identified. In the last exon cluster, a mouse model variant and four different patient variants including our patient’s K448X variant are described (Panel B, red). The patient variant falls on the disordered C-terminus of ODC, where the two active sites are composed of amino acids from each of two ODC proteins forming a dimer (Panel C). The patient with K448X variant displays alterations of metabolic pathways (Panel D) including polyamines (triangle), urea (square), and others (circle). Metabolites measured are marked in cyan and those altered by K448X with red arrows based on direction of changes seen in the patient. Panel E shows changes in metabolite levels during treatment with eflornithine, with elevated levels of N-acetylputrescine and acisoga decreasing on therapy.

Remarkably, these patients all represent human phenotypes of a transgenic mouse described in 1996, overexpressing C-terminally deleted ODC in the dermal tissue, leading to higher ODC enzyme activity and increased putrescine biosynthesis (Soler et al., 1996). The phenotypic changes first described in a mouse model included hair loss that was reversible with ODC inhibitor α-difluoromethylornithine (DFMO; common name eflornithine) (Soler et al., 1996). Experiments with the patient’s cultured primary dermal fibroblasts showed eflornithine reduced ODC activity, resulting in putrescine levels comparable to controls without affecting cell morphology or inducing cell death (Schultz et al., 2019).

Based on previously published murine data with eflornithine for gain-of-function variants (Soler et al., 1996), multiple long-term safety studies for clinical use in African sleeping sickness (trypanosomiasis), colorectal cancer, and neuroblastoma (Alirol et al., 2013; Priotto et al., 2009; Saulnier Sholler et al., 2015; Meyskens et al., 2008), and the absense of toxicity in the patient’s primary cell culture inresponse to eflornithine (Schultz et al., 2019), we surmised eflornithine might be a novel therapy for patients with this syndrome.

Materials and methods

Key resources table
Reagent type
(species) or
resource
DesignationSource or
reference
IdentifiersAdditional
information
Gene (Homo sapiens)ODC1NCBI GeneGene ID: 4953https://www.ncbi.nlm.nih.gov/gene/4953
Chemical compound, drugEflornithine (DFMO)Sanofi Aventis Supplied for studyhttps://pubchem.ncbi.nlm.nih.gov/compound/Eflornithine
Biological sample (Homo sapiens)Blood EDTA tubesFreshly isolated blood from patient
Software, algorithmYASARAYASARAhttp://www.yasara.org/Protein modelling
Commercial assay or kitLiquid chromatography paired massspectrometryMetabolon, Morrisville, NChttps://www.metabolon.com/

Study participants and consent 

Request a detailed protocol

Following FDA approval of our single-patient Investigational New Drug (IND) Application (144022) as a compassionate use treatment protocol, the study was further reviewed and approved by the Spectrum Health Institutional Review Board (IRB). IRB approval for sample collection with informed consent was received to conduct global metabolomics that included, among others, the polyamine metabolites spermidine and N-acetylputrescine.

The patient first presented at Spectrum Health, Helen DeVos Children’s Hospital (Grand Rapids, MI) at 11 months of age (Figure 1A). We diagnosed the ODC C-terminal deletion at age 19 months through whole exome sequencing and characterized the metabolic dyshomeostasis by 32 months (ODC protein and polyamine abnormalities). Eflornithine oral solution was prepared by diluting the lyophilized powder with purified water to a final concentration of 100 mg/mL. At age 4 years and 8 months, we started eflornithine (Sanofi Aventis) treatment with 500 mg/m2/dose bid twice daily via a gastrostomy tube along with a low polyamine diet on November 14, 2019, for 3 months, increasing to 750 mg/m2/dose twice daily, and a final increase to 1000 mg/m2/dose twice daily after 3.5 months. Dosing was based on what had been demonstrated to be safe in pediatric patients in maintenance therapy for neuroblastoma treated with eflornithine (Saulnier Sholler et al., 2015).

