Parkinson’s disease is a progressive and incurable brain disorder. Currently available therapies only alleviate symptoms rather than deter the development of the disease itself. As a novel drug candidate, CDNF has the potential to stop the progression of Parkinson’s disease by protecting neurons from degeneration and restoring the functions of already damaged neurons.

CDNF is currently in a Phase 1-2 randomized, placebo-controlled, double-blind, multicenter clinical study in three university hospitals in Sweden and Finland for the treatment of Parkinson’s disease.

About CDNF

CDNF is a protein naturally present in humans. It was discovered by Professor Mart Saarma at the University of Helsinki and published in the leading scientific journal Nature in 2007. Following this, Herantis patented CDNF worldwide and launched a drug development program based on this discovery. The research and development efforts have confirmed that CDNF is a promising neuroprotective and neurorestorative drug candidate, which functions via several mechanisms relevant to Parkinson’s disease. It can protect neurons from degeneration and restore the function of already degenerating neurons. This suggests that CDNF has the potential to stop the progression of Parkinson’s disease, which would make a significant therapeutic impact on the lives of patients. If successful, CDNF therapy would enable Parkinson’s patients to maintain their quality of life.

CDNF Mode-of-action

CDNF has a multi-modal mechanism by which it improves neuronal survival in Parkinson’s disease and other neurodegenerative diseases.

  1. CDNF promotes neuronal survival and functionality by reducing endoplasmic reticulum (ER) stress
    CDNF is internalized by stressed neurons and reduces endoplasmic reticulum (ER) stress, a common feature in neurodegenerative diseases. Reduced ER stress levels support recovery of neuronal functionality via multiple mechanisms, such as improved calcium homeostasis, mitochondrial function, and protein translation and secretion.
  2. CDNF promotes neuronal survival by activating Protein kinase B (Akt)
    Akt is a protein kinase that is centrally involved in neuronal survival signaling. CDNF stimulates Akt activity in neurons.
  3. Inhibiting formation and toxicity of alpha-synuclein aggregates
    Aggregated alpha-synuclein is the main component of Lewy bodies which are abnormal protein inclusions found in the brains of Parkinson’s disease patients. Alpha-synuclein is an aggregation-prone protein and various abnormal forms of alpha-synuclein can be toxic to neurons. CDNF protects neurons by reducing the formation and toxicity of alpha-synuclein aggregates.
  4. Decreasing neuroinflammation
    CDNF reduces production and secretion of pro-inflammatory cytokines, such as TNF-alpha, interleukin-1beta and interleukin-6, by glial cells, thereby reducing chronic neuroinflammation in the brain, which is an important pathological mechanism in most neurodegenerative diseases.
  5. Improving functionality of stressed and degenerating neurons
    CDNF has long-term effects in the brain which are related to the regulation of gene transcription and the maintenance of functionality of dopamine neurons.

CDNF Clinical Development Status

CDNF is currently in a Phase 1-2 randomized, placebo-controlled, double-blind, multicenter clinical study in three university hospitals in Sweden and Finland for the treatment of Parkinson’s disease. The patient recruitment has been completed with 17 randomized patients.

As a protein, CDNF cannot pass the blood-brain barrier, the organ protecting our brains from toxins that may appear in the circulating blood stream. Therefore, in the Phase 1-2 clinical study, CDNF is administered using a drug delivery device that directly targets the putamen, a specific area in the brain that is affected in Parkinson’s disease. Implanting the clinically tested device requires a neurosurgical procedure comparable to the placement of a Deep Brain Stimulation device, a common procedure in advanced-stage Parkinson’s patients. The drug delivery device used in the Phase 1-2 clinical study is manufactured by Renishaw Plc.

The clinical trial, also called TreatER, is partially financed by the European Union. More details on the study are available here: www.treater.eu.

About Parkinson’s Disease

Parkinson’s disease is an incurable, progressive brain disorder estimated to affect over seven million patients worldwide. It is caused by the degeneration of dopamine-producing neurons in the brain. The underlying reasons that trigger degeneration of dopamine neurons In Parkinson’s disease remain poorly understood. However, the symptoms are a consequence of reduced brain levels of dopamine, a neurotransmitter, in the brain. The typical symptoms include tremor, slowness of movement, muscle stiffness and impaired balance. As the disease progresses symptoms get worse, and also various non-motor symptoms, including sleep problems, depression, speech changes, and severe constipation, may occur.