Blood collection and processing

Request a detailed protocol

EDTA blood tubes collected from the patient were mixed by inversion 8–10 times, centrifuged at 1000×g for 10 min at 4°C to separate plasma (minimum of 0.25 mL, free of hemolysis from red blood cells) from cellular fraction, and both fractions were immediately placed at −80°C. The plasma specimens were coded and anonymized, kept frozen, and shipped in batch to Metabolon, Morrisville, NC, for metabolomics analysis. N-acetylputrescine, the only polyamine that meets CAP/CLIA standards in this analysis, served as the primary indicator of putrescine levels. N-acetylputrescine and additional metabolites meeting CAP/CLIA standards (Figure 2E) and supplemental metabolites were measured in the EDTA plasma samples using ultra-performance liquid chromatography paired with mass spectrometry and Z-scores were calculated for each metabolite against a reference cohort of 866 pediatric patients as described previously (Squitti et al., 2019).

Blood draws for polyamine levels were obtained at initiation of therapy, 1-week post-initiation, immediately prior to each dose increase and then 7 days after each dose increase. These draws were performed in conjunction with safety screening, which included a complete blood count, liver function test, lactate dehydrogenase, complete metabolic panel, calcium, magnesium, and phosphate.

Results

The novel treatment of this ultra-rare (less than 10 known cases) genetic syndrome presented unique challenges for monitoring efficacy over time. Growth parameters and metabolite levels were monitored easily, whereas others such as cognitive and motor functioning proved challenging, making us dependent on her standardized neurological examination.

Eflornithine improves clinical findings

The patient was born with a full head of silver-blond hair similar to a previously described murine phenotype (Soler et al., 1996), which fell out in early months and she remained hairless other than a few scattered, long hairs on the scalp. One month into treatment, hair growth was noted, with eyebrows appearing first (Figure 1B–C). Two months into treatment, scalp hair began to diffusely appear in the normal pattern of hair distribution increasing to resemble normal growth for age (Figure 1). She had a history of recurring follicular cyst formation and enlargement. Multiple lesions located on the posterior scalp and back that first were small maculopapular pustules slowly increased in size to approximately 6–7 cm in diameter (Figure 1B). These lysed spontaneously, but some would enlarge until painful, requiring surgical removal. Upon initiation of eflornithine, the formation of cysts ceased immediately (Figure 1B).

Prior to therapy, she had delayed development which manifested with no standing, cruising, or sitting, and limited fine motor skills. Her BMI increased during eflornithine treatment from 25th percentile to 90th percentile primarily due to increase in weight. This quantitative change was not accompanied by any change in body habitus but rather an increase in muscle bulk. She gained muscle strength demonstrated by acquisition of her ability to hold up her head without support (Figure 1B). As the video file shows after 4 months of eflornithine therapy, she was able to sit unsupported and maintain posture with the physical therapist providing resistance, use a walker, and feed herself with a spoon with some assistance. Video 1 allows for optimal visualization of this rapid improvement of our patient with this gain-of-function mutation in the ODC1 gene. The drastic external change in hair growth, and visible improvement in coordination, attention, and interaction can be clearly seen.

Video 1
Treatment progression after 4 months of eflornithine therapy.

A neonatal brain MRI showed abnormal cerebral white matter and subependymal cysts (Figure 1D). Repeat MRI done at the end of the 9-month treatment trial with eflornithine demonstrated normalization of the cerebral white matter signal with decrease in volume with white matter loss and resolution of all previously noted cysts. Post-treatment magnetic resonance spectroscopy was also performed showing normalization of the N-acetylaspartate and choline signals relative to creatine Figure 1D.

Eflornithine normalizes metabolomic findings

N-acetylputrescine, the only polyamine metabolite measurement that is CAP/CLIA-certified, was quantified in addition to others using a global metabolomics approach (Figure 2) before and after initiating therapy with eflornithine. Metabolite levels from a reference cohort of 866 pediatric patients were converted into Z-scores, a calculation of standard deviations from the mean of the reference populationthat our patient’s values are compared to. In the global analysis of 915 metabolites of the patient before treatment, a total of 16 had values above the 97.5th percentile and 38 below the 2.5th percentile, with a noted difference in polyamine connected metabolites (Source data 1) without any marked disruption of any other metabolic pathways on treatment. The initial elevation of both N-acetylputrescine as well as the polyamine metabolite N-(3-acetamidopropyl) pyrrolidin-2-one (acisoga), which were above the 97.5th percentile, decreased at initiation of therapy and remained reduced at all time points (Figure 2), indicating that eflornithine treatment had the expected effect. Ornithine and N-acetylarginine were below the 2.5th percentile at start of therapy and normalized to the larger pediatric values over the course of therapy. Urea cycle components citrulline and arginine, along with other metabolites, remained at 1 to −1 standard deviation throughout the study period (Figure 2).

Discussion

The introduction of both whole genome and exome sequencing into clinical practice has led to rare diseases being diagnosed at rates never before seen (Turro et al., 2020; Tarailo-Graovac et al., 2016; Splinter et al., 2018). There are over 6000 rare diseases (incidence of greater than 1 in 2000 people) with over 300 million people worldwide affected (Nguengang Wakap et al., 2020). Though collectively common, each rare disease is unique making it challenging to develop specific therapies.

The process of developing treatment options for these rare diseases starts with a description of the genetic abnormality and developing an understanding of the molecular disruptions downstream from the affected protein. Once the biochemical perturbations are identified, then the quest to identify a drug that will return molecular pathways to normal begins. In genetic diseases, the correct mechanism to adopt could be challenging as many options exist such as activating or repressing pathways, enzyme blockade therapy, gene therapy regimens (Mendell et al., 2017), and potentially circumventing or correcting a genetic mutation such as treatments for muscular dystrophy (Iyer et al., 2019). Taking a genetic defect to human trials requires cell cultures, animal studies, and phased trials to determine safety and efficacy of such therapies. For multiple patients, often with unique genetic variants, to see benefit from this process could take the best part of a decade even as identification of successful drugs has been enhanced by the Orphan Drug Act (Augustine et al., 2013; Griggs et al., 2009).

We show a more rapid strategy of matching a patient with an ultra-rare newly identified syndrome to a drug with subsequent treatment being able to safely correct many phenotypic features. Once the whole exome identified the biochemical pathway, we used data from a previously described transgenic mouse model and our published cell culture study to surmise, eflornithine therapy could be of benefit to the patient. Though experimental data suggested that eflornithine could be beneficial, there is a chasm between ex vivo and in vivo studies with difficulties in extrapolating efficacy or safety from a fibroblast study alone (Schultz et al., 2019). We were fortunate that studies existed for eflornithine in a large enough population to suggest dosage and safety (Alirol et al., 2013; Priotto et al., 2009; Saulnier Sholler et al., 2015; Meyskens et al., 2008).

Once therapy was initiated, some neurological improvement in the patient was noted with better posture, weight gain, reduction, elimination of cyst formation, and significant hair growth. Six months into therapy, she had fine motor capability that she previously lacked, such as the capacity to feed herself and sit with some support. Brain imaging also showed changes that are beyond what would be explained merely by the passage of time, suggesting improvement related to eflornithine treatment.

While COVID-19 restrictions interrupted neurological assessments over the treatment period, the improvements noted throughout the relatively short treatment period of 6 months are truly remarkable, especially given the neurological deterioration in the patient prior to eflornithine therapy. This could be especially consequential if we could initiate therapy in a neonate diagnosed early before neurological damage occurs. We are now aware of other patients identified that present with similar gain-of-function ODC variants and polyamine abnormalities such as elevated N-acetylputrescine (Rodan et al., 2018). The therapy outlined here should allow for replication of the findings with a promise for significant improvement in quality of life for these patients. For such patients we recommend continued monitoring of multiple metabolites including N-acetylputrescine and acisoga to ensure that eflornithine dosing and urea/polyamine metabolite levels stay within normal ranges. The advent of global metabolomics presents a unique opportunity not only to develop a complete understanding of the dyshomeostasis prior to therapy but also a way to appreciate the drug’s impact on interconnected metabolic cycles simultaneously and perhaps a means of identifying disruptions early and predicting adverse effects. This may lead to earlier initiation of therapy in future patients, thereby perhaps avoiding some of the neurological delay that has come to characterize the disease in our patient.