Available treatments for Parkinson’s disease do not cure the disease or even slow down its progression because the pathological processes resulting in degeneration and death of dopamine neurons are not affected. Current standard-of-care treatments are drugs, such as L-dopa, that increase dopamine levels in the brain. The efficacy of the L-dopa is typically gradually lost with disease progression as an increasing amount of the dopamine-producing neurons have degenerated. One currently available treatment for advanced-stage Parkinson’s disease patients is Deep Brain Stimulation, which together with the required neurosurgery, can cost over EUR 75,000.

Parkinson’s disease is associated with a significant societal economic burden in addition to the immense human suffering. The majority of costs are not linked to treatments but, for instance, lost productive years and supported living arrangements for disabled patients. In 2010 the societal costs of Parkinson’s disease in Europe alone totaled approximately EUR 14 billion. A study in the USA suggested that a treatment, which could stop the progression of Parkinson’s disease would save society about EUR 400,000 per patient. This is Herantis’ goal with CDNF.

CDNF has shown preclinical activity also in other neurodegenerative diseases

CDNF affects cellular mechanisms that are involved in pathophysiology of a variety of central nervous system diseases. Particularly, endoplasmic reticulum stress, unfolded protein response and neuroinflammation are involved in many chronic neurodegenerative diseases. Preclinical data suggests that CDNF has therapeutic potential in diverse neurodegenerative disease in addition to Parkinson’s disease. It is possible that CDNF could be used as a basis of developing novel disease-modifying treatments for e.g. Alzheimer’s disease and amyotrophic lateral sclerosis (ALS).

Selected publications

Huttunen HJ and Saarma M. CDNF Protein Therapy in Parkinson’s Disease. Cell Transplant. Apr 4, 2019.

Lindahl M, Saarma M, Lindholm P. Unconventional neurotrophic factors CDNF and MANF: Structure, physiological functions and therapeutic potential. Neurobiol. Dis. 97(Pt B): 90-102, 2017.

Non-invasive xCDNF is an engineered fragment of the CDNF protein targeted at treating neurodegenerative diseases with systemic administration

The drug candidate CDNF, which has advanced to clinical development, is a protein that does not pass the blood-brain barrier (BBB). The BBB is a border that separates our brain from circulating blood. Therefore, CDNF cannot be administered to patients for instance as a pill or intravenously, because the BBB would prevent it from reaching the brain and thus from protecting the neurons. Instead, CDNF is administered directly in the brain using a drug delivery device, which requires a neurosurgical procedure comparable to the placement of a Deep Brain Stimulation device. While this is an acceptable approach in the treatment of Parkinson’s disease, we have also studied alternative methods for a simpler dosing of the drug.

In 2017, it was discovered that a certain part of the CDNF protein maintains its biological activity and also passes the BBB. Based on this discovery, Herantis has launched the development of the non-invasive xCDNF. Available data suggest that the biological activity of xCDNF is comparable to full length CDNF and that it could be administered, for instance, by a subcutaneous injection (similar to, e.g., insulin injections). While xCDNF is a novel drug candidate, and as such will require a complete preclinical development program, its development will benefit from the methods and know-how cumulated in the development of CDNF. This suggests that the early stage development of xCDNF may be markedly faster than it was for CDNF.

Herantis has not yet disclosed any estimates on the possible development schedule or market potential for xCDNF.

Lymfactin® aims to become the first drug for treating secondary lymphedema

Lymfactin® is currently in a randomized, double-blind, placebo-controlled, multi center, Phase 2 clinical study in Finland and Sweden in patients suffering from breast cancer associated secondary lymphedema.