Conclusion

In this study we have laid forth a promising example of going from first publication of a new syndrome to FDA-approved single-patient investigational repurposed drug treatment in 16 months, a methodology and speed rarely seen in the clinical science of rare diseases.

Data availability

Data is provided in Source data 1.

References

    1. Turro E
    2. Astle WJ
    3. Megy K
    4. Gräf S
    5. Greene D
    6. Shamardina O
    7. Allen HL
    8. Sanchis-Juan A
    9. Frontini M
    10. Thys C
    11. Stephens J
    12. Mapeta R
    13. Burren OS
    14. Downes K
    15. Haimel M
    16. Tuna S
    17. Deevi SVV
    18. Aitman TJ
    19. Bennett DL
    20. Calleja P
    21. Carss K
    22. Caulfield MJ
    23. Chinnery PF
    24. Dixon PH
    25. Gale DP
    26. James R
    27. Koziell A
    28. Laffan MA
    29. Levine AP
    30. Maher ER
    31. Markus HS
    32. Morales J
    33. Morrell NW
    34. Mumford AD
    35. Ormondroyd E
    36. Rankin S
    37. Rendon A
    38. Richardson S
    39. Roberts I
    40. Roy NBA
    41. Saleem MA
    42. Smith KGC
    43. Stark H
    44. Tan RYY
    45. Themistocleous AC
    46. Thrasher AJ
    47. Watkins H
    48. Webster AR
    49. Wilkins MR
    50. Williamson C
    51. Whitworth J
    52. Humphray S
    53. Bentley DR
    54. Abbs S
    55. Abulhoul L
    56. Adlard J
    57. Ahmed M
    58. Aitman TJ
    59. Alachkar H
    60. Allsup DJ
    61. Almeida-King J
    62. Ancliff P
    63. Antrobus R
    64. Armstrong R
    65. Arno G
    66. Ashford S
    67. Astle WJ
    68. Attwood A
    69. Aurora P
    70. Babbs C
    71. Bacchelli C
    72. Bakchoul T
    73. Banka S
    74. Bariana T
    75. Barwell J
    76. Batista J
    77. Baxendale HE
    78. Beales PL
    79. Bennett DL
    80. Bentley DR
    81. Bierzynska A
    82. Biss T
    83. Bitner-Glindzicz MAK
    84. Black GC
    85. Bleda M
    86. Blesneac I
    87. Bockenhauer D
    88. Bogaard H
    89. Bourne CJ
    90. Boyce S
    91. Bradley JR
    92. Bragin E
    93. Breen G
    94. Brennan P
    95. Brewer C
    96. Brown M
    97. Browning AC
    98. Browning MJ
    99. Buchan RJ
    100. Buckland MS
    101. Bueser T
    102. Diz CB
    103. Burn J
    104. Burns SO
    105. Burren OS
    106. Burrows N
    107. Calleja P
    108. Campbell C
    109. Carr-White G
    110. Carss K
    111. Casey R
    112. Caulfield MJ
    113. Chambers J
    114. Chambers J
    115. Chan MMY
    116. Cheah C
    117. Cheng F
    118. Chinnery PF
    119. Chitre M
    120. Christian MT
    121. Church C
    122. Clayton-Smith J
    123. Cleary M
    124. Brod NC
    125. Coghlan G
    126. Colby E
    127. Cole TRP
    128. Collins J
    129. Collins PW
    130. Colombo C
    131. Compton CJ
    132. Condliffe R
    133. Cook S
    134. Cook HT
    135. Cooper N
    136. Corris PA
    137. Furnell A
    138. Cunningham F
    139. Curry NS
    140. Cutler AJ
    141. Daniels MJ
    142. Dattani M
    143. Daugherty LC
    144. Davis J
    145. De Soyza A
    146. Deevi SVV
    147. Dent T
    148. Deshpande C
    149. Dewhurst EF
    150. Dixon PH
    151. Douzgou S
    152. Downes K
    153. Drazyk AM
    154. Drewe E
    155. Duarte D
    156. Dutt T
    157. Edgar JDM
    158. Edwards K
    159. Egner W
    160. Ekani MN
    161. Elliott P
    162. Erber WN
    163. Erwood M
    164. Estiu MC
    165. Evans DG
    166. Evans G
    167. Everington T
    168. Eyries M
    169. Fassihi H
    170. Favier R
    171. Findhammer J
    172. Fletcher D
    173. Flinter FA
    174. Floto RA
    175. Fowler T
    176. Fox J
    177. Frary AJ
    178. French CE
    179. Freson K
    180. Frontini M
    181. Gale DP
    182. Gall H
    183. Ganesan V
    184. Gattens M
    185. Geoghegan C
    186. Gerighty TSA
    187. Gharavi AG
    188. Ghio S
    189. Ghofrani H-A
    190. Gibbs JSR
    191. Gibson K
    192. Gilmour KC
    193. Girerd B
    194. Gleadall NS
    195. Goddard S
    196. Goldstein DB
    197. Gomez K
    198. Gordins P
    199. Gosal D
    200. Gräf S
    201. Graham J
    202. Grassi L
    203. Greene D
    204. Greenhalgh L
    205. Greinacher A
    206. Gresele P
    207. Griffiths P
    208. Grigoriadou S
    209. Grocock RJ
    210. Grozeva D
    211. Gurnell M
    212. Hackett S
    213. Hadinnapola C
    214. Hague WM
    215. Hague R
    216. Haimel M
    217. Hall M
    218. Hanson HL
    219. Haque E
    220. Harkness K
    221. Harper AR
    222. Harris CL
    223. Hart D
    224. Hassan A
    225. Hayman G
    226. Henderson A
    227. Herwadkar A
    228. Hoffman J
    229. Holden S
    230. Horvath R
    231. Houlden H
    232. Houweling AC
    233. Howard LS
    234. Hu F
    235. Hudson G
    236. Hughes J
    237. Huissoon AP
    238. Humbert M
    239. Humphray S
    240. Hunter S
    241. Hurles M
    242. Irving M
    243. Izatt L
    244. James R
    245. Johnson SA
    246. Jolles S
    247. Jolley J
    248. Josifova D
    249. Jurkute N
    250. Karten T
    251. Karten J
    252. Kasanicki MA
    253. Kazkaz H
    254. Kazmi R
    255. Kelleher P
    256. Kelly AM
    257. Kelsall W
    258. Kempster C
    259. Kiely DG
    260. Kingston N
    261. Klima R
    262. Koelling N
    263. Kostadima M
    264. Kovacs G
    265. Koziell A
    266. Kreuzhuber R
    267. Kuijpers TW
    268. Kumar A
    269. Kumararatne D
    270. Kurian MA
    271. Laffan MA
    272. Lalloo F
    273. Lambert M
    274. Allen HL
    275. Lawrie A
    276. Layton DM
    277. Lench N
    278. Lentaigne C
    279. Lester T
    280. Levine AP
    281. Linger R
    282. Longhurst H
    283. Lorenzo LE
    284. Louka E
    285. Lyons PA
    286. Machado RD
    287. MacKenzie Ross RV
    288. Madan B
    289. Maher ER
    290. Maimaris J
    291. Malka S
    292. Mangles S
    293. Mapeta R
    294. Marchbank KJ
    295. Marks S
    296. Markus HS
    297. Marschall H-U
    298. Marshall A
    299. Martin J
    300. Mathias M
    301. Matthews E
    302. Maxwell H
    303. McAlinden P
    304. McCarthy MI
    305. McKinney H
    306. McMahon A
    307. Meacham S
    308. Mead AJ
    309. Castello IM
    310. Megy K
    311. Mehta SG
    312. Michaelides M
    313. Millar C
    314. Mohammed SN
    315. Moledina S
    316. Montani D
    317. Moore AT
    318. Morales J
    319. Morrell NW
    320. Mozere M
    321. Muir KW
    322. Mumford AD
    323. Nemeth AH
    324. Newman WG
    325. Newnham M
    326. Noorani S
    327. Nurden P
    328. O’Sullivan J
    329. Obaji S
    330. Odhams C
    331. Okoli S
    332. Olschewski A
    333. Olschewski H
    334. Ong KR
    335. Oram SH
    336. Ormondroyd E
    337. Ouwehand WH
    338. Palles C
    339. Papadia S
    340. Park S-M
    341. Parry D
    342. Patel S
    343. Paterson J
    344. Peacock A