About Lymfactin®

Lymfactin® is based on the scientific discovery of VEGF-C, the natural human protein necessary for the growth of new lymphatic vessels. Lymfactin® is a gene therapy, which delivers the human gene coding for VEGF-C and thereby promotes the formation of new lymphatic vessels. Lymfactin® is administered locally at the site with injuries in the lymphatic system with the aim of repairing those injuries. In disease models, this local VEGF-C expression, which lasts for about two weeks, has resulted in the formation of new lymphatic vessels. This may eventually normalize the lymphatic flow and thereby stop the accumulation of the lymph in the patient’s tissue. If Lymfactin® works in human patients as well as it has worked in disease models, it can lead to a significant breakthrough in the treatment of secondary lymphedema. VEGF-C was discovered by Professor Kari Alitalo and his research group at the University of Helsinki.

Lymfactin® mode-of-action

Lymfactin® Clinical Development Status

Lymfactin® is presently being developed for the treatment of breast cancer associated secondary lymphedema (BCAL) in patients who undergo lymph node transplantation surgery. A Phase 1 clinical study is currently in a long-term follow-up and a Phase 2 clinical study is currently ongoing. The patient recruitment has been completed.

The ongoing Phase 2 clinical study is a multi-center, randomized, double-blind, placebo-controlled study. The study is planned to enroll about 40 patients in Finland and Sweden at five university hospitals in Uppsala, Stockholm, Helsinki, Tampere, and Turku. The Phase 2 study will assess the efficacy, safety, and tolerability of Lymfactin®. Half of the patients will receive one dose of Lymfactin® and half will receive placebo in combination with the lymph node transplantation surgery. The efficacy endpoints include the volume measurement of the affected vs. non-affected limb prior and after the treatment, lymphoscintigraphy prior vs. after the treatment for assessing the functionality of the lymphatic system, and the assessment of quality-of-life. More information about the ongoing clinical study is found at www.lymfactin.eu.

The Phase 1 clinical study recruited 15 patients from which the first three patients received a lower and the last 12 patients a higher dose of Lymfactin®. Both doses were safe and well tolerated based on the one-year follow-up. The higher dose was selected for the Phase 2 clinical study. The Phase 1 study continues with a long-term follow-up on all patients. In the Phase 1 study, there was no control group and, thus, no conclusions of the efficacy of the Lymfactin® treatment can be made based on the Phase 1 data.

About Secondary Lymphedema

Secondary lymphedema is caused by local injuries of the lymphatic system, which can manifest as a result of cancer treatments such as surgery and radiotherapy. The injuries of the lymphatic system may disrupt the normal flow of lymph, which will then start to accumulate in tissue, for instance in a limb. This results in chronic, progressive swelling.

Secondary lymphedema is a painful, deforming disease that often has a significant impact on the quality of life of the patients. Symptoms of secondary lymphedema include progressive swelling of the affected limb, pain, decreased mobility, and increased forming of connective tissue. Many patients also suffer from repeated infections of the affected tissue. Patients are often ashamed of their deformed appearance and may fail to seek appropriate treatment.

According to the global patient organization, LE&RN, misdiagnosis is common. Patients or even their treating oncologists or physicians may not know they are suffering from a disease.

A curative treatment for lymphedema is not known. Depending on the case, the symptoms of LE can be alleviated by physiotherapy or massage. Many patients who have lymphedema of the arm wear a compression garment. These kinds of treatments do not repair injuries of the lymphatic system, which cause the disease. Surgical procedures such as lymph node transplantation, lymphaticovenous anastomosis, and lymphaticolymphatic bypass are also used.

Based on published cancer incident data we estimate that about 30,000 breast cancer associated secondary lymphedema cases are diagnosed annually in the USA and Europe. Secondary lymphedema is also associated with other cancers including melanoma, gynaecologic cancers, and genitourinary cancers resulting in estimated 150,000 secondary lymphedema cases in the USA and Europe. In the USA it has been estimated that the treatment of breast cancer associated secondary lymphedema costs over 10,000 USD a year per patient.

Selected publications

Tervala TV, Hartiala P, Tammela T, Visuri MT, Ylä-Herttuala S, Alitalo K, Saarikko AM. Growth factor therapy and lymph node graft for lymphedema. J. Surg. Res. 196(1): 200-7, 2015.

Lähteenvuo M, Honkonen K, Tervala T, Tammela T, Suominen E, Lähteenvuo J, Kholová I, Alitalo K, Ylä-Herttuala S, Saaristo A. Growth factor therapy and autologous lymph node transfer in lymphedema. Circulation 123: 613-20, 2011.

This page offers a representative collection of publications related to the scientific background of Herantis’ drug candidates. A comprehensive PubMed listing of publications can be found by clicking the topic title. Please note that in some cases full-text access to the articles may require payment to the publisher.

CDNF-family neurotrophic factors

2019
Huttunen HJ, Saarma M. CDNF Protein Therapy in Parkinson's Disease. Cell Transplant. Apr 4:963689719840290, 2019.
2019
Sousa-Victor P, Neves J, Cedron-Craft W, Britten Ventura PB, Liao CY, Riley RR, Soifer I, van Bruggen N, Kolumam GA, Villeda SA, Lamba DA and Jasper H. MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage. Nat. Metab. 1: 276-290, 2019.
2019
Yan Y, Rato C, Rohland L, Preissler S, Ron D. MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP. Nat. Commun. 10(1): 541, 2019.
2018
Huotarinen A, Penttinen AM, Bäck S, Voutilainen MH, Julku U, Petteri Piepponen T, Männistö PT, Saarma M, Tuominen R, Laakso A, Airavaara M. Combination of CDNF and deep brain stimulation decreases neurological deficits in late-stage model Parkinson's disease. Neuroscience epub Feb 3 2018. pii: S0306-4522(18)30082-4.
2018
Mätlik K, Anttila JE, Kuan-Yin T, Smolander OP, Pakarinen E, Lehtonen L, Abo-Ramadan U, Lindholm P, Zheng C, Harvey B, Arumäe U, Lindahl M, Airavaara M. Poststroke delivery of MANF promotes functional recovery in rats. Sci. Adv. 4(5): eaap8957, 2018
2018
Renko JM, Bäck S, Voutilainen MH, Piepponen TP, Reenilä I, Saarma M, Tuominen RK. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Elevates Stimulus-Evoked Release of Dopamine in Freely-Moving Rats. Mol. Neurobiol. epub Jan 18 2018. doi: 10.1007/s12035-018-0872-8.
2018
Sousa-Victor P, Jasper H, Neves J. Trophic Factors in Inflammation and Regeneration: The Role of MANF and CDNF. Front. Physiol. 9:1629, 2018.
2018
Tseng KY, Anttila JE, Khodosevich K, Tuominen RK, Lindahl M, Domanskyi A, Airavaara M. MANF Promotes Differentiation and Migration of Neural Progenitor Cells with Potential Neural Regenerative Effects in Stroke. Mol. Ther. 26(1): 238-255, 2018.
2017
Yang S, Yang H, Chang R, Yin P, Yang Y, Yang W, Huang S, Gaertig MA, Li S, Li XJ. MANF regulates hypothalamic control of food intake and body weight. Nat. Commun. 8(1): 579, 2017.
2017
Gao FJ, Wu JH, Li TT, Du SS, Wu Q. Identification of Mesencephalic Astrocyte-Derived Neurotrophic Factor as a Novel Neuroprotective Factor for Retinal Ganglion Cells. Front. Mol. Neurosci. 10: 76, 2017.
2017
Lindahl M, Saarma M, Lindholm P. Unconventional neurotrophic factors CDNF and MANF: Structure, physiological functions and therapeutic potential. Neurobiol. Dis. 97(Pt B): 90-102, 2017.
2017
Lindström R, Lindholm P, Palgi M, Saarma M, Heino TI. In vivo screening reveals interactions between Drosophila Manf and genes involved in the mitochondria and the ubiquinone synthesis pathway. BMC Genet. 18(1): 52, 2017.
2017
Mätlik K, Vihinen H, Bienemann A, Palgi J, Voutilainen MH, Booms S, Lindahl M, Jokitalo E, Saarma M, Huttunen HJ, Airavaara M, Arumäe U. Intrastriatally Infused Exogenous CDNF Is Endocytosed and Retrogradely Transported to Substantia Nigra. eNeuro 4(1) pii: ENEURO.0128-16.2017, 2017.
2017
Tang T, Li Y, Jiao Q, Du X, Jiang H. Cerebral Dopamine Neurotrophic Factor: A Potential Therapeutic Agent for Parkinson's Disease. Neurosci. Bull. 33(5): 568-575, 2017.
2017
Voutilainen MH, De Lorenzo F, Stepanova P, Bäck S, Yu LY, Lindholm P, Pörsti E, Saarma M, Männistö PT, Tuominen RK. Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action. eNeuro 4(1). pii: ENEURO.0117-16.2017, 2017.
2017