    345. Pearce SH
    346. Peden J
    347. Peerlinck K
    348. Penkett CJ
    349. Pepke-Zaba J
    350. Petersen R
    351. Pilkington C
    352. Poole KES
    353. Prathalingam R
    354. Psaila B
    355. Pyle A
    356. Quinton R
    357. Rahman S
    358. Rankin S
    359. Rao A
    360. Raymond FL
    361. Rayner-Matthews PJ
    362. Rees C
    363. Rendon A
    364. Renton T
    365. Rhodes CJ
    366. Rice ASC
    367. Richardson S
    368. Richter A
    369. Robert L
    370. Roberts I
    371. Rogers A
    372. Rose SJ
    373. Ross-Russell R
    374. Roughley C
    375. Roy NBA
    376. Ruddy DM
    377. Sadeghi-Alavijeh O
    378. Saleem MA
    379. Samani N
    380. Samarghitean C
    381. Sanchis-Juan A
    382. Sargur RB
    383. Sarkany RN
    384. Satchell S
    385. Savic S
    386. Sayer JA
    387. Sayer G
    388. Scelsi L
    389. Schaefer AM
    390. Schulman S
    391. Scott R
    392. Scully M
    393. Searle C
    394. Seeger W
    395. Sen A
    396. Sewell WAC
    397. Seyres D
    398. Shah N
    399. Shamardina O
    400. Shapiro SE
    401. Shaw AC
    402. Short PJ
    403. Sibson K
    404. Side L
    405. Simeoni I
    406. Simpson MA
    407. Sims MC
    408. Sivapalaratnam S
    409. Smedley D
    410. Smith KR
    411. Smith KGC
    412. Snape K
    413. Soranzo N
    414. Soubrier F
    415. Southgate L
    416. Spasic-Boskovic O
    417. Staines S
    418. Staples E
    419. Stark H
    420. Stephens J
    421. Steward C
    422. Stirrups KE
    423. Stuckey A
    424. Suntharalingam J
    425. Swietlik EM
    426. Syrris P
    427. Tait RC
    428. Talks K
    429. Tan RYY
    430. Tate K
    431. Taylor JM
    432. Taylor JC
    433. Thaventhiran JE
    434. Themistocleous AC
    435. Thomas E
    436. Thomas D
    437. Thomas MJ
    438. Thomas P
    439. Thomson K
    440. Thrasher AJ
    441. Threadgold G
    442. Thys C
    443. Tilly T
    444. Tischkowitz M
    445. Titterton C
    446. Todd JA
    447. Toh C-H
    448. Tolhuis B
    449. Tomlinson IP
    450. Toshner M
    451. Traylor M
    452. Treacy C
    453. Treadaway P
    454. Trembath R
    455. Tuna S
    456. Turek W
    457. Turro E
    458. Twiss P
    459. Vale T
    460. Geet CV
    461. Zuydam Nvan
    462. Vandekuilen M
    463. Vandersteen AM
    464. Vazquez-Lopez M
    465. von Ziegenweidt J
    466. Vonk Noordegraaf A
    467. Wagner A
    468. Waisfisz Q
    469. Walker SM
    470. Walker N
    471. Walter K
    472. Ware JS
    473. Watkins H
    474. Watt C
    475. Webster AR
    476. Wedderburn L
    477. Wei W
    478. Welch SB
    479. Wessels J
    480. Westbury SK
    481. Westwood J-P
    482. Wharton J
    483. Whitehorn D
    484. Whitworth J
    485. Wilkie AOM
    486. Wilkins MR
    487. Williamson C
    488. Wilson BT
    489. Wong EKS
    490. Wood N
    491. Wood Y
    492. Woods CG
    493. Woodward ER
    494. Wort SJ
    495. Worth A
    496. Wright M
    497. Yates K
    498. Yong PFK
    499. Young T
    500. Yu P
    501. Yu-Wai-Man P
    502. Zlamalova E
    503. Kingston N
    504. Walker N
    505. Bradley JR
    506. Ashford S
    507. Penkett CJ
    508. Freson K
    509. Stirrups KE
    510. Raymond FL
    511. Ouwehand WH
    (2020) Whole-genome sequencing of patients with rare diseases in a national health system
    Nature 583:96–102.
    https://doi.org/10.1038/s41586-020-2434-2