Wang L, Wang Z, Zhu R, Bi J, Feng X, Liu W, Wu J, Zhang H, Wu H, Kong W, Yu B, Yu X. Therapeutic efficacy of AAV8-mediated intrastriatal delivery of human cerebral dopamine neurotrophic factor in 6-OHDA-induced parkinsonian rat models with different disease progression. PLoS One 12(6): e0179476, 2017.
2016
Garea-Rodríguez E, Eesmaa A, Lindholm P, Schlumbohm C, König J, Meller B, Krieglstein K, Helms G, Saarma M, Fuchs E. Comparative Analysis of the Effects of Neurotrophic Factors CDNF and GDNF in a Nonhuman Primate Model of Parkinson's Disease. PLoS ONE 11(2): e0149776, 2016.
2016
Neves J, Zhu J, Sousa-Victor P, Konjikusic M, Riley R, Chew S, Qi Y, Jasper H, Lamba DA. Immune modulation by MANF promotes tissue repair and regenerative success in the retina. Science 353(6294):aaf3646, 2016.
2016
Zhao H, Cheng L, Du X, Hou Y, Liu Y, Cui Z, Nie L. Transplantation of Cerebral Dopamine Neurotrophic Factor Transducted BMSCs in Contusion Spinal Cord Injury of Rats: Promotion of Nerve Regeneration by Alleviating Neuroinflammation. Mol. Neurobiol. 53(1): 187-99, 2016.
2016
Lindström R, Lindholm P, Kallijärvi J, Palgi M, Saarma M, Heino TI. Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster. PLoS ONE 11(3): e0151550, 2016.
2015
Kemppainen S, Lindholm P, Galli E, Lahtinen HM, Koivisto H, Hämäläinen E, Saarma M, Tanila H. Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice. Behav Brain Res. 291: 1-11, 2015.
2015
Latge C, Cabral KM, de Oliveira GA, Raymundo DP, Freitas JA, Johanson L, Romão LF, Palhano FL, Herrmann T, Almeida MS, Foguel D. The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers. J. Biol. Chem. 290(33): 20527-40, 2015.
2015
Mätlik K, Yu LY, Eesmaa A, Hellman M, Lindholm P, Peränen J, Galli E, Anttila J, Saarma M, Permi P, Airavaara M, Arumäe U. Role of two sequence motifs of mesencephalic astrocyte-derived neurotrophic factor in its survival-promoting activity. Cell Death Dis. 6: e2032, 2015.
2015
Voutilainen MH, Arumäe U, Airavaara M, Saarma M. Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson's disease. FEBS Lett. 589:3739-48, 2015.
2014
Lindahl M, Danilova T, Palm E, Lindholm P, Võikar V, Hakonen E, Ustinov J, Andressoo JO, Harvey BK, Otonkoski T, Rossi J, Saarma M. MANF Is Indispensable for the Proliferation and Survival of Pancreatic β Cells. Cell Rep. 7: 366-75, 2014.
2014
Yang S, Huang S, Gaertig MA, Li XJ, Li S. Age-dependent decrease in chaperone activity impairs MANFexpression, leading to Purkinje cell degeneration in inducible SCA17 mice. Neuron 81(2): 349-65, 2014.
2012
Airavaara M, Harvey BK, Voutilainen MH, Shen H, Chou J, Lindholm P, Lindahl M, Tuominen RK, Saarma M, Hoffer B, Wang Y. CDNF protects the nigrostriatal dopamine system and promotes recovery after MPTP treatment in mice. Cell Transplant. 21: 1213-23, 2012.
2011
Hellman M, Arumäe U, Yu LY, Lindholm P, Peränen J, Saarma M, Permi P. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons. J. Biol. Chem. 286: 2675-80, 2011.
2011
Voutilainen MH, Bäck S, Peränen J, Lindholm P, Raasmaja A, Männistö PT, Saarma M, Tuominen RK. Chronic infusion of CDNF prevents 6-OHDA-induced deficits in a rat model of Parkinson's disease. Exp. Neurol. 228: 99-108, 2011.
2010
Lindholm P, Saarma M. Novel CDNF/MANF family of neurotrophic factors. Dev. Neurobiol. 70: 360-71, 2010.
2009
Parkash V, Lindholm P, Peränen J, Kalkkinen N, Oksanen E, Saarma M, Leppänen VM, Goldman A. The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional. Protein Eng. Des. Sel. 22: 233-41, 2009.
2007
Lindholm, P Voutilainen MH, Laurén J, Peränen J, Leppänen VM, Andressoo JO, Lindahl M, Janhunen S, Kalkkinen N, Timmusk T, Tuominen RK, Saarma M. Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature 448: 73-77, 2007.