Article and author information

Author details

  1. Surender Rajasekaran

    1. Pediatric Critical Care Medicine, Helen DeVos Children’s Hospital, Grand Rapids, United States
    2. Spectrum Health Office of Research and Education, Grand Rapids, United States
    3. Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United States
    Contribution
    Conceptualization, Investigation, Project administration
    Contributed equally with
    Caleb P Bupp
    For correspondence
    surender.rajasekaran@helendevoschildrens.org
    Competing interests
    Inventor on a pending US patent (US-2020215010-A1), methods for treating or preventing developmental disorders associated with mutations in the OCD1 gene.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4430-006X
  2. Caleb P Bupp

    1. Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United States
    2. Medical Genetics, Spectrum Health and Helen DeVos Children’s Hospital, Grand Rapids, United States
    Contribution
    Conceptualization, Investigation
    Contributed equally with
    Surender Rajasekaran
    Competing interests
    Inventor on a pending US patent (US-2020215010-A1), methods for treating or preventing developmental disorders associated with mutations in the OCD1 gene.
  3. Mara Leimanis-Laurens

    1. Pediatric Critical Care Medicine, Helen DeVos Children’s Hospital, Grand Rapids, United States
    2. Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United States
    Contribution
    Investigation, Methodology
    Competing interests
    No competing interests declared
  4. Ankit Shukla

    Department of Pharmacy, Helen DeVos Children’s Hospital, Grand Rapids, United States
    Contribution
    Methodology
    Competing interests
    No competing interests declared
  5. Christopher Russell

    Spectrum Health Office of Research and Education, Grand Rapids, United States
    Contribution
    Resources, Supervision
    Competing interests
    No competing interests declared
  6. Joseph Junewick

    Department of Diagnostic Radiology, Spectrum Health and Helen DeVos Children's Hospital, Grand Rapids, United States
    Contribution
    Writing - review and editing
    Competing interests
    No competing interests declared
  7. Emily Gleason

    Spectrum Health Office of Research and Education, Grand Rapids, United States
    Contribution
    Resources
    Competing interests
    No competing interests declared
  8. Elizabeth A VanSickle

    Medical Genetics, Spectrum Health and Helen DeVos Children’s Hospital, Grand Rapids, United States
    Contribution
    Writing - review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5504-9248
  9. Yvonne Edgerly

    Spectrum Health Office of Research and Education, Grand Rapids, United States
    Contribution
    Supervision
    Competing interests
    No competing interests declared
  10. Bryan M Wittmann

    Metabolon, Morrisville, United States
    Contribution
    Formal analysis, Methodology
    Competing interests
    No competing interests declared
  11. Jeremy W Prokop

    1. Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United States
    2. Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, United States
    Contribution
    Data curation, Investigation, Visualization
    Competing interests
    No competing interests declared
  12. André S Bachmann

    Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, United States
    Contribution
    Conceptualization, Methodology, Writing - original draft, Writing - review and editing
    For correspondence
    bachma26@msu.edu
    Competing interests
    Inventor on a pending US patent (US-2020215010-A1), methods for treating or preventing developmental disorders associated with mutations in the OCD1 gene.

Funding

No external funding was received for this work.

Acknowledgements

The authors wish to thank the patient and family for their participation. We would like to dedicate this article to our patient who is a first in so many ways, and to her incredible family. We acknowledge the support we received from the research team at Spectrum Health. We are most grateful to Sanofi-Aventis for providing eflornithine for this study. We also thank Dr B Keith English, MD, Charles Schwartz, PhD, and Brittany Essenmacher for the critical review and editing of this manuscript, David Tack, PhD, for the design of some of the figures, and Olivia Verburg for her help with processing samples and logging samples.

Ethics

Human subjects: FDA approval (IND# 144022) was first acquired before therapy was initiated. The Spectrum Health IRB approved the study (IRB# 2019-161) and informed consent was acquired before blood sample collection. Consent was obtained for use of identifying patient images and videos within this manuscript. After study, authorization for publication was obtained from the parents of the child, now been placed in the medical records.

Version history

  1. Received: January 31, 2021
  2. Accepted: June 16, 2021
  3. Version of Record published: July 20, 2021 (version 1)

Copyright

© 2021, Rajasekaran et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,944
    views
  • 186
    downloads
  • 16
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Surender Rajasekaran
  2. Caleb P Bupp
  3. Mara Leimanis-Laurens
  4. Ankit Shukla
  5. Christopher Russell
  6. Joseph Junewick
  7. Emily Gleason
  8. Elizabeth A VanSickle
  9. Yvonne Edgerly
  10. Bryan M Wittmann
  11. Jeremy W Prokop
  12. André S Bachmann
(2021)
Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease
eLife 10:e67097.
https://doi.org/10.7554/eLife.67097

Share this article

https://doi.org/10.7554/eLife.67097

Further reading

    1. Cell Biology
    2. Genetics and Genomics
    Yangzi Zhao, Lijun Ren ... Zhukuan Cheng
    Research Article

    Cohesin is a multi-subunit protein that plays a pivotal role in holding sister chromatids together during cell division. Sister chromatid cohesion 3 (SCC3), constituents of cohesin complex, is highly conserved from yeast to mammals. Since the deletion of individual cohesin subunit always causes lethality, it is difficult to dissect its biological function in both mitosis and meiosis. Here, we obtained scc3 weak mutants using CRISPR-Cas9 system to explore its function during rice mitosis and meiosis. The scc3 weak mutants displayed obvious vegetative defects and complete sterility, underscoring the essential roles of SCC3 in both mitosis and meiosis. SCC3 is localized on chromatin from interphase to prometaphase in mitosis. However, in meiosis, SCC3 acts as an axial element during early prophase I and subsequently situates onto centromeric regions following the disassembly of the synaptonemal complex. The loading of SCC3 onto meiotic chromosomes depends on REC8. scc3 shows severe defects in homologous pairing and synapsis. Consequently, SCC3 functions as an axial element that is essential for maintaining homologous chromosome pairing and synapsis during meiosis.

    1. Genetics and Genomics
    David V Ho, Duncan Tormey ... Peter Baumann
    Research Article

    Facultative parthenogenesis (FP) has historically been regarded as rare in vertebrates, but in recent years incidences have been reported in a growing list of fish, reptile, and bird species. Despite the increasing interest in the phenomenon, the underlying mechanism and evolutionary implications have remained unclear. A common finding across many incidences of FP is either a high degree of homozygosity at microsatellite loci or low levels of heterozygosity detected in next-generation sequencing data. This has led to the proposal that second polar body fusion following the meiotic divisions restores diploidy and thereby mimics fertilization. Here, we show that FP occurring in the gonochoristic Aspidoscelis species A. marmoratus and A. arizonae results in genome-wide homozygosity, an observation inconsistent with polar body fusion as the underlying mechanism of restoration. Instead, a high-quality reference genome for A. marmoratus and analysis of whole-genome sequencing from multiple FP and control animals reveals that a post-meiotic mechanism gives rise to homozygous animals from haploid, unfertilized oocytes. Contrary to the widely held belief that females need to be isolated from males to undergo FP, females housed with conspecific and heterospecific males produced unfertilized eggs that underwent spontaneous development. In addition, offspring arising from both fertilized eggs and parthenogenetic development were observed to arise from a single clutch. Strikingly, our data support a mechanism for facultative parthenogenesis that removes all heterozygosity in a single generation. Complete homozygosity exposes the genetic load and explains the high rate of congenital malformations and embryonic mortality associated with FP in many species. Conversely, for animals that develop normally, FP could potentially exert strong purifying selection as all lethal recessive alleles are purged in a single generation.