Lymfactin®

2017
Jha SK, Rauniyar K, Karpanen T, Leppänen VM, Brouillard P, Vikkula M, Alitalo K, Jeltsch M. Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1. Sci. Rep. 7(1): 4916, 2017.
2017
Vaahtomeri K, Karaman S, Mäkinen T, Alitalo K. Lymphangiogenesis guidance by paracrine and pericellular factors. Genes Dev. 31(16): 1615-1634, 2017.
2016
Aspelund A, Robciuc MR, Karaman S, Makinen T, Alitalo K. Lymphatic System in Cardiovascular Medicine. Circ. Res. 118(3): 515-30, 2016.
2015
Han J, Calvo CF, Kang TH, Baker KL, Park JH, Parras C, Levittas M, Birba U, Pibouin-Fragner L, Fragner P, Bilguvar K, Duman RS, Nurmi H, Alitalo K, Eichmann AC, Thomas JL. Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans. Cell Rep. 10(7): 1158-72, 2015.
2015
Tervala TV, Hartiala P, Tammela T, Visuri MT, Ylä-Herttuala S, Alitalo K, Saarikko AM. Growth factor therapy and lymph node graft for lymphedema. J. Surg. Res. 196(1): 200-7, 2015. Abstract | Full text
2015
Visuri MT, Honkonen KM, Hartiala P, Tervala TV, Halonen PJ, Junkkari H, Knuutinen N, Ylä-Herttuala S, Alitalo KK, Saarikko AM. VEGF-C and VEGF-C156S in the pro-lymphangiogenic growth factor therapy of lymphedema: a large animal study. Angiogenesis 18(3): 313-26, 2015.
2013
Honkonen KM, Visuri MT, Tervala TV, Halonen PJ, Koivisto M, Lähteenvuo MT, Alitalo KK, Ylä-Herttuala S, Saaristo AM. Lymph node transfer and perinodal lymphatic growth factor treatment for lymphedema. Ann. Surg. 257(5): 961-7, 2013.
2011
Lähteenvuo M, Honkonen K, Tervala T, Tammela T, Suominen E, Lähteenvuo J, Kholová I, Alitalo K, Ylä-Herttuala S, Saaristo A. Growth factor therapy and autologous lymph node transfer in lymphedema. Circulation 123: 613-20, 2011.
2004
Saaristo A, Tammela T, Timonen J, Yla-Herttuala S, Tukiainen E, Asko-Seljavaara S, Alitalo K. Vascular endothelial growth factor-C gene therapy restores lymphatic flow across incision wounds. FASEB J. 18: 1707-9, 2004.
2002
Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1: 219-27, 2002.
2002
Saaristo A, Veikkola T, Tammela T, Enholm B, Karkkainen MJ, Pajusola K, Bueler H, Ylä-Herttuala S, Alitalo K. Lymphangiogenic gene therapy with minimal blood vascular side effects. J. Exp. Med. 196: 719-30, 2002.
2001
Karkkainen MJ, Jussila L, Ferrell RE, Finegold DN, Alitalo K. Molecular regulation of lymphangiogenesis and targets for tissue edema. Trends Mol. Med. 7: 18-22, 2001.
1997
Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276: 1423-5, 1997